title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Quality of wastewater reuse in agricultural irrigation and its impact on public health. | This study is planned to perform a sanitary survey of the largest sewage treatment plant in Riyadh, KSA, fortnightly for 6 months to examine its effluent quality as an example for the growing dependence on reuse of treated municipal wastewater in agricultural irrigation purposes to cope with increasing water shortage. The biological and physico-chemical parameters of 12 wastewater samples from the plant were examined using standard methods. The physico-chemical analysis indicated that the surveyed municipal wastewater treatment plant contained some of the studied parameters, such as turbidity, total suspended solids, biochemical oxygen demand, chemical oxygen demand and residual chlorine above the maximum permissible wastewater limits set by the Saudi Standards. However, heavy metal concentrations in all samples were lower than the recommended standards. Total and faecal coliform counts were above the permissible limits indicating poor sanitation level. Fifty percent of all wastewater samples were contaminated with faecal coliforms but, surprisingly, Escherichia coli were only detected in 8.3 % of the samples. Regular monitoring and enhancement of microbial and physico-chemical parameters of the wastewater quality served by different wastewater treatment plants for reuse in agricultural irrigation is recommended to preserve the environment and public health. | 25,085,428 | [
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Evaluation of a head-to-head study of lisdexamfetamine dimesylate and atomoxetine: evaluation of Dittmann RW, Cardo E, Nagy P, et al. Efficacy and safety of lisdexamfetamine dimesylate and atomoxetine in the treatment of attention-deficit/hyperactivity disorder: a head-to-head, randomised, double-blind, Phase IIIb study. CNS Drugs 2013;27:1081-1092. doi: 10.1007/s40263-013-0104-8 ClinicalTrials.gov: NCT01106430. | Here, we evaluate a report of a head-to-head study of the prodrug stimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant atomoxetine hydrochloride (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). An inadequate response to previous methylphenidate (MPH) treatment was a notable inclusion criterion. The primary efficacy outcome of a more rapid clinical response to LDX than to ATX was predictable from the known properties of the two drugs. However, secondary efficacy outcomes indicated that LDX was significantly more effective than ATX in relieving investigator-rated symptoms of ADHD, with an effect size of 0.56. Safety and tolerability profiles were consistent with the known properties of LDX and ATX. Despite some issues with the study design, the conclusion that LDX is more effective than ATX over the short term appears robust. In addition, the magnitude of improvement with both treatments indicated that previous MPH treatment is not a factor affecting the potential for patients to benefit from LDX or ATX. The results may help to inform clinical practice in Europe, where LDX is approved for treating children and adolescents with ADHD and a previous inadequate response to MPH, and in other regions where generic MPH formulations are typically the first-line therapeutic option. | 25,085,429 | [
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Hodgkin disease (1973-2002): long-term survival and cure fractions. | The Nottinghamshire Lymphoma Registry contains the details of all patients diagnosed with lymphoma (since 1 January 1973) within a defined geographical area with a stable population of 1.1 million. The aim of this study was to investigate the relative survival and estimate the cure fraction for patients with Hodgkin disease (HD) using various cure fraction models. Five- and 10-year survival was estimated in comparison to the general population of the same age, gender and year of diagnosis. Relative survival probabilities at 10 years were 52.3% for the 1973-1982 cohort, 67.8% (1983-1992) and 75.7% (1993-2002). The estimated cured fraction (π) was 45%, 65% and 75%, respectively, for the same cohorts. There was very little excess mortality after 4 years from treatment. The prognosis of patients with HD has improved progressively within a defined unselected population over this 30-year period. In the 1993-2002 cohort the prognosis after 4 years of treatment is almost the same as for a normal population. | 25,085,435 | [
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Prevalence and characterization of methicillin-resistant Staphylococcus aureus isolates from healthy university student athletes. | The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing in the general population, and there is concern that close or physical contact, such as in professional and collegiate sports, may increase spread of MRSA. We sought to determine the prevalence of MRSA colonization of male and female athletes from 9 different sports at a major, Division I University during a 12-week period, and determine the USA and SCCmec type from select isolates. Swabs for culture of MRSA were obtained from nasal, axillary, and inguinal sites from healthy, asymptomatic student athletes and support staff each week for 12 weeks. Select MRSA isolates were typed by pulsed field gel electrophoresis (PFGE), and the genes encoding for MecA, cassette chromosome recombinase (Ccr), and several toxins were determined by multiplex polymerase chain reaction (PCR). Discrepant results were clarified by multi-locus sequence typing (MLST) and spa typing. Thirty-five percent (78/223) of test subjects were positive for MRSA during the study period, resulting in isolation of 139 MRSA isolates. However, 47% (37/78) of MRSA-positive participants carried MRSA in axillary or inguinal sites, but not in the anterior nares. There was significant correlation between MRSA carriage and participation in wrestling (76%, 19/25; adjusted odds ratio 29.7, 95% CI 5.8-151.5) and baseball (44%, 17/39; adjusted odds ratio 4.4, 95% CI 1.1- 17.4), compared with a staff prevalence of 18.1% (4/22), but other factors were not examined. Multiplex PCR analysis indicated that of the 32 isolates examined 26 could be typed, and all of these carried the SCCmec type IV cassette. PFGE typing identified USA types 300, 400, 500, 700, and 800. However, one isolate was not a known USA type, but was identified as a novel ST951 by MLST, and as spa type t216. Of the strains typed from the same individual, there was consistency, but also variation and alternation of the SCCmec and spa types isolated from individual subjects. Various staphylococcal toxin genes were identified in 31 of the 32 isolates analyzed. Colonization by MRSA was greater in some student athletes than the average carriage rate for the general population, and only 53% of MRSA carriers were identified by nasal cultures. Carriage of MRSA clones on the same individual and transmission to contacts could vary over time, indicating colonization can be a dynamic process that may be difficult to control. | 25,085,442 | [
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Applying Health in All Policies to obesity in South Australia. | Public policy strategies impact on population health by acting on the effectiveness, availability and distribution of the social determinants of health. Reducing obesity and promoting healthy weight is a key focus of governments, health promoters and researchers, and can benefit from a systems approach with 'upstream' policy action beyond the health sector. Although the literature identifies many areas for hypothetical non-health policy action, and in particular relating to food and activity environments, few have identified practical, politically viable and relatively cost-free processes by which non-health sectors would want to commit to such action. This article details how the Government of South Australia used the Health in All Policies (HiAP) approach in the SA HiAP Healthy Weight Project. It mapped the core business and policy directions of 44 state departments against research on 'what works' to address obesity. Negotiations then developed high-level policy commitments to address factors promoting healthy weight which predominantly changed ways of working rather than requiring new expenditure and also assisted departments in meeting their own goals; departmental chief executives endorsed the commitments. By starting from departmental documents, and not restricting the project to departments with more 'obvious' obesity prevention potential, we gained commitment to a broader range of policy actions than identified elsewhere; for example, for prisons, environment and botanic gardens, housing and vocational education. The SA HiAP Healthy Weight Project provides one example of a workable, evidence-based systems approach to increase commitment to practical and politically viable opportunities across government to address the non-health environments supporting healthy weight. | 25,085,460 | [
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Time trend in Alzheimer diagnoses and the association between distance to an Alzheimer clinic and Alzheimer diagnosis. | Centralization of specialized health care in Denmark has caused increased geographical distance to health-care providers, which may be a barrier for Alzheimer patients to seek health care. We examined the incidence of Alzheimer diagnosis in Denmark between 2000 and 2009 and investigated the association between patients' distance to Alzheimer clinics and Alzheimer diagnoses. Data of all individuals aged 65+ years were collected from Danish national registers. Incidences of Alzheimer diagnoses were analysed with joinpoint regression and hazard ratios (HRs) for Alzheimer diagnoses were analysed with Cox regressions. The annual incidence of Alzheimer diagnoses increased with 32.5% [95% confidence interval (CI): 7.1-63.8] among individuals aged 65-74 years from 2000 to 2002 and with 29.1% (95% CI: 11.0-50.2) among individuals aged 75+ years from 2000 to 2003. For both groups, incidence during subsequent years stagnated (0.4%, 95% CI: -1.7 to 2.6; 2.3%, 95% CI: 1.5-6.). From 2008 to 2009, 8605 individuals got an Alzheimer diagnosis. These individuals had a shorter distance to Alzheimer clinics (16.6 vs. 19.1 km, P < 0.001), higher mean age (80.7 vs. 73.7 years, P < 0.001) and were more often women (63.1 vs. 55.9%, P < 0.001). There were inverse associations between distance to Alzheimer clinics and Alzheimer diagnoses (0-19 km: reference; 20-39 km: HR = 0.80, 95% CI: 0.70-0.92; 40-59 km: HR = 0.65, 95% CI: 0.52-0.81). The incidence of Alzheimer diagnoses stagnated from 2002/03 to 2009 in Denmark--a period during which distances to health-care providers in general increased. The inverse association between geographical distance to Alzheimer clinics and Alzheimer diagnoses suggests that distance exclude a segment of the elderly population from an appropriate diagnostic workup and treatment. | 25,085,468 | [
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The role of conspicuity in preventing bicycle crashes involving a motor vehicle. | Bicycle use, despite its proven health and other benefits, is rarely part of everyday travel for many people due to the perceived risk of injury from collision crashes. This article investigated the role of physical vs. attention conspicuity in preventing bicycle crashes involving a motor vehicle in New Zealand. The Taupo Bicycle Study involved 2590 adult cyclists recruited in 2006 (43.1% response rate) and followed for bicycle crash outcomes through linkage to four national databases. A composite measure of physical conspicuity was created using latent class analysis based on the use of fluorescent colours, lights and reflective materials, and the main colour of top, helmet and bike frame. Attention conspicuity was assessed based on regional differences in travel patterns and the amount of riding in a bunch. Cox regression modelling for repeated events was performed with multivariate adjustments. During a median follow-up period of 6.4 years, 162 participants experienced 187 bicycle-motor vehicle crashes. The crash risk was not predicted by the four latent classes identified and the amount of bunch riding but was higher in Auckland, the region with the lowest level of bicycle use relative to car use. In subgroup analyses, compared to other latent classes, the most physically conspicuous group had a higher risk in Auckland but a lower risk in other regions. Conspicuity aids may not be effective in preventing bicycle-motor vehicle crashes in New Zealand, particularly in Auckland, where attention conspicuity is low. | 25,085,469 | [
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Midwives' perceptions and experiences of health promotion practice in Ghana. | This research explores midwives' perceptions and experiences of health promotion practice in Ghana. A qualitative descriptive exploratory design was used in order to gain better insight into midwives' perceptions and experiences of health promotion practice. A total of 21 midwives took part in the study. Data were collected by individual in-depth semi-structured interviews. Thematic analysis was used to analyse the transcript. Five dominant themes emerged from the interview transcripts, namely: health promotion as education, health promotion activities, the value of health promotion, client participation, and midwives' barriers to promoting health. Although midwives underscored the importance of health promotion to their work, their reports indicated that, in practice, midwives mostly delivered health education and behaviour change communication rather than health promotion. The midwives expressed the view that by way of their close association with women, they were in a better position to influence women's health. Health promotion activities engaged by the midwives included weight management, healthy eating, infection prevention, personal hygiene, counselling on family planning, and screening for hazardous and harmful substance use such as alcohol and smoking. All the midwives mentioned that clients participated in their health promotion activities. Factors that were identified by the midwives to enhance client participation were trust, attitude of the midwife, building rapport, creating enabling environment, listening and paying attention to clients and using simple language. The barriers to health promotion identified by the midwives included time, stress, culture, lack of training and inadequate health educational materials. Midwives in this study had limited knowledge about health promotion, yet could play a significant role in influencing health; thus there is a need for on-going in-service training for midwives to focus on health promotion. | 25,085,477 | [
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A compound control strategy combining velocity compensation with ADRC of electro-hydraulic position servo control system. | In order to enhance the anti-jamming ability of electro-hydraulic position servo control system at the same time improve the control precision of the system, a compound control strategy that combines velocity compensation with Active Disturbance Rejection Controller (ADRC) is proposed, and the working principle of the compound control strategy is given. ADRC controller is designed, and the extended state observer is used for observing internal parameters uncertainties and external disturbances, so that the disturbances of the system are suppressed effectively. Velocity compensation controller is designed and the compensation model is derived to further improve the positioning accuracy of the system and to achieve the velocity compensation without disturbance. The compound control strategy is verified by the simulation and experiment respectively, and the simulation and experimental results show that the electro-hydraulic position servo control system with ADRC controller can effectively inhibit the external disturbances, the precise positioning control is realized after introducing the velocity compensation controller, and verify that the compound control strategy is effective. | 25,085,480 | [
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Functional and phylogenetic divergence of fungal adenylate-forming reductases. | A key step in fungal L-lysine biosynthesis is catalyzed by adenylate-forming L-α-aminoadipic acid reductases, organized in domains for adenylation, thiolation, and the reduction step. However, the genomes of numerous ascomycetes and basidiomycetes contain an unexpectedly large number of additional genes encoding similar but functionally distinct enzymes. Here, we describe the functional in vitro characterization of four reductases which were heterologously produced in Escherichia coli. The Ceriporiopsis subvermispora serine reductase Nps1 features a terminal ferredoxin-NADP+ reductase (FNR) domain and thus belongs to a hitherto undescribed class of fungal multidomain enzymes. The second major class is characterized by the canonical terminal short-chain dehydrogenase/reductase domain and represented by Ceriporiopsis subvermispora Nps3 as the first biochemically characterized L-α-aminoadipic acid reductase of basidiomycete origin. Aspergillus flavus l-tyrosine reductases LnaA and LnbA are members of a distinct phylogenetic clade. Phylogenetic analysis supports the view that fungal adenylate-forming reductases are more diverse than previously recognized and belong to four distinct classes. | 25,085,485 | [
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A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. | The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage. | 25,085,497 | [
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Characterization and analysis of the Burkholderia pseudomallei BsaN virulence regulon. | Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis. A conserved type III secretion system (T3SS3) and type VI secretion system (T6SS1) are critical for intracellular survival and growth. The T3SS3 and T6SS1 genes are coordinately and hierarchically regulated by a TetR-type regulator, BspR. A central transcriptional regulator of the BspR regulatory cascade, BsaN, activates a subset of T3SS3 and T6SS1 loci. To elucidate the scope of the BsaN regulon, we used RNAseq analysis to compare the transcriptomes of wild-type B. pseudomallei KHW and a bsaN deletion mutant. The 60 genes positively-regulated by BsaN include those that we had previously identified in addition to a polyketide biosynthesis locus and genes involved in amino acid biosynthesis. BsaN was also found to repress the transcription of 51 genes including flagellar motility loci and those encoding components of the T3SS3 apparatus. Using a promoter-lacZ fusion assay in E. coli, we show that BsaN together with the chaperone BicA directly control the expression of the T3SS3 translocon, effector and associated regulatory genes that are organized into at least five operons (BPSS1516-BPSS1552). Using a mutagenesis approach, a consensus regulatory motif in the promoter regions of BsaN-regulated genes was shown to be essential for transcriptional activation. BsaN/BicA functions as a central regulator of key virulence clusters in B. pseudomallei within a more extensive network of genetic regulation. We propose that BsaN/BicA controls a gene expression program that facilitates the adaption and intracellular survival of the pathogen within eukaryotic hosts. | 25,085,508 | [
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Pairwise transcriptomic analysis of the interactions between the ectomycorrhizal fungus Laccaria bicolor S238N and three beneficial, neutral and antagonistic soil bacteria. | Ectomycorrhizal fungi are surrounded by bacterial communities with which they interact physically and metabolically during their life cycle. These bacteria can have positive or negative effects on the formation and the functioning of ectomycorrhizae. However, relatively little is known about the mechanisms by which ectomycorrhizal fungi and associated bacteria interact. To understand how ectomycorrhizal fungi perceive their biotic environment and the mechanisms supporting interactions between ectomycorrhizal fungi and soil bacteria, we analysed the pairwise transcriptomic responses of the ectomycorrhizal fungus Laccaria bicolor (Basidiomycota: Agaricales) when confronted with beneficial, neutral or detrimental soil bacteria. Comparative analyses of the three transcriptomes indicated that the fungus reacted differently to each bacterial strain. Similarly, each bacterial strain produced a specific and distinct response to the presence of the fungus. Despite these differences in responses observed at the gene level, we found common classes of genes linked to cell-cell interaction, stress response and metabolic processes to be involved in the interaction of the four microorganisms. | 25,085,516 | [
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Potential of Kalopanax septemlobus leaf extract in synthesis of silver nanoparticles for selective inhibition of specific bacterial strain in mixed culture. | Silver nanoparticles (AgNPs) were synthesised using Kalopanax septemlobus plant leaf extracts. UV-visible spectrophotometric, Fourier-transform infrared, electron dispersive X-ray spectroscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses confirmed synthesis of AgNPs. TEM micrographs revealed presence of well-dispersed AgNPs predominantly of small size and different shapes with an average particle size of 30.8 nm. Antimicrobial susceptibility tests of AgNP treatments revealed variability in sensitivity of bacteria Bacillus cereus and Saccharophagus degradans under study. Minimum inhibitory concentration (MIC) values of the AgNPs for B. cereus and S. degradans were found to be 30 and 10 μg/mL, respectively. The mixed culture of B. cereus and S. degradans treated with AgNPs at 10 μg/mL showed increase in growth with time, suggesting survival of bacteria in liquid media. The plating of mixed culture before AgNP treatment showed presence of both bacteria, but 24-h-old mixed culture treated with AgNPs at the concentration of 10 μg/mL showed presence of B. cereus colonies. SEM micrographs revealed damage to S. degradans cells but no effect on B. cereus cells after AgNP treatment. Confocal microscopic observations of AgNP-treated mixed cultures by Nile blue A staining indicated intact polyhydroxyalkanoates producing flourescent cells of B. cereus but damage and deformities in S. degradans cells. This study suggests that AgNPs can selectively inhibit growth of S. degradans and retain B. cereus at MIC of S. degradans. This report is a case study for selective inhibition of one bacteria and growth of the other in a culture using plant-synthesized silver nanoparticles. | 25,085,530 | [
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Extrapyramidal symptoms during treatment of first schizophrenia episode: results from EUFEST. | The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems. | 25,085,534 | [
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A propensity-matched analysis of wedge resection and stereotactic body radiotherapy for early stage lung cancer. | Patients who present with early stage non-small cell lung cancer and are poor candidates for lobar resection may be offered sublobar resection (commonly wedge) or stereotactic body radiotherapy (SBRT). However, comparing the relative effectiveness of these techniques is difficult because of differences in patient selection. We performed a propensity-matched analysis to compare the different treatment modalities. We compared the overall recurrence, overall survival, disease-free survival, and recurrence-free survival between treatment groups. A prospectively collected database was reviewed for patients who underwent a wedge resection, a wedge plus brachytherapy, or SBRT for clinical stage IA non-small cell lung cancer from 2001 to 2012. Patients who underwent SBRT were further assessed to confirm operability. Univariate and Cox regression multivariate analysis were performed for predictors of a composite end point of recurrence and mortality. There were 164 patients identified, from which 99 were matched by age, sex, and histology. There were 61 women (62%) and 38 men (38%) with a median age of 73 years. Thirty-eight patients underwent a wedge resection only, 38 patients underwent a wedge with brachytherapy, and 23 patients had SBRT. Median follow-up was 35 months. Overall recurrence (local and distant) was significantly higher after SBRT (wedge, 9%; SBRT, 30%; p = 0.016). Although recurrence-free 3 -year survival was significantly better after wedge resection (88% versus 72%; p = 0.001), there was no difference between the two groups in disease-free 3-year survival (77% versus 59%; p = 0.066). Multivariate regression analysis identified male sex and SBRT as significant predictors for mortality and recurrence. Patients with clinical stage IA non-small cell lung cancer treated by SBRT appear to have higher overall disease recurrence than those treated by wedge resection. However, there was no significant difference in disease-free survival. A randomized trial is needed to define the role of SBRT in the potentially operable patient. | 25,085,557 | [
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Biosynthesis of pinocembrin from glucose using engineered escherichia coli. | Pinocembrin is a flavonoid that exhibits diverse biological properties. Although the major source of pinocembrin is propolis, it can be synthesized biologically using microorganisms such as Escherichia coli, which has been used to synthesize diverse natural compounds. Pinocembrin is synthesized from phenylalanine by the action of three enzymes; phenylalanine ammonia lyase (PAL), 4-coumarate:CoA ligase (4CL), and chalcone synthase (CHS). In order to synthesize pinocembrin from glucose in Escherichia coli, the PAL, 4CL, and CHS genes from three different plants were introduced into an E. coli strain. Next, we tested the different constructs containing 4CL and CHS. In addition, the malonyl-CoA level was increased by overexpressing acetyl-CoA carboxylase. Through these strategies, a high production yield (97 mg/l) of pinocembrin was achieved. | 25,085,569 | [
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Retrospective study of factors affecting multiple ovulations, embryo recovery, quality, and diameter in a commercial equine embryo transfer program. | In this study, 198 donor mares of different breeds, ages, and reproductive category were inseminated with fresh, cooled and frozen or frozen and cooled semen at the embryo transfer station or in private artificial insemination centers during 10 breeding seasons. The results of this activity were retrospectively analyzed by Pearson Chi-square test and logistic regression to evaluate factors affecting multiple ovulations, embryo recovery, embryo quality, and embryo diameter. Out of the 661 cycles, 937 ovulations were recorded (mean ovulations/cycle: 1.42 ± 0.58). Ovulation rate and incidence of multiple ovulations were significantly affected by age, breed, and reproductive category. Uterine flushings for embryo recovery were performed between 7 and 10 days after ovulation and resulted in the recovery of 338 embryos (51.1% embryos/cycle and 36.1% embryos/ovulation, respectively). At least one embryo was recovered in 298 flushings (45.1%). The factors affecting embryo recovery were age, breed, reproductive category, type of semen, number of ovulations, and location of artificial insemination. Flushing protocol and day of flushing had no effect on embryo recovery. Age, type of semen, number of ovulations, and day of flushing had a significant influence on embryo diameter (N = 215). None of the factors included in the model had an effect on embryo quality distribution. | 25,085,596 | [
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Rhabdoid tumor: the Irish experience 1986-2013. | Nomenclature for the three recognized forms of rhabdoid tumor reflect their anatomic localization and include malignant rhabdoid tumor of the kidney (MRTK), extrarenal extracranial rhabdoid tumor (EERT), and atypical teratoid rhabdoid tumor (ATRT) involving the central nervous system. A strikingly simple karyotype belies the fact that rhabdoid tumors are among the most lethal human cancers, and now early strides are beginning to elucidate their molecular pathogenesis. Rhabdoid tumors are largely confined to the pediatric population, where they occur preferentially during infancy. Given the rarity of this tumor, international consensus on best treatment has only recently been achieved in conjunction with the establishment of the European Rhabdoid Tumor Registry. Between 1986 and 2013, 25 pediatric patients were diagnosed with rhabdoid tumor in the Republic of Ireland. Of these patients, 13 presented with ATRT, eight had MRTK, and four had EERT. The mean age at diagnosis was 38.8 months, with an equal sex incidence. Because of the lack of a standardized treatment strategy for rhabdoid tumors, these patients have been treated largely according to anatomic site, based on sarcoma, renal, or brain tumor protocols contemporary to their diagnoses. Of the patients, 84% received chemotherapy, 80% underwent surgery, and 44% had radiation therapy. The outcome overall was poor, independent of anatomic location. The overall survival rate was 24%, and mean time to death was just under 9 months. | 25,085,603 | [
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Acidosis: progression of chronic kidney disease and quality of life. | Metabolic acidosis (MA) is relatively common in patients with chronic kidney disease (CKD) particularly in stages 4 and 5. It is assumed to play a contributory role in the development of several complications including bone disease, skeletal muscle wasting, altered protein synthesis, and degradation. Recent evidence also suggests that even mild acidosis might play a role in progressive glomerular filtration rate loss. Experimental and clinical studies suggest that correction of acidosis by alkali therapy attenuates these complications and improves quality of life. Despite several recent small and single-center studies supporting this notion, more robust evidence is required with regard to the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate. | 25,085,611 | [
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How many Coccolithovirus genotypes does it take to terminate an Emiliania huxleyi bloom? | Giant viruses are known to be significant mortality agents of phytoplankton, often being implicated in the terminations of large Emiliania huxleyi blooms. We have previously shown the high temporal variability of E. huxleyi-infecting coccolithoviruses (EhVs) within a Norwegian fjord mesocosm. In the current study we investigated EhV dynamics within a naturally-occurring E. huxleyi bloom in the Western English Channel. Using denaturing gradient gel electrophoresis and marker gene sequencing, we uncovered a spatially highly dynamic Coccolithovirus population that was associated with a genetically stable E. huxleyi population as revealed by the major capsid protein gene (mcp) and coccolith morphology motif (CMM), respectively. Coccolithoviruses within the bloom were found to be variable with depth and unique virus populations were detected at different stations sampled indicating a complex network of EhV-host infections. This ultimately will have significant implications to the internal structure and longevity of ecologically important E. huxleyi blooms. | 25,085,627 | [
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Ergonomics and sustainable development in the past two decades (1992-2011): Research trends and how ergonomics can contribute to sustainable development. | The need for sustainable development has been widely recognized and sustainable development has become a hot topic of various disciplines even though the role of ergonomics in it is seldom reported or considered. This study conducts a systematic survey of research publications in the fields of ergonomics and sustainable development over the past two decades (1992-2011), in order to identify their research trends and convergent areas where ergonomics can play an important role in sustainable development. The results show that 'methods and techniques', 'human characteristics', 'work design and organization', 'health and safety' and 'workplace and equipment design' are the top five frequently researched areas in ergonomics. Ergonomics has an opportunity to contribute its knowledge especially to 'industrial and product design', 'architecture', 'health and safety' and 'HCI' (especially for energy reduction issues) categories of sustainable development. Typical methodologies and general guidance on how to contribute the expertise of ergonomist to sustainable development are also discussed. | 25,085,643 | [
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Enhanced skin permeation of 5α-reductase inhibitors entrapped into surface-modified liquid crystalline nanoparticles. | The objective of this study is to enhance skin permeation of finasteride and dutasteride for the treatment of androgenetic alopecia using surface-modified liquid crystalline nanoparticle (sm-LCN) dispersion. LCN entrapped with the drugs was prepared by using monoolein as a liquid crystal former, and surface modification was performed by treatment of the LCN dispersion with same volume of 1 % v/v acetic acid solution containing chitosan. Physicochemical properties of the LCN's were studied with regard to particle size, polydispersity index, zeta potential, and release of the drugs. Skin permeation of drugs entrapped into the LCN and sm-LCN was investigated with porcine abdominal skin using Franz diffusion cell. Cytotoxicity of the LCN's was also studied using human skin keratinocytes. The particle size and zeta potential of the LCN were 197.9 ± 2.5 nm and -20.2 ± 1.9 mV, respectively, and sm-LCN showed slightly bigger size and positive zeta potential due to the presence of thin coating on the surface of the nanoparticles. Compared to LCN, sm-LCN resulted in significantly enhanced skin permeation of the drugs whereas in vitro release was significantly reduced. Cell viability as a measure of cytotoxicity was above 80 % up to 20 μg/ml concentration of both LCN and sm-LCN. In conclusion, sm-LCN may provide a strategy to maximize therapeutic efficacy minimizing unwanted systemic side effects associated with the use of the drugs for the treatment of androgenetic alopecia. | 25,085,659 | [
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Accuracy, sensitivity and robustness of five different methods for the estimation of gait temporal parameters using a single inertial sensor mounted on the lower trunk. | In the last decade, various methods for the estimation of gait events and temporal parameters from the acceleration signals of a single inertial measurement unit (IMU) mounted at waist level have been proposed. Despite the growing interest for such methodologies, a thorough comparative analysis of methods with regards to number of extra and missed events, accuracy and robustness to IMU location is still missing in the literature. The aim of this work was to fill this gap. Five methods have been tested on single IMU data acquired from fourteen healthy subjects walking while being recorded by a stereo-photogrammetric system and two force platforms. The sensitivity in detecting initial and final contacts varied between 81% and 100% across methods, whereas the positive predictive values ranged between 94% and 100%. For all tested methods, stride and step time estimates were obtained; three of the selected methods also allowed estimation of stance, swing and double support time. Results showed that the accuracy in estimating step and stride durations was acceptable for all methods. Conversely, a statistical difference was found in the error in estimating stance, swing and double support time, due to the larger errors in the final contact determination. Except for one method, the IMU positioning on the lower trunk did not represent a critical factor for the estimation of gait temporal parameters. Results obtained in this study may not be applicable to pathologic gait. | 25,085,660 | [
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The skin microbiome: potential for novel diagnostic and therapeutic approaches to cutaneous disease. | A vast diversity of microorganisms, including bacteria, fungi, viruses, and arthropods, colonize the human skin. Culture-independent genomic approaches for identifying and characterizing microbial communities have provided glimpses into the topographical, temporal, and interpersonal complexity that defines the skin microbiome. Identification of changes associated with cutaneous disease, including acne, atopic dermatitis, rosacea, and psoriasis, are being established. In this review, our current knowledge of the skin microbiome in health and disease is discussed, with particular attention to potential opportunities to leverage the skin microbiome as a diagnostic, prognostic, and/or therapeutic tool. | 25,085,669 | [
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The devil is in the details: confidentiality challenges in the age of genetics. | This clinical case report illustrates the potential dilemmas that can arise from knowledge gained through genetic analysis. These conflicts require careful ethical analysis of presumed duties to protect patient privacy and maintain confidentiality, the duty to warn a second party of a health risk, and the duty of veracity. While the questions raised by genetic testing of one individual for disease that reveals potentially important information about relatives, such as risk for Huntington chorea or breast cancer, have been discussed, the continuing expansion in our capacity for sophisticated genetic analysis continues to present new and challenging situations. The resolution of this case and others like it requires close collaboration among the treatment team, geneticists, and clinical ethicists. | 25,085,670 | [
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Markerless motion capture can provide reliable 3D gait kinematics in the sagittal and frontal plane. | Estimating 3D joint rotations in the lower extremities accurately and reliably remains unresolved in markerless motion capture, despite extensive studies in the past decades. The main problems have been ascribed to the limited accuracy of the 3D reconstructions. Accordingly, the purpose of the present study was to develop a new approach based on highly detailed 3D reconstructions in combination with a translational and rotational unconstrained articulated model. The highly detailed 3D reconstructions were synthesized from an eight camera setup using a stereo vision approach. The subject specific articulated model was generated with three rotational and three translational degrees of freedom for each limb segment and without any constraints to the range of motion. This approach was tested on 3D gait analysis and compared to a marker based method. The experiment included ten healthy subjects in whom hip, knee and ankle joint were analysed. Flexion/extension angles as well as hip abduction/adduction closely resembled those obtained from the marker based system. However, the internal/external rotations, knee abduction/adduction and ankle inversion/eversion were less reliable. | 25,085,672 | [
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Index of thermal stress for cows (ITSC) under high solar radiation in tropical environments. | This paper presents a new thermal stress index for dairy cows in inter-tropical regions, with special mention to the semi-arid ones. Holstein cows were measured for rectal temperature (T R), respiratory rate (F R) and rates of heat exchange by convection (C), radiation (R), skin surface evaporation (E S) and respiratory evaporation (E R) in the north eastern region of Brazil, after exposure to sun for several hours. Average environmental measurements during the observations were air temperature (T A) 32.4 °C (24.4-38.9°), wind speed (U) 1.8 m.s(-1) (0.01-11.0), relative humidity 63.6 % (36.8-81.5) and short-wave solar radiation 701.3 W m(-2) (116-1,295). The effective radiant heat load (ERHL) was 838.5 ± 4.9 W m(-2). Values for the atmospheric transmittance (τ) were also determined for tropical regions, in order to permit adequate estimates of the solar radiation. The average value was τ = 0.611 ± 0.004 for clear days with some small moving clouds, with a range of 0.32 to 0.91 in the day period from 1000 to 1300 hours. Observed τ values were higher (0.62-0.66) for locations near the seacoast and in those regions well-provided with green fields. Effects of month, location and time of the day were all statistically significant (P < 0.01). A total of 1,092 data were obtained for cows exposed for 1 to 8 h to sun during the day; in 7 months (February, March, April, July, August, September and November), 4 days per month on the average. A principal component analysis summarised the T R, F R, C, R, E S and E R measurements into just one synthetic variable (y 1); several indexes were then obtained by multiple regression of y 1 on the four environmental variables and its combinations, by using Origin 8.1 software (OriginLab Corp.). The chosen equation was the index of thermal stress for cows, ITSC = 77.1747 + 4.8327 T A - 34.8189 U + 1.111 U (2) + 118.6981 P V - 14.7956 P V (2) - 0.1059 ERHL with r (2) = 0.812. The correlations of ITSC with T R, F R, C, E S, R and E R were 0.275, 0.255, -0.493, -0.647, -0.818 and 0.075, respectively. Correlations of the index with the physiological variables are presented, and ITSC is compared to three other indexes. | 25,085,700 | [
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Effect of histone deacetylase inhibitor JNJ-26481585 in pain. | Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1β increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin. | 25,085,711 | [
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Audiological evidence of therapeutic effect of steroid treatment in neuromyelitis optica with hearing loss. | Neuromyelitis optica (NMO) is an autoimmune astrocytopathy caused by anti-aquaporin 4 antibody. Only two patients with NMO have been reported presenting with hearing disorders to our knowledge. We recently treated a 40-year-old woman with NMO complaining of right hearing loss. Audiometry showed minimal asymmetry, but the auditory brainstem responses (ABR) were severely attenuated on the right. The attenuated ABR and her aural symptoms (hearing loss and fullness) improved after steroid treatment. The present case shows that the retrocochlear-type hearing loss may be associated with NMO. | 25,085,730 | [
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Live attenuated vaccines against pertussis. | The intensive use of pertussis vaccines has dramatically reduced the incidence of whooping cough during the 20th century. However, recent outbreaks in countries with high vaccination coverage illustrate the shortcomings of current vaccination regimens, and immunity induced by the most recent, acellular vaccines wanes much faster than anticipated. As an alternative, live attenuated vaccine candidates have recently been developed in order to mimic natural infection, which induces long-lasting immunity. One of them has successfully completed a Phase I trial in humans and is now undergoing further product and clinical developments. This article describes the development of such vaccines, discusses their advantages over existing vaccines and their interesting bystander properties as powerful anti-inflammatory agents, which widens their potential use far beyond that for protection against whooping cough. | 25,085,735 | [
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Dual computer monitors to increase efficiency of conducting systematic reviews. | Systematic reviews (SRs) are the cornerstone of evidence-based medicine. In this study, we evaluated the effectiveness of using two computer screens on the efficiency of conducting SRs. A cohort of reviewers before and after using dual monitors were compared with a control group that did not use dual monitors. The outcomes were time spent for abstract screening, full-text screening and data extraction, and inter-rater agreement. We adopted multivariate difference-in-differences linear regression models. A total of 60 SRs conducted by 54 reviewers were included in this analysis. We found a significant reduction of 23.81 minutes per article in data extraction in the intervention group relative to the control group (95% confidence interval: -46.03, -1.58, P = 0.04), which was a 36.85% reduction in time. There was no significant difference in time spent on abstract screening, full-text screening, or inter-rater agreement between the two groups. Using dual monitors when conducting SRs is associated with significant reduction of time spent on data extraction. No significant difference was observed on time spent on abstract screening or full-text screening. Using dual monitors is one strategy that may improve the efficiency of conducting SRs. | 25,085,736 | [
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High-yield recombinant xylanase production by Aspergillus nidulans under pyridoxine limitation. | The present study investigated the limitation of pyridoxine on an Aspergillus nidulans culture that produces xylanase B (XynB) as a client enzyme and was unable to synthesize pyridoxine. This technique was used to limit cell growth and divert substrate to product formation for a surface grown culture that could be used in trickle bed reactors. It was observed that growth was limited when pyridoxine was absent, while enzyme production was unaffected. Enzyme production was 1,026 U after 480 h of continuous fermentation, which was similar to a culture that grew on medium with pyridoxine. Furthermore, the present study investigated the growth rate of A. nidulans with pyridoxine in the medium and determined the productivity of XynB production with and without pyridoxine. A maximum growth rate of 0.311/h was observed. The maximum XynB productivity of 21.14 U/g h was achieved when pyridoxine was not added to the medium. | 25,085,742 | [
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AAV-mediated gene therapy for atherosclerosis. | The prognosis of patients with coronary artery disease and stroke has improved substantially over the last decade as a result of advances in primary and secondary preventive care as well as novel interventional approaches, including the development of drug-eluting stents and balloons. Despite this progress, however, cardiovascular disease remains the leading cause of death in industrialized nations. Sustained efforts to elucidate the underlying mechanisms of atherogenesis, reperfusion-induced cardiac injury, and ischemic heart failure have led to the identification of several target genes as key players in the development and progression of atherosclerotic vascular disease. This knowledge has now enabled genetic therapeutic modulation not only for inherited diseases with a single gene defect, such as familial hypercholesterolemia, but also for multifactorial disorders. This review will focus on approaches in adeno-associated viral (AAV)-mediated gene therapy for atherosclerosis and its long-term sequelae. | 25,085,755 | [
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Applying decision tree for identification of a low risk population for type 2 diabetes. Tehran Lipid and Glucose Study. | The aim of this study was to create a prediction model using data mining approach to identify low risk individuals for incidence of type 2 diabetes, using the Tehran Lipid and Glucose Study (TLGS) database. For a 6647 population without diabetes, aged ≥20 years, followed for 12 years, a prediction model was developed using classification by the decision tree technique. Seven hundred and twenty-nine (11%) diabetes cases occurred during the follow-up. Predictor variables were selected from demographic characteristics, smoking status, medical and drug history and laboratory measures. We developed the predictive models by decision tree using 60 input variables and one output variable. The overall classification accuracy was 90.5%, with 31.1% sensitivity, 97.9% specificity; and for the subjects without diabetes, precision and f-measure were 92% and 0.95, respectively. The identified variables included fasting plasma glucose, body mass index, triglycerides, mean arterial blood pressure, family history of diabetes, educational level and job status. In conclusion, decision tree analysis, using routine demographic, clinical, anthropometric and laboratory measurements, created a simple tool to predict individuals at low risk for type 2 diabetes. | 25,085,758 | [
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Predictive factors for local control in primary and metastatic lung tumours after four to five fraction stereotactic ablative body radiotherapy: a single institution's comprehensive experience. | We report the outcomes of a large lung stereotactic ablative body radiotherapy (SABR) programme for primary non-small cell lung cancer (NSCLC) and pulmonary metastases. The primary study aim was to identify factors predictive for local control. In total, 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR using 48-60 Gy in four to five fractions. Local, regional and distant failure data were collected prospectively, whereas other end points were collected retrospectively. Potential clinical and dosimetric predictors of local control were evaluated using univariate and multivariate analyses. Of the 311 tumours, 240 were NSCLC and 71 were other histologies. The 2 year local control rate was 96% in stage I NSCLC, 76% in colorectal cancer (CRC) metastases and 91% in non-lung/non-CRC metastases. Predictors of better local control on multivariate analysis were non-CRC tumours and a larger proportion of the planning target volume (PTV) receiving ≥100% of the prescribed dose (higher PTV V100). Among the 45 CRC metastases, a higher PTV V100 and previous chemotherapy predicted for better local control. Lung SABR of 48-60 Gy/four to five fractions resulted in high local control rates for all tumours except CRC metastases. Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control. | 25,085,765 | [
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Cumulative occupational shoulder exposures and surgery for subacromial impingement syndrome: a nationwide Danish cohort study. | The primary aim was to examine exposure-response relationships between cumulative occupational shoulder exposures and surgery for subacromial impingement syndrome (SIS), and to compare sex-specific exposure-response relationships. The secondary aim was to examine the time window of relevant exposures. We conducted a nationwide register study of all persons born in Denmark (1933-1977), who had at least 5 years of full-time employment. In the follow-up period (2003-2008), we identified first-time events of surgery for SIS. Cumulative exposure estimates for a 10-year exposure time window with a 1-year lag time were obtained by linking occupational codes with a job exposure matrix. The exposure estimates were expressed as, for example, arm-elevation-years in accordance with the pack-year concept of tobacco consumption. We used a multivariable logistic regression technique equivalent to discrete survival analysis. The adjusted OR (ORadj) increased to a maximum of 2.1 for arm-elevation-years, repetition-years and force-years, and to 1.5 for hand-arm-vibration-years. Sex-specific exposure-response relationships were similar for men and women, when assessed using a relative risk scale. The ORadj increased gradually with the number of years contributing to the cumulative exposure estimates. The excess fraction was 24%. Cumulative occupational shoulder exposures carried an increase in risk of surgery for SIS with similar exposure-response curves for men and women. The risk of surgery for SIS increased gradually, when the period of exposure assessment was extended. In the general working population, a substantial fraction of all first-time operations for SIS could be related to occupational exposures. | 25,085,767 | [
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Seroprevalence of Toxoplasma gondii infection in yaks (Bos grunniens) on the Qinghai-Tibetan Plateau of China. | Toxoplasma gondii (T. gondii), a zoonotic parasite infects almost all warm-blooded animals and causes significant economic losses. To date, however, it is still unclear whether yaks from the Qinghai-Tibetan plateau of China are exposed to T. gondii. On the present study, a survey was conducted for the first time, to investigate the seroprevalence of T. gondii infection in yaks (Bos grunniens) on the Qinghai-Tibetan Plateau (Qinghai, Tibet, Hongyuan area of Sichuan province). A total of 905 and 736 serum samples were collected from yaks in these areas in 2012 and 2013, respectively and assayed for T. gondii antibodies by an indirect hemagglutination test (IHA). The results showed that seroprevalence on plateau was 21.7% and 29.1% in 2012 and 2013, respectively with the prevalence of 22.4%, 19.4% and 25.5% in 2012 for Qinghai, Tibet and Hongyuan of Sichuan, respectively and of 26.4%, 27.0% and 33.7% for these three regions in 2013, respectively. The present survey indicated that the infection with T. gondii in yaks was widely spread in recent years on the plateau causing a high risk factor for animals and humans. | 25,085,769 | [
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Autoantibodies to iron-binding proteins in pigs infested with Sarcoptes scabiei. | Despite the availability of effective treatments, Sarcoptes scabiei remains a major health problem in the pig industry. Unsuccessful control of the disease is often due to the lack of reliable detection methods, with current tests relying on skin scrapings and crude antigen ELISAs. A previous analysis of antigens in pig skin scrapings reported that anti-transferrin antibodies were present in S. scabiei infected animals and that this finding might be considered as a useful diagnostic tool. This paper confirms IgG autoantibodies against transferrin, including the first report of IgM autoantibodies, in both naturally and experimentally infected pigs using ELISA and dot blot assays. Autoantibodies were also detected in pigs to ferritin and to a lesser extent lactoferrin. Immunoblotting confirmed the presence of IgG and IgM autoantibodies in mange positive pigs, as well as IgM antibodies to transferrin and albumin in mange negative pigs. These findings suggest the presence of natural autoantibodies to transferrin and albumin in pigs. The development of the IgG autoimmune response may either be a host mechanism for limiting iron to the mite via antibody mediated clearance, the result of host exposure to mite iron-binding homologues or because of a mite-induced antigenic change to host transferrin. Further investigation into the formation of these autoantibodies may provide insights into the importance of iron in scabies infections and the development and perseverance of S. scabiei infections in pigs. The specificity and sensitivity of the anti-transferrin response reinforces its potential in the diagnosis of scabies in pigs. | 25,085,772 | [
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In vitro and in vivo acaricide action of juvenoid analogs produced from the chemical modification of Cymbopogon spp. and Corymbia citriodora essential oil on the cattle tick Rhipicephalus (Boophilus) microplus. | The present study aimed to evaluate the acaricidal action of the chemically modified essential oil of Cymbopogon spp. and Corymbia citriodora on Rhipicephalus (Boophilus) microplus. Citronellal was converted into N-butylcitronellylamine and in N-prop-2-inylcitronellylamine, analogs of juvenoids, by reductive amination using butylamine (N1 to N3) and propargylamine (N4 to N7). In vitro assays included the adult immersion, and larval packet tests. Engorged females were weighed in groups of 10 and tested in three replicates for six concentrations. They were immersed in the modified oils or control solution and incubated. In the larval packet test, the same substances and concentrations were evaluated in three replicates. In the in vivo test, six pastured heifers naturally infested with R. (B.) microplus were used per treatment: negative control, positive control (amitraz, Triatox(®)), original oil of C. citriodora at 1.5%, and modified oil containing 0.9% N-prop-2-inylcitronellylamine (N7). Ticks were counted in the right side of the body in 24 animals from day D-3 to D21. LC50 and LC90 were obtained by Probit analysis, while the in vivo results were log transformed and compared using the Tukey test. Among the nitrocellylamines tested in vitro, N6 was most effective on the engorged females (100% efficacy at 50mg/mL) and N7 on the larvae (100% efficacy at 6.25mg/mL). In the test with larvae, the original oil of C. citriodora was less effective than the counterpart modified oil (N7), proving that the chemical modification optimized its effect. In the in vivo test, no significant difference was observed between N7 and the negative control. The average numbers of ticks on the animals' right side were 32.8, 8.1, 37.9 and 35.4 for the negative control, positive control, original oil and N7, respectively. The chemical modification improved the efficacy in vitro, but it was not observed in vivo, perhaps due to the low stability of the amines under field conditions. The evaluation carried out here has not been previously studied, so this concept expands the horizon for research into chemically modified substances for parasite control and shed light on the challenges to find effective formulations and application methods. | 25,085,774 | [
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Molecular pathways: translational potential of deubiquitinases as drug targets. | The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitin moieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation of DUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed in many tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivo models with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer. | 25,085,788 | [
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89Zr-trastuzumab and 89Zr-bevacizumab PET to evaluate the effect of the HSP90 inhibitor NVP-AUY922 in metastatic breast cancer patients. | HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using (89)Zr-trastuzumab PET (for HER2-positive breast cancer) or (89)Zr-bevacizumab PET [for estrogen receptor (ER)-positive breast cancer] to determine in vivo degradation of client proteins caused by the novel HSP90 inhibitor NVP-AUY922. Of note, 70 mg/m(2) NVP-AUY922 was administered intravenously in a weekly schedule to patients with advanced HER2 or ER-positive breast cancer. Biomarker analysis consisted of serial PET imaging with 2[18F]fluoro-2-deoxy-D-glucose (FDG), (89)Zr-trastuzumab, or (89)Zr-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, (89)Zr-trastuzumab, and (89)Zr-bevacizumab distributions were scored visually and quantitatively by calculating the maximum standardized uptake values (SUVmax). In blood samples, serial HSP70 levels, extracellular form of HER2 (HER2-ECD), and pharmacokinetic and pharmacodynamic parameters were measured. Sixteen patients (ten HER2-positive and six ER-positive tumors) were included. One partial response was observed; seven patients showed stable disease. SUVmax change in individual tumor lesions on baseline versus 3 weeks (89)Zr-trastuzumab PET was heterogeneous and related to size change on CT after 8 weeks treatment (r(2) = 0.69; P = 0.006). Tumor response on (89)Zr-bevacizumab PET and FDG-PET was not correlated with CT response. NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on (89)Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT. | 25,085,789 | [
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Liver failure in patients treated with chemotherapy for colorectal liver metastases: Role of chronic disease scores in patients undergoing major liver surgery. A case-matched analysis. | An accurate and noninvasive tool to predict Chemotherapy Associated Liver Injury (CALI) still lacks. Study aimed to evaluate chronic liver disease scores (Aspartate aminotransferase to Platelet Ratio Index, APRI and Fibrosis-4, FIB-4) as Postoperative Liver Failure (PLF) predictors in patients treated with Oxaliplatin for Colorectal Liver Metastases (CLM). 8 patients who developed PLF after major hepatectomy (Group B) were compared to 24 patients who did not develop PLF (Group A) in a case-matched analysis for patients and disease characteristics. ROC curves analysis was performed to assess score accuracy. In Group A number of CT cycles was lower, (6 vs 9, p NS), interval between treatment and surgery was longer (11 vs 7 weeks, p < 0.05) and bevacizumab was more frequently administered (66.7% vs 37.5%, p < 0.05). In Group B median APRI score was 0.53 (range: 0.86-4.26) whereas in Group A was 0.30 (range: 0.06-2.21, p < 0.05). Median FIB-4 score was 2.46 (range: 0.86-13.65) in Group B and 1.58 (range: 0.27-7.68) in Group A (p < 0.001). Multivariate analysis showed a significant correlation between APRI and the onset of PLF. A good accuracy of APRI score was evident in ROC curves with an area under the curve of 0.72 (p 0.003). APRI score is calculated considering both liver damage and platelet count, it is cost effective and easily available. This study demonstrates that there is a good accuracy in PLF prediction and consequently in CT induced liver damage evaluation. | 25,085,794 | [
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Survival, Continence and Potency (SCP) recovery after radical retropubic prostatectomy: a long-term combined evaluation of surgical outcomes. | To offer a comprehensive account of surgical outcomes on a defined series of patients treated with radical retropubic prostatectomy (RRP) for prostate cancer in a single European Center after 5-year minimum follow-up according to the Survival, Continence and Potency (SCP) system. We evaluated our Institutional database of patients who underwent RRP from November 1995 to September 2008. Oncological and functional outcomes were reported according to the recently proposed SCP system. The 5- and 10-year biochemical recurrence-free survival rates were 80.1% and 55.8%, respectively. At the end of follow-up, 611 (78.5%) patients were fully continent (C0), 107 (13.8%) used 1 pad for security (C1) and 60 (7.7%) patients were incontinent (C2). Of the 112 patients who underwent nerve-sparing RRP, 22 (19.6%) were fully potent without aids (P0), 13 (11.6%) were potent with assumption of PDE-5 inhibitors (P1) and 77 (68.8%) experienced erectile dysfunction (P2). The combined SCP outcomes were reported together only in 95 (12.2%) evaluable patients. In patients preoperatively continent and potent, who received a nerve-sparing and did not require adjuvant therapy, oncological and functional success was attained by 29 (30.5%) patients. In the subgroup of 508 patients not evaluable for potency recovery, oncological and continence outcomes were obtained in 357 patients (70.3%). Survival, Continence and Potency (SCP) classification offer a comprehensive report of surgical results, even in those patients who do not represent the best category, thus allowing to provide a much more accurate evaluation of outcomes after RP. | 25,085,795 | [
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Do column frits contribute to the on-column, flow-induced degradation of macromolecules? | Flow-induced, on-column degradation is a major hindrance to the accurate characterization of ultra-high molar mass macromolecules and colloids. This degradation is a direct result of the large shear rates which are generated within the column, which cause chain scission to occur both in the interstitial medium and, it has been postulated, at the packing particle pore boundary. An additional putative source of degradation has been the column frits, though little experimental evidence exists to either support or refute this claim. To this effect, the present experiments examine the role of the frits in the degradation of high molar mass macromolecules. Two narrow dispersity polystyrene standards, the molar mass of which differs by a factor of two, were analyzed on three different size-exclusion chromatography (SEC) columns, each with frits of different pore size, at various flow rates. In the smallest pore size column, which also contained the smallest frits and which was packed with the smallest diameter particles, the larger standard was forced to degrade by increasing the flow rate of the mobile phase. During the course of the latter portion of the study, the inlet and the outlet frits were removed from the column, in stepwise fashion. It was concluded that neither frit played any appreciable role in the degradation. Results of our studies were applied to explain previously observed degradation in ultra-high pressure liquid chromatography of polymers. The general conclusion arrived at herein is that the column frits are likely to have a secondary role (as compared to interstitial and pore boundary stresses), or no role at all, in polymer degradation for cases where the frit radius is larger than or equal to the hydraulic radius rcof the column. | 25,085,820 | [
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Novel dummy molecularly imprinted polymers for matrix solid-phase dispersion extraction of eight fluoroquinolones from fish samples. | A series of novel dummy molecularly imprinted polymers (DMIPs) were prepared as highly class-selective sorbents for fluoroquinolones. A non-poisonous dummy template, daidzein, was used for the first time to create specific molecular recognition sites for fluoroquinolones in the synthesized polymers. The influence of porogen polarity on dummy molecular imprinting effect was studied. The DMIP prepared using dimethylsulfoxide-acetonitrile (1:1.8, v/v) as porogen achieved the highest imprinting factors (IF) for fluoroquinolones over a range of IF 13.4-84.0. This DMIP was then used for selective extraction of eight fluoroquinolones (fleroxacin, ofloxacin, norfloxacin, pefloxacin, ciprofloxacin, lomefloxacin, enrofloxacin and gatifloxacin) from fish samples based on dummy molecularly imprinted matrix solid-phase dispersion (DMI-MSPD). The extracted fluoroquinolones were subsequently analyzed by high-performance liquid chromatography (HPLC) equipped with a fluorescence detector (FLD). The developed method had acceptable recoveries (64.4-102.7%) and precision (RSDs: 1.7-8.5%, n=5) for determination of fluoroquinolones in fish samples fortified at levels of 10 and 100ngg(-1). The limits of detection (LODs) for identification of eight fluoroquinolones ranged between 0.06 and 0.22ngg(-1). The results demonstrated great potential of the optimized method for sample preparation in routine analysis of trace fluoroquinolones in fish samples. | 25,085,823 | [
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Determination of prostaglandin analogs in cosmetic products by high performance liquid chromatography with tandem mass spectrometry. | A method was developed and validated for the determination of 16 prostaglandin analogs in cosmetic products. The QuEChERS (Quick, Easy, Cheap, Efficient, Rugged, Safe) liquid-liquid extraction method, typically used for pesticide residue analysis, was utilized as the sample preparation technique. The prostaglandin analogs were chromatographically separated and quantified using high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Thirty-one cosmetic products were surveyed, and 13 products were determined to contain a prostaglandin analog with amounts ranging from 27.4 to 297μg/g. The calculated concentrations for the cosmetic products were in a similar range when compared to the concentrations of three different prostaglandin analog-containing prescription products. | 25,085,824 | [
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"No justice, no peace" and the right to self-determination: an interview with Gary Grant and Naeema Muhammed of the North Carolina Environmental Justice Network. | This is an interview with Gary Grant and Naeema Muhammed, leaders of the North Carolina Environmental Justice Network. Each of them talks about where they grew up, their politicization, how their paths crossed, their work together after Hurricane Floyd, and the unique challenges of organizing for social justice for black communities in the South. We learn of their fight against concentrated animal feeding operations (CAFOs), primarily for the hog trade, and they take us up to North Carolina's Moral Monday protests of 2013 against legislation that threatens voting rights, public education, access to medical services, unemployment benefits, workers rights, occupational and environmental health, and women's access to reproductive health care. We are grateful to these two friends of New Solutions for their contribution to the journal, and we hope that their insights regarding struggles for social and environmental justice can serve as guides for us all. | 25,085,831 | [
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It's not about energy--it's about power! | Teri Blanton is a former chairperson and current fellow at Kentuckians for the Commonwealth, a statewide organization that works "for a new balance of power and a just society aimed at changing unfair political, economic, and social systems." In March 2014 she was a keynote speaker addressing the annual conference of the Toxics Action Center in Boston, Massachusetts. We are publishing her speech, presented to the many environmental activists from community- and labor-based organizations that work on state and regional concerns. Ms. Blanton energized the conference with her message of persistent organizing to attain justice against the threats posed to our communities, health, and environment by powerful forces who exploit our lives and labor for their profit and power. She calls upon us to build the power to make the transition to more sustainable and democratic human development. | 25,085,832 | [
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Vitamin D in blood and risk of prostate cancer: lessons from the Selenium and Vitamin E Cancer Prevention Trial and the Prostate Cancer Prevention Trial. | The effects of blood levels of 25-hydroxyvitamin D (25-OHD) on the risk of total, low-, and high-grade prostate cancer were examined in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and the Prostate Cancer Prevention Trial (PCPT). In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent "U"-shaped effect in other men. The "U-shaped" curve may reflect detection bias. In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers. The results from these large prevention trials support the hypothesis that circulating levels of 25-OHD decrease the risk of clinically relevant prostate cancers. | 25,085,835 | [
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Sevoflurane-enriched blood cardioplegia: the intramyocardial delivery of a volatile anesthetic. | Myocardial ischemia/reperfusion injury is a major problem in cardiac surgery, characterized by an enhanced inflammatory response postoperatively. Sevoflurane has anti-inflammatory effects and may attenuate this injury. This study describes a novel approach to using sevoflurane as a local anti-inflammatory drug and not as an anesthetic. Therefore, a pediatric oxygenator with a sevoflurane vaporizer was integrated into the blood cardioplegia system of an adult bypass system. In addition, a gas blender was implemented to regulate pO2 and pCO2 concentrations in the cardioplegia. This proof-of-principle study was tested in vivo and shows that it is feasible to deliver sevoflurane locally while regulating O2 and CO2 concentrations. Moreover, this set-up enables one to use only the specific cardioprotective features of sevoflurane. Inflammatory responses were attenuated, both locally (i.e. the heart) as well as systemically through intramyocardial delivery of sevoflurane. | 25,085,855 | [
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Computational modeling of thrombotic microparticle deposition in nonparallel flow regimes. | Thrombotic microparticles (MPs) released from cells and platelets in response to various stimuli are present in elevated numbers in various disease states that increase the risk for thrombotic events. In order to understand how particles of this size may localize in nonparallel flow regimes and increase thrombotic risk, a computational analysis of flow and MP deposition was performed for 3 deg of stenosis at moderate Reynolds number (20<Re<80) and for recirculation zones at low Reynolds (1) number. The results indicate that MP deposition results primarily from impaction and not by diffusive flux. | 25,085,867 | [
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Hybanthus calceolaria poisoning in cattle. | Hybanthus calceolaria, also known as "papaconha" or "ipepacuanha," is a herbaceous plant found in northeastern Brazil, which is often implicated by farmers as the cause of neurological signs in livestock grazing. Several poisoning outbreaks associated with the ingestion of this plant were observed in cattle in the municipalities of Colônia de Gurguéia in the state of Piauí and Sirinhaém in the state of Pernambuco, Brazil. The main clinical signs were ataxia, recumbency, and myokymia. No significant lesions were observed during necropsy or on histological examination. The disease was experimentally reproduced by the administration of 2 daily doses of 40 g/kg/body weight of the fresh green plant containing fruits. The plants without fruits were nontoxic, which is in accordance with the farmers' information, as it was stated that the poisoning only occurs when the plant is fruiting. | 25,085,870 | [
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Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age. | Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks. | 25,085,875 | [
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CXCR7 Receptor Controls the Maintenance of Subpial Positioning of Cajal-Retzius Cells. | Cajal-Retzius (CR) cells are essential for cortical development and lamination. These pioneer neurons arise from distinct progenitor sources, including the cortical hem and the ventral pallium at pallium-subpallium boundary (PSB). CXCR4, the canonical receptor for the chemokine CXCL12, controls the superficial location of hem-derived CR cells. However, recent studies showed that CXCR7, a second CXCL12 receptor, is also expressed in CR cells at early developmental stages. We thus investigated the role of CXCR7 during CR cell development using multiple loss-of-function approaches. Cxcr7 gene inactivation led to aberrant localization of Reelin-positive cells within the pallium. In addition, Cxcr7(-/-) mice were characterized by significant accumulation of ectopic CR cells in the lateral part of the dorsal pallium compared with Cxcr4 knockout mice. Loss-of-function approaches, using either gene targeting or pharmacological receptor inhibition, reveal that CXCR7 and CXCR4 act both in CR positioning. Finally, conditional Cxcr7 deletion in cells derived from Dbx1-expressing progenitors indicates an essential role of CXCR7 in controlling the positioning of a subpopulation of PSB-derived CR cells. Our data demonstrate that CXCR7 has a role in the positioning of hem and PSB-derived CR cells, CXCL12 regulating CR cell subpial localization through the combined action of CXCR4 and CXCR7. | 25,085,881 | [
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Direct 3D Analyses Reveal Barrel-Specific Vascular Distribution and Cross-Barrel Branching in the Mouse Barrel Cortex. | Whether vascular distribution is spatially specific among cortical columns is a fundamental yet controversial question. Here, we have obtained 1-μm resolution 3D datasets that cover the whole mouse barrel cortex by combining Nissl staining with micro-optical sectioning tomography to simultaneously visualize individual cells and blood vessels, including capillaries. Pinpointing layer IV of the posteromedial barrel subfield, direct 3D reconstruction and quantitative analysis showed that (1) penetrating vessels preferentially locate in the interbarrel septa/barrel wall (75.1%) rather than the barrel hollows, (2) the branches of 70% penetrating vessels only reach the neighboring but not always all the neighboring barrels and the other 30% extend beyond the neighboring barrels and may provide cross-barrel blood supply or drainage, (3) the branches of 59.6% penetrating vessels reach all the neighboring barrels, while the rest only reach part of them, and (4) the length density of microvessels in the interbarrel septa/barrel wall is lower than that in the barrel hollows with a ratio of 0.92. These results reveal that the penetrating vessels and microvessels exhibit a barrel-specific organization, whereas the branches of penetrating vessels do not, which suggests a much more complex vascular distribution pattern among cortical columns than previously thought. | 25,085,882 | [
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Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance. | Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8(+) T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin(+) dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin(+) dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8(+) T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8(+) T cells. Langerin/OVA combined with imiquimod could not prime CD8(+) T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin(+) dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8(+) T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs. | 25,085,878 | [
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Modulation of the poly (ADP-ribose) polymerase inhibitor response and DNA recombination in breast cancer cells by drugs affecting endogenous wild-type p53. | Synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) and homologous recombination (HR) repair pathways have been exploited for the development of novel mono- and combination cancer therapies. The tumor suppressor p53 was demonstrated to exhibit indirect and direct regulatory activities in DNA repair, particularly in DNA double-strand break (DSB)-induced and replication-associated HR. In this study, we tested a potential influence of the p53 status on the response to PARP inhibition, which is known to cause replication stress. Silencing endogenous or inducibly expressing p53 we found a protective effect of p53 on PARP inhibitor (PARPi)-mediated cytotoxicities. This effect was specific for wild-type versus mutant p53 and observed in cancer but not in non-transformed cell lines. Enhanced cytotoxicities after treatment with the p53-inhibitory drug Pifithrinα further supported p53-mediated resistance to PARP inhibition. Surprisingly, we equally observed increased PARPi sensitivity in the presence of the p53-activating compound Nutlin-3. As a common denominator, both drug responses correlated with decreased HR activities: Pifithrinα downregulated spontaneous HR resulting in damage accumulation. Nutlin-3 induced a decrease of DSB-induced HR, which was accompanied by a severe drop in RAD51 protein levels. Thus, we revealed a novel link between PARPi responsiveness and p53-controlled HR activities. These data expand the concept of cell and stress type-dependent healer and killer functions of wild-type p53 in response to cancer therapeutic treatment. Our findings have implications for the individualized design of cancer therapies using PARPi and the potentially combined use of p53-modulatory drugs. | 25,085,902 | [
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Unstable C-spine injury with normal C-spine radiographs. | There is some controversy surrounding the optimal mode of imaging in trauma patients with suspected cervical (C) spine injury. Various rules (most notably the Canadian C-spine rules and the NEXUS rules) have been designed to help reduce the need for imaging given the poor yield. Some authorities advocate CT for almost all cases whereas others advocate three view radiographs unless the patient is at high risk, in which case CT is the preferred choice. One meta-analysis showed sensitivity of 58% (39-76%) for plain radiographs and 98% for CT in identification of C-spine injuries following blunt trauma. This case report illustrates how very unstable C-spine injuries may not be apparent on plain radiographs and a degree of clinical suspicion may be required for further imaging. | 25,085,950 | [
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Regenerative medicine: transforming the drug discovery and development paradigm. | Despite the explosion of knowledge in basic biological processes controlling tissue regeneration and the growing interest in repairing/replacing diseased tissues and organs through various approaches (e.g., small and large molecule therapeutics, stem cell injection, tissue engineering), the pharmaceutical industry (pharma) has been reluctant to fully adopt these technologies into the traditional drug discovery and research and development (R&D) process. In this article, I discuss knowledge-base gaps and other possible factors that may delay full incorporation of these innovations in pharma R&D. I hope that this discussion will illuminate key issues that currently limit synergistic relationships between pharma and academic institutions and may even stimulate initiation of such collaborative research. | 25,085,955 | [
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Alignment errors strongly impact likelihood-based tests for comparing topologies. | Estimating phylogenetic trees from sequence data is an extremely challenging and important statistical task. Within the maximum-likelihood paradigm, the best tree is a point estimate. To determine how strongly the data support such an evolutionary scenario, a hypothesis testing methodology is required. To this end, the Kishino-Hasegawa (KH) test was developed to determine whether one topology is significantly more supported by the sequence data than another one. This test and its derivatives are widely used in phylogenetics and phylogenomics. Here, we show that the KH test is biased in the presence of alignment error and can lead to erroneous conclusions. Using simulations we demonstrated that due to alignment errors the KH test often rejects one of the competing topologies, even though both topologies are equally supported by the data. Specifically, we show that the KH test favors the guide tree used to align the analyzed sequences. Further, branch length optimization renders the test too conservative. We propose two possible corrections for these biases. First, we evaluated the impact of removing unreliable alignment columns and found out that it decreases the bias at the cost of substantially reducing the test's power. Second, we developed a parametric test that entirely abolishes the biases without data filtering. This test incorporates the alignment construction step into the test's hypothesis, thus removing the above guide tree effect. We extend this methodology for the case of multiple-topology comparisons and demonstrate the applicability of the new methodology on an exemplary data set. | 25,085,999 | [
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Multihost experimental evolution of the pathogen Ralstonia solanacearum unveils genes involved in adaptation to plants. | Ralstonia solanacearum, the causal agent of a lethal bacterial wilt plant disease, infects an unusually wide range of hosts. These hosts can further be split into plants where R. solanacearum is known to cause disease (original hosts) and those where this bacterium can grow asymptomatically (distant hosts). Moreover, this pathogen is able to adapt to many plants as supported by field observations reporting emergence of strains with enlarged pathogenic properties. To investigate the genetic bases of host adaptation, we conducted evolution experiments by serial passages of a single clone of the pathogen on three original and two distant hosts over 300 bacterial generations and then analyzed the whole-genome of nine evolved clones. Phenotypic analysis of the evolved clones showed that the pathogen can increase its fitness on both original and distant hosts although the magnitude of fitness increase was greater on distant hosts. Only few genomic modifications were detected in evolved clones compared with the ancestor but parallel evolutionary changes in two genes were observed in independent evolved populations. Independent mutations in the regulatory gene efpR were selected for in three populations evolved on beans, a distant host. Reverse genetic approaches confirmed that these mutations were associated with fitness gain on bean plants. This work provides a first step toward understanding the within-host evolutionary dynamics of R. solanacearum during infection and identifying bacterial genes subjected to in planta selection. The discovery of EfpR as a determinant conditioning host adaptation of the pathogen illustrates how experimental evolution coupled with whole-genome sequencing is a potent tool to identify novel molecular players involved in central life-history traits. | 25,086,002 | [
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Bias correction for selecting the minimal-error classifier from many machine learning models. | Supervised machine learning is commonly applied in genomic research to construct a classifier from the training data that is generalizable to predict independent testing data. When test datasets are not available, cross-validation is commonly used to estimate the error rate. Many machine learning methods are available, and it is well known that no universally best method exists in general. It has been a common practice to apply many machine learning methods and report the method that produces the smallest cross-validation error rate. Theoretically, such a procedure produces a selection bias. Consequently, many clinical studies with moderate sample sizes (e.g. n = 30-60) risk reporting a falsely small cross-validation error rate that could not be validated later in independent cohorts. In this article, we illustrated the probabilistic framework of the problem and explored the statistical and asymptotic properties. We proposed a new bias correction method based on learning curve fitting by inverse power law (IPL) and compared it with three existing methods: nested cross-validation, weighted mean correction and Tibshirani-Tibshirani procedure. All methods were compared in simulation datasets, five moderate size real datasets and two large breast cancer datasets. The result showed that IPL outperforms the other methods in bias correction with smaller variance, and it has an additional advantage to extrapolate error estimates for larger sample sizes, a practical feature to recommend whether more samples should be recruited to improve the classifier and accuracy. An R package 'MLbias' and all source files are publicly available. tsenglab.biostat.pitt.edu/software.htm. ctseng@pitt.edu Supplementary data are available at Bioinformatics online. | 25,086,004 | [
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In vitro splicing reactions in Drosophila Kc nuclear extracts. | This protocol describes how to generate and analyze products and intermediates in a pre-mRNA splicing reaction. The reaction relies on the use of labeled, capped, synthetic pre-mRNAs, prepared by in vitro transcription, and Drosophila Kc cell culture nuclear extracts. The pre-mRNA substrate is incubated in the nuclear extract under splicing conditions for 1-2 h. The products of the reaction are purified by phenol:chloroform extraction and precipitation with ethanol, and then loaded directly onto a denaturing urea-acrylamide gel. Visualization of the splicing reactions will reveal the pre-mRNA, the spliced mRNA, and the intermediates generated by the first step of splicing. For inefficient reactions, a more sensitive detection method, such as RNase protection, primer extension, or RT-PCR (reverse transcription-polymerase chain reaction), may be required. | 25,086,019 | [
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Binding induced RNA conformational changes control substrate recognition and catalysis by the thiostrepton resistance methyltransferase (Tsr). | Ribosomal RNA (rRNA) post-transcriptional modifications are essential for ribosome maturation, translational fidelity, and are one mechanism used by both antibiotic-producing and pathogenic bacteria to resist the effects of antibiotics that target the ribosome. The thiostrepton producer Streptomyces azureus prevents self-intoxication by expressing the thiostrepton-resistance methyltransferase (Tsr), which methylates the 2'-hydroxyl of 23 S rRNA nucleotide adenosine 1067 within the thiostrepton binding site. Tsr is a homodimer with each protomer containing an L30e-like amino-terminal domain (NTD) and a SPOUT methyltransferase family catalytic carboxyl-terminal domain (CTD). We show that both enzyme domains are required for high affinity RNA substrate binding. The Tsr-CTD has intrinsic, weak RNA affinity that is necessary to direct the specific high-affinity Tsr-RNA interaction via NTDs, which have no detectable RNA affinity in isolation. RNA structure probing experiments identify the Tsr footprint on the RNA and structural changes in the substrate, induced specifically upon NTD binding, which are necessary for catalysis by the CTD. Additionally, we identify a key amino acid in each domain responsible for CTD-RNA binding and the observed NTD-dependent RNA structural changes. These studies allow us to develop a model for Tsr-RNA interaction in which the coordinated substrate recognition of each Tsr structural domain is an obligatory pre-catalytic recognition event. Our findings underscore the complexity of substrate recognition by RNA modification enzymes and the potential for direct involvement of the RNA substrate in controlling the process of its modification. | 25,086,036 | [
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Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation. | Folate, an important nutrient in the human diet, has been implicated in cancer, but its role in metastasis is not established. We have shown previously that the withdrawal of medium folate leads to the inhibition of migration and invasion of A549 lung carcinoma cells. Here we have demonstrated that medium folate regulates the function of Rho GTPases by enabling their carboxyl methylation and translocation to plasma membrane. Conversely, the lack of folate leads to the retention of these proteins in endoplasmic reticulum. Folate also promoted the switch from inactive (GDP-bound) to active (GTP-bound) GTPases, resulting in the activation of downstream kinases p21-activated kinase and LIM kinase and phosphorylation of the actin-depolymerizing factor cofilin. We have further demonstrated that in A549 cells two GTPases, RhoA and Rac1, but not Cdc42, are immediate sensors of folate status: the siRNA silencing of RhoA or Rac1 blocked effects of folate on cofilin phosphorylation and cellular migration and invasion. The finding that folate modulates metastatic potential of cancer cells was confirmed in an animal model of lung cancer using tail vein injection of A549 cells in SCID mice. A folate-rich diet enhanced lung colonization and distant metastasis to lymph nodes and decreased overall survival (35 versus 63 days for mice on a folate-restricted diet). High folate also promoted epithelial-mesenchymal transition in cancer cells and experimental mouse tumors. Our study provides experimental evidence for a mechanism of metastasis promotion by dietary folate and highlights the interaction between nutrients and metastasis-related signaling. | 25,086,046 | [
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Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis. | Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)-induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2-4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine. This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis. | 25,086,069 | [
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Crowding is reduced by onset transients in the target object (but not in the flankers). | In peripheral vision, objects that are visible in isolation become difficult to identify in clutter. This crowding effect is typically strong when objects are similar in a given dimension (e.g., color) and weak when they differ. Here we examine the selectivity of crowding for temporal differences-namely, the transient signals associated with object onsets and offsets. Observers judged the orientation of a peripheral Gabor target surrounded by four flankers. Midway through each trial, selected elements "blinked" off and on again. Performance was poor (crowding was strong) when all Gabors blinked simultaneously or when only the flankers blinked. In contrast, performance improved dramatically when the target alone blinked despite the continued presence of the flankers. This asymmetric release from crowding occurs across a range of blink durations and target-flanker separations. A similar release was found when the target onset was delayed relative to the flanker onsets, though varying the target offset had little effect. This suggests that blinks (composed of offset and onset events) reduce crowding specifically because they separate target and flanker onsets. Finally, with luminance pedestals added to the Gabors, crowding was reduced by blinks in the target pedestal only when the target Gabor was present; pedestal blinks before/after the stimulus Gabors (as precues/postcues) had no effect. That is, transients do not simply cue the target location. The asymmetry of this effect (reduced crowding with target transients, no effect with flanker transients) also precludes explanations based on similarity or grouping. We attribute our findings to the isolation of the target in transient (vs. sustained) visual channels. | 25,086,085 | [
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A systematic review and meta-analysis of patient-specific instrumentation for improving alignment of the components in total knee replacement. | We conducted a meta-analysis, including randomised controlled trials (RCTs) and cohort studies, to examine the effect of patient-specific instruments (PSI) on radiological outcomes after total knee replacement (TKR) including: mechanical axis alignment and malalignment of the femoral and tibial components in the coronal, sagittal and axial planes, at a threshold of > 3º from neutral. Relative risks (RR) for malalignment were determined for all studies and for RCTs and cohort studies separately. Of 325 studies initially identified, 16 met the eligibility criteria, including eight RCTs and eight cohort studies. There was no significant difference in the likelihood of mechanical axis malalignment with PSI versus conventional TKR across all studies (RR = 0.84, p = 0.304), in the RCTs (RR = 1.14, p = 0.445) or in the cohort studies (RR = 0.70, p = 0.289). The results for the alignment of the tibial component were significantly worse using PSI TKR than conventional TKR in the coronal and sagittal planes (RR = 1.75, p = 0.028; and RR = 1.34, p = 0.019, respectively, on pooled analysis). PSI TKR showed a significant advantage over conventional TKR for alignment of the femoral component in the coronal plane (RR = 0.65, p = 0.028 on pooled analysis), but not in the sagittal plane (RR = 1.12, p = 0.437). Axial alignment of the tibial (p = 0.460) and femoral components (p = 0.127) was not significantly different. We conclude that PSI does not improve the accuracy of alignment of the components in TKR compared with conventional instrumentation. | 25,086,121 | [
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Functional outcome and quality of life after the surgical treatment for diffuse-type giant-cell tumour around the knee: a retrospective analysis of 30 patients. | We retrospectively reviewed 30 patients with a diffuse-type giant-cell tumour (Dt-GCT) (previously known as pigmented villonodular synovitis) around the knee in order to assess the influence of the type of surgery on the functional outcome and quality of life (QOL). Between 1980 and 2001, 15 of these tumours had been treated primarily at our tertiary referral centre and 15 had been referred from elsewhere with recurrent lesions. The mean follow-up was 64 months (24 to 393). Functional outcome and QOL were assessed with range of movement and the Knee injury and Osteoarthritis Outcome Score (KOOS), the Musculoskeletal Tumour Society (MSTS) score, the Toronto Extremity Salvage Score (TESS) and the SF-36 questionnaire. There was recurrence in four of 14 patients treated initially by open synovectomy. Local control was achieved after a second operation in 13 of 14 (93%). Recurrence occurred in 15 of 16 patients treated initially by arthroscopic synovectomy. These patients underwent a mean of 1.8 arthroscopies (one to eight) before open synovectomy. This achieved local control in 8 of 15 (53%) after the first synovectomy and in 12 of 15 (80%) after two. The functional outcome and QOL of patients who had undergone primary arthroscopic synovectomy and its attendant subsequent surgical procedures were compared with those who had had a primary open synovectomy using the following measures: range of movement (114º versus 127º; p = 0.03); KOOS (48 versus 71; p = 0.003); MSTS (19 versus 24; p = 0.02); TESS (75 versus 86; p = 0.03); and SF-36 (62 versus 80; p = 0.01). Those who had undergone open synovectomy needed fewer subsequent operations. Most patients who had been referred with a recurrence had undergone an initial arthroscopic synovectomy followed by multiple further synovectomies. At the final follow-up of eight years (2 to 32), these patients had impaired function and QOL compared with those who had undergone open synovectomy initially. We conclude that the natural history of Dt-GCT in patients who are treated by arthroscopic synovectomy has an unfavourable outcome, and that primary open synovectomy should be undertaken to prevent recurrence or residual disease. | 25,086,129 | [
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The influence of the choice of closing wedge angle on leg length discrepancy after proximal femoral varus osteotomy. | Proximal femoral varus osteotomy improves the biomechanics of the hip and can stimulate normal acetabular development in a dysplastic hip. Medial closing wedge osteotomy remains the most popular technique, but is associated with shortening of the ipsilateral femur. We produced a trigonometric formula which may be used pre-operatively to predict the resultant leg length discrepancy (LLD). We retrospectively examined the influence of the choice of angle in a closing wedge femoral osteotomy on LLD in 120 patients (135 osteotomies, 53% male, mean age six years, (3 to 21), 96% caucasian) over a 15-year period (1998 to 2013). A total of 16 of these patients were excluded due to under or over varus correction. The patients were divided into three age groups: paediatric (< 10 years), adolescent (10 to 16 years) and adult (> 16 years). When using the same saw blades as in this series, the results indicated that for each 10° of angle of resection the resultant LLD equates approximately to multiples of 4 mm, 8 mm and 12 mm in the three age groups, respectively. Statistical testing of the 59 patients who had a complete set of pre- and post-operative standing long leg radiographs, revealed a Pearson's correlation coefficient for predicted versus radiologically observed shortening when using a wedge of either 10° or 20° of 0.93 (p < 0.001). The 95% limits of agreement from the Bland-Altman analysis for this subgroup were -3.5 mm to +3.3 mm. It has been accepted that a 10 mm discrepancy is clinically acceptable. This study identified a geometric model that provided satisfactory accuracy when using specific saw blades of known thicknesses for this formula to be used in clinical practice. | 25,086,131 | [
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Toker cells of the nipple are commonly associated with underlying sebaceous glands but not with lactiferous ducts. | Toker cells are clear cells present in the squamous epithelium of the nipple of some women. In contrast to squamous epithelium, they are cytokeratin 7 (CK7) positive. The origin of these cells is not completely understood. It has been suggested that they may represent abortive glands or migratory ductal cells; and may be precursors of Paget's disease of the nipple. Our aim was to investigate the incidence and distribution of Toker cells and their relationship with lactiferous ducts. We examined nipple sections from 100 consecutive mastectomies performed at Charing Cross hospital. New sections were stained for CK7 using the immunoperoxidase technique. Toker cells were identified in 11 cases. They were always clustered within the squamous epithelium superficial to sebaceous glands with no relationship with lactiferous ducts. Two cases in the study had Paget's disease and these were not associated with underlying sebaceous glands. This study suggests that Toker cells are more likely to be developmentally related to sebaceous glands rather than lactiferous ducts. This raises doubts about the presence of a relationship between Toker cells and the common forms of Paget's disease, as the latter are commonly seen in association with ductal carcinoma in situ (DCIS) involving underlying lactiferous ducts. Toker cells, however, may be related to a less common form of Paget's disease which is not associated with underlying DCIS. | 25,086,135 | [
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Assessment of a novel module for training dental students in child abuse recognition and reporting. | This study assessed the merits of introducing a novel, online interactive training module designed to positively engage dental students and teach them to recognize and report signs of child abuse and neglect. The study aimed to determine if the online training module educated the students equivalently or better than a lecture presentation of the same content. Seventy-two students from Columbia University College of Dental Medicine's class of 2015 (90 percent of the class) agreed to participate and were randomly assigned to either a traditional lecture-based presentation or the online training module. Study participants were given a twenty-question multiple-choice pretest on their knowledge of child abuse recognition and reporting prior to the start of the study. The same instrument was administered as a posttest. At the end of the training, questionnaires were also given to both groups to assess students' perceptions of the two educational methodologies. The results showed that the interactive online training module was more effective than the lecture-based method. Results of the posttest comparison of the two groups were statistically significant (p<0.05) in favor of the online training group. Additionally, the students reported that the interactive online training module was engaging and a helpful resource, but on average they did not prefer it as a total replacement for the lecture-based approach. | 25,086,150 | [
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Effectiveness of an online tutorial on intimate partner violence for dental students: a pilot study. | This pilot study sought to determine whether New York University College of Dentistry's online tutorial on domestic violence is effective for dental students poised to embark on their professional careers. The modular program is based on the RADAR model developed by the Massachusetts Medical Society. RADAR stands for Routinely screen, Ask direct questions, Document findings, Assess patient safety, and Review options and refer as indicated. An objective and validated measure, the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS), was given pre- and post-tutorial to determine whether it impacted senior dental students' knowledge, attitudes, beliefs, and behaviors about intimate partner violence. Study participants were twenty-five senior dental students (7 percent of a class of 358) who had not received didactic instruction in domestic violence for over two years. A quasi-experimental research design was utilized. Data analysis indicated statistically significant improvements in composite scale scores on the PREMIS Perceived Preparation, Perceived Knowledge, and Actual Knowledge sections. There was a statistically significant improvement on the self-efficacy and constraint opinion scales. The other six opinion scale scores showed improved but not statistically significant scores. This online tutorial was found to be effective in increasing the participants' perceived preparation, knowledge, and self-efficacy and decreasing perceptions of provider constraints in managing victims of intimate partner violence. | 25,086,151 | [
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Utilization of blended learning to teach preclinical endodontics. | Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level. | 25,086,153 | [
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Antigen signal strength during priming determines effector CD4 T cell function and antigen sensitivity during influenza virus challenge. | TCR signal strength during priming is a key determinant of CD4 T cell activation, but its impact on effector CD4 T functions in vivo remains unclear. In this study, we compare the functionality of CD4 T cell responses induced by peptides displaying varying binding half-lives with MHC class II before and after influenza virus infection. Although significant quantitative and qualitative differences in CD4 T cell responses were observed before infection between mice vaccinated with low- or high-stability peptides, both mice mounted robust early Th1 effector cytokine responses upon influenza challenge. However, only effector CD4 T cells induced by low-stability peptides proliferated and produced IL-17A after influenza challenge. In contrast, effector T cells elicited by higher-stability peptides displayed a terminally differentiated phenotype and divided poorly. This defective proliferation was T cell intrinsic but could not be attributed to a reduced expression of lymph node homing receptors. Instead, we found that CD4 T cells stimulated with higher-stability peptides exhibited decreased responsiveness to low levels of Ag presentation. Our study reveals the critical role of TCR signal strength during priming for the function and Ag sensitivity of effector CD4 T cells during viral challenge. | 25,086,170 | [
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Mutually exclusive FGFR2, HER2, and KRAS gene amplifications in gastric cancer revealed by multicolour FISH. | Gastric cancer (GC) is a major cause of global cancer mortality. Previous genomic studies have reported that several RTK-RAS pathway components are amplified in GC, with individual tumours often amplifying one component and not others ("mutual exclusivity"). Here, we sought to validate these findings for three RTK/RAS components (FGFR2, HER2, KRAS) using fluorescence in situ hybridisation (FISH) on a series of gastric tumours, cell lines and patient-derived xenografts. Applying dual-colour FISH on 137 gastric tumours (89 FFPE surgical resections and 48 diagnostic biopsies), we observed FGFR2 amplification in 7.3% and HER2 amplification in 2.2% of GCs. GCs exhibiting FGFR2 amplification were associated with high tumour grade (p = 0.034). In FISH positive tumours, striking differences in copy number levels between cancer cells in the same tumour were observed, suggesting intra-tumour heterogeneity. Using a multicolour FISH assay allowing simultaneous detection of FGFR2, HER2, and KRAS amplifications, we confirmed that these components exhibited a mutually exclusive pattern of gene amplification across patients. The FISH data were also strongly correlated with Q-PCR levels and at the protein level by immunohistochemistry. Our data confirm that RTK/RAS components are mutually exclusively amplified in GC, and demonstrate the feasibility of identifying multiple aneuploidies using a single FISH assay. Application of this assay to GC samples, particularly diagnostic biopsies, may facilitate enrollment of GC patients into clinical trials evaluating RTK/RAS directed therapies. However, the presence of intra-tumour heterogeneity may require multiple biopsy samples to be obtained per patient before a definitive diagnosis can be attained. | 25,086,186 | [
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Parahippocampal cortex is involved in material processing via echoes in blind echolocation experts. | Some blind humans use sound to navigate by emitting mouth-clicks and listening to the echoes that reflect from silent objects and surfaces in their surroundings. These echoes contain information about the size, shape, location, and material properties of objects. Here we present results from an fMRI experiment that investigated the neural activity underlying the processing of materials through echolocation. Three blind echolocation experts (as well as three blind and three sighted non-echolocating control participants) took part in the experiment. First, we made binaural sound recordings in the ears of each echolocator while he produced clicks in the presence of one of three different materials (fleece, synthetic foliage, or whiteboard), or while he made clicks in an empty room. During fMRI scanning these recordings were played back to participants. Remarkably, all participants were able to identify each of the three materials reliably, as well as the empty room. Furthermore, a whole brain analysis, in which we isolated the processing of just the reflected echoes, revealed a material-related increase in BOLD activation in a region of left parahippocampal cortex in the echolocating participants, but not in the blind or sighted control participants. Our results, in combination with previous findings about brain areas involved in material processing, are consistent with the idea that material processing by means of echolocation relies on a multi-modal material processing area in parahippocampal cortex. | 25,086,210 | [
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Magnetic iron oxide nanoparticles induce autophagy preceding apoptosis through mitochondrial damage and ER stress in RAW264.7 cells. | Magnetic nanoparticles have been widely used in a broad range of disciplines owing to their unique properties. However, many unexpected risks have been reported in their use. In this study, we investigated the uptake process and toxic mechanism of magnetic iron oxide nanoparticles (M-FeNPs) using RAW264.7 cells, a murine peritoneal macrophage cell line. M-FeNPs markedly enhanced the mobility of cells. At 24h after exposure, M-FeNPs were located freely in the cytosol or within autolysosomes containing various organelles, especially the endoplasmic reticulum (ER). Cell viability decreased in a dose-dependent manner in conjunction with the arrest in S phase. ATP production also rapidly decreased together with mitochondrial damage, the number of cells that generate ROS increased, and the secretions of pro-inflammatory cytokines enhanced. The levels of oxidative stress- and ER stress-related genes were up-regulated, whereas the levels of transcription-related genes were down-regulated. Additionally, the levels of autophagy- and ER stress-related proteins increased, and the number of apoptotic cells increased with time. We also investigated the function of the autolysosome in the cellular response after exposure of M-FeNPs. When cells were exposed to M-FeNPs for 24h with BaFA1 pretreatment, the plasma membrane disintegrated, cytosolic components disappeared, and the number of apoptotic cells significantly increased. Taken together, these results show that M-FeNPs induce autophagy preceding apoptosis through mitochondrial dysfunction and ER stress in RAW264.7 cells. Furthermore, blocking of autolysosome formation may accelerate apoptotic cell death and ER stress. | 25,086,211 | [
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Acetaldehyde dehydrogenase 2 (ALDH2) deficiency exacerbates pressure overload-induced cardiac dysfunction by inhibiting Beclin-1 dependent autophagy pathway. | Mitochondrial aldehyde dehydrogenase 2 (ALDH2) was demonstrated to play cardioprotective roles in cardiovascular diseases. Nonetheless, little is known about the roles and mechanisms of ALDH2 in pressure overload-induced cardiac damages. In this study, we revealed that ALDH2 deficiency overtly exacerbated transverse aortic constriction (TAC)-induced cardiac dysfunction. Cardiomyocyte enlargement was observed in both WT and ALDH2-/- mice in HE-stained myocardial tissue samples at 8 weeks post TAC surgery. Mitochondrial morphology and structure were also significantly damaged post TAC surgery and the changes were aggravated in ALDH2-/- TAC hearts. ALDH2 deficiency also depressed myocardial autophagy in hearts at 8 weeks post TAC surgery with a potential mechanism of repressing the expression of Beclin-1 and promoting the interaction between Bcl-2 and Beclin-1. These data indicate that ALDH2 deficiency exacerbates the pressure overload induced cardiac dysfunction partly by inhibiting Beclin-1 dependent autophagy pathway. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. | 25,086,229 | [
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Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents. | Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines. | 25,086,238 | [
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Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection. | The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines. | 25,086,242 | [
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Longitudinal shifts in bacterial diversity and fermentation pattern in the rumen of steers grazing wheat pasture. | Grazing steers on winter wheat forage is routinely practiced in the Southern Great Plains of the US. Here, we investigated the dynamics in bacterial populations of both solid and liquid ruminal fractions of steers grazing on maturing wheat forage of changing nutritive quality. The relationship between bacterial diversity and fermentation parameters in the liquid fraction was also investigated. During the first 28 days, the wheat was in a vegetative phase with a relatively high crude protein content (CP; 21%), which led to the incidence of mild cases of frothy bloat among steers. Rumen samples were collected on days 14, 28, 56 and 76, separated into solid and liquid fractions and analyzed for bacterial diversity using 16S pyrotag technology. The predominant phyla identified were Bacteroidetes (59-77%) and Firmicutes (20-33%) across both ruminal fractions. Very few differences were observed in the rumen bacterial communities within solid and liquid fractions on day 14. However, by day 28, the relatively high CP content complemented a distinct bacterial and chemical composition of the rumen fluid that was characterized by a higher ratio (4:1) of Bacteroidetes:Firmicutes and a corresponding lower acetate:propionate (3:1) ratio. Further, a greater accumulation of biofilm (mucopolysaccharide complex) on day 28 was strongly associated with the abundance of Firmicutes lineages such as Clostridium, Ruminococcus, Oscillospira and Moryella (P<0.05) in the fiber fraction. Such changes were diminished as the CP concentration declined over the course of the study. The abundance of Firmicutes was noticeable by 76 d in both fractions which signifies the development of a core microbiome associated with digestion of a more recalcitrant fiber in the mature wheat. This study demonstrates dynamics in the rumen microbiome and their association with fermentation activity in the rumen of steers during the vegetative (bloat-prone) and reproductive stages of wheat forage. | 25,086,244 | [
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Pre-steady-state fluorescence analysis of damaged DNA transfer from human DNA glycosylases to AP endonuclease APE1. | DNA glycosylases remove the modified, damaged or mismatched bases from the DNA by hydrolyzing the N-glycosidic bonds. Some enzymes can further catalyze the incision of a resulting abasic (apurinic/apyrimidinic, AP) site through β- or β,δ-elimination mechanisms. In most cases, the incision reaction of the AP-site is catalyzed by special enzymes called AP-endonucleases. Here, we report the kinetic analysis of the mechanisms of modified DNA transfer from some DNA glycosylases to the AP endonuclease, APE1. The modified DNA contained the tetrahydrofurane residue (F), the analogue of the AP-site. DNA glycosylases AAG, OGG1, NEIL1, MBD4(cat) and UNG from different structural superfamilies were used. We found that all DNA glycosylases may utilise direct protein-protein interactions in the transient ternary complex for the transfer of the AP-containing DNA strand to APE1. We hypothesize a fast "flip-flop" exchange mechanism of damaged and undamaged DNA strands within this complex for monofunctional DNA glycosylases like MBD4(cat), AAG and UNG. Bifunctional DNA glycosylase NEIL1 creates tightly specific complex with DNA containing F-site thereby efficiently competing with APE1. Whereas APE1 fast displaces other bifunctional DNA glycosylase OGG1 on F-site thereby induces its shifts to undamaged DNA regions. Kinetic analysis of the transfer of DNA between human DNA glycosylases and APE1 allows us to elucidate the critical step in the base excision repair pathway. | 25,086,253 | [
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Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. | Thromboembolic complications remain one of the most severe adverse events associated with catheter ablation of atrial fibrillation (AF), but data on such events are limited. The purpose of this study was to evaluate the incidence, characteristics, and risk factors of thromboembolic complications after AF ablation. Cerebral thromboembolic complications occurring within 1 month of 3360 consecutive AF radiofrequency catheter ablations were assessed. Stroke was defined as a neurologic deficit lasting more than 24 hours or with imaging study showing new infarction. Transient ischemic attack (TIA) was defined as a deficit lasting less than 24 hours and without documented infarction. There were 17 peri-interventional cerebral thromboembolic events (0.5%). Nine cases (53%) were diagnosed as strokes and 8 (47%) as TIAs. Sixty percent of the events occurred within 48 hours after the ablation; the rest occurred within 1 week. In univariate analysis, peri-interventional thromboembolism was associated with peripheral vascular disease (P = .010), impaired left ventricular ejection fraction (P = .040), periprocedural bridging with heparin (P = .007), and previous stroke (P = .026). Multivariable analysis demonstrated that peripheral vascular disease (odds ratio [OR] 8.81, confidence interval [CI] 1.61-48.31, P = .012) and previous stroke (OR 6.13, CI 1.18-31.91, P = .031) were independent predictors. In a different model, the CHA2DS2-VASc score was associated with thromboembolism (OR 1.35, CI 1.00-1.80, P = .049). Cerebral thromboembolic complications after AF radiofrequency catheter ablation are rare. They mostly occur within 48 hours after the procedure and remain without lasting neurologic deficits in the majority of cases. Such complications are associated with peripheral vascular disease, previous stroke, and the CHA2DS2-VASc score. | 25,086,257 | [
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Comparison of the physiologic and prognostic implications of the heart rate versus the RR interval. | Heart rate (HR) and RR interval are inversely related. The purpose of this study was to determine which parameter better describes the autonomic changes that occur after exercise and which provides stronger prognostic significance. Healthy volunteers (n = 33) underwent sequential bicycle exercise tests with selective autonomic blockade during exercise to define HR and RR interval changes in recovery due to parasympathetic effect, sympathetic effect, and sympathetic-parasympathetic interaction. The prognostic significance of resting HR and RR interval was assessed in a cohort study (n = 33,781). The prognostic significance of exercise HR and RR interval and 1-minute HR and RR interval recovery was assessed in patients referred for exercise testing (n = 2387). Parasympathetic effect on HR and RR interval both increased in recovery (P < .001), while the sympathetic effect on HR declined (P < .001) and the sympathetic effect on the RR interval paradoxically increased. Significant sympathetic-parasympathetic interaction was noted with the HR analysis but not with the RR interval. Resting HR and RR interval had similar prognostic implications by age and gender. While resting and exercise HR and RR interval had similar prognostic implications, 1-minute HR recovery was a multivariate predictor of mortality (HR 0.81; 95%CI 0.69-0.95), while 1-minute RR interval recovery was not. Based on these findings, HR (and its changes) is not necessarily interchangeable with the RR interval (and its changes) in either physiologic or prognostic studies. It is important to consider underlying physiologic constraints and identify wisely which parameter (or even other transformation of these parameters) is most suitable for a given analysis. | 25,086,258 | [
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Characterization and phylogenetic identification of a species of spherical multicellular magnetotactic prokaryotes that produces both magnetite and greigite crystals. | Magnetotactic bacteria (MTB) are a group of Gram-negative bacteria synthesizing magnetic crystals that allow them aligning along magnetic field lines. They have diverse morphologies including cocci, rods, vibrio, spirilla, and multicellular magnetotactic prokaryotes (MMPs). MMPs are composed of 10-57 cells with peritrichous flagella on their outer surfaces and swim as an entire unit. Here, we describe a species of spherical MMPs isolated from intertidal sediments of Lake Yuehu (Yellow Sea, China). They were mainly found in the subsurface layer of gray-black sediments. Microscopy revealed that these spherical MMPs were 5.6 ± 0.9 μm in diameter and composed of approximately 16-32 ovoid cells with a helical arrangement and peritrichous flagellation. High-resolution transmission electron microscopy showed that the MMPs contained both bullet-shaped magnetite and irregular greigite magnetosomes that were arranged in chains or clusters. These MMPs displayed typical escape motility and negative phototaxis. The 16S rRNA genes of micromanipulation-purified spherical MMPs were cloned and sequenced. Phylogenetic analysis revealed that the MMP species was affiliated with Deltaproteobacteria and displayed >2.8% sequence divergence with respect to previously reported MMPs. This is the first phylogenetic identification of a spherical MMP that produces both magnetite and greigite magnetosomes. | 25,086,260 | [
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Vibrational spectroscopy of photosystem I. | Fourier transform infrared difference spectroscopy (FTIR DS) has been widely used to study the structural details of electron transfer cofactors (and their binding sites) in many types of photosynthetic protein complexes. This review focuses in particular on work that has been done to investigate the A₁cofactor in photosystem I photosynthetic reaction centers. A review of this subject area last appeared in 2006 [1], so only work undertaken since then will be covered here. Following light excitation of intact photosystem I particles the P700⁺A⁻(1) secondary radical pair state is formed within 100ps. This state decays within 300ns at room temperature, or 300μs at 77K. Given the short-lived nature of this state, it is not easily studied using "static" photo-accumulation FTIR difference techniques at either temperature. Time-resolved techniques are required. This article focuses on the use of time-resolved step-scan FTIR DS for the study of the P700⁺A⁻(1) state in intact photosystem I. Up until now, only our group has undertaken studies in this area. So, in this article, recent work undertaken in our lab is described, where we have used low-temperature (77K), microsecond time-resolved step-scan FTIR DS to study the P700⁺A⁻(1) state in photosystem I. In photosystem I a phylloquinone molecule occupies the A₁binding site. However, different quinones can be incorporated into the A1 binding site, and here work is described for photosystem I particles with plastoquinone-9, 2-phytyl naphthoquinone and 2-methyl naphthoquinone incorporated into the A₁binding site. Studies in which ¹⁸O isotope labeled phylloquinone has been incorporated into the A1 binding site are also discussed. To fully characterize PSI particles with different quinones incorporated into the A1 binding site nanosecond to millisecond visible absorption spectroscopy has been shown to be of considerable value, especially so when undertaken using identical samples under identical conditions to that used in time-resolved step-scan FTIR measurements. In this article the latest work that has been undertaken using both visible and infrared time resolved spectroscopies on the same sample will be described. Finally, vibrational spectroscopic data that has been obtained for phylloquinone in the A1 binding site in photosystem I is compared to corresponding data for ubiquinone in the QA binding site in purple bacterial reaction centers. This article is part of a Special Issue entitled: Vibrational spectroscopies and bioenergetic systems. | 25,086,273 | [
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Spontaneous swallowing occurs during autoresuscitation in the in situ brainstem preparation of rat. | Previous studies report that upper airway reflexes are operational during autoresuscitation from respiratory arrest. We investigated swallowing/breathing interactions, measured by recording of vagal (VNA) and phrenic nerve activities (PNA), during autoresuscitation in the in situ perfused brainstem preparation of juvenile rats. During the initial surgery, respiratory arrest was induced by exsanguination and cooling. Reperfusion (i.e. re-oxygenation and re-warming) of the brainstem circuits was associated with frequent spontaneous swallowing before resumption of respiration (n=6, 'stage 1 autoresuscitation'). When recovered, the respiratory pattern was transiently apneustic-like ('stage 2 autoresuscitation'). Spontaneous swallowing often occurred at the end of the prolonged PNA (n=9/12). Successful autoresuscitation was characterised by re-establishment of the 3 phase respiratory motor pattern and no spontaneous swallowing. Pharmacological inhibition (isoguvacine, 10 mM, 50-75 nl; n=10) of the Kölliker-Fuse nucleus (KF) mimicked stage 2 autoresuscitation. However, the frequency of spontaneous swallowing after KF inhibition did not correlate with subsequent recovery of the eupneic respiratory motor pattern. | 25,086,277 | [
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CA72-4 combined with CEA, CA125 and CAl9-9 improves the sensitivity for the early diagnosis of gastric cancer. | To determine whether the combination of tumor markers (CA72-4, CA125, CA19-9 and CEA) could increase the sensitivity and accuracy for in the diagnosis of gastric cancer (GC). This study is a retrospective analysis. A total of 426 patients, including 106 patients with GC, 149 patients with benign gastric diseases and 171 healthy people, who visited Zhejiang Xiaoshan Hospital from January 2011 to December 2013, were measured by serum markers, including CA72-4, CA125, CA19-9 and CEA. Statistical analyses including area under curve (AUC) of receiver operating characteristic (ROC) curve, and logistic regression analysis, were performed to evaluate the diagnostic value of these markers on GC. Serum levels of CA72-4, CEA, CA125 and CA19-9 were higher in the GC group than those in the benign gastric disease group and the healthy control group (P<0.005). The sensitivities of CA72-4, CEA, CA125 and CA19-9 at the recommended cut-off level for all patients were 33.0%, 25.5%, 31.1% and 38.7%, respectively. However, when all four markers were used in combination the sensitivity increased to 66.0%. But by using an optimal cut-off value, the sensitivities of all four markers for the diagnosis of GC were improved. Especially the sensitivity of CEA increased to 73.6% and the sensitivity of the combination of the tumor markers increased to 75.5%. The age and gender had no effects on the diagnostic value of these markers. With the help of optimal cut-off values based on ROC curve and logistic regression analysis, the combination of these markers could improve the sensitivity for the diagnosis of GC based on common serum tumor markers. | 25,086,284 | [
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Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ⁹-tetrahydrocannabinol administration. | Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing. Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain-computer interfaces and nonlinear neuronal models. Neurons involved in memory processing ("Functional Cell Types" or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid type-1 receptor (CB1R) partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons. WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events. z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain-computer interfaces. | 25,086,297 | [
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Comparison of statistical tests for group differences in brain functional networks. | Brain functional connectivity has been studied by analyzing time series correlations in regional brain activities based on resting-state fMRI data. Brain functional connectivity can be depicted as a network or graph defined as a set of nodes linked by edges. Nodes represent brain regions and an edge measures the strength of functional correlation between two regions. Most of existing work focuses on estimation of such a network. A key but inadequately addressed question is how to test for possible differences of the networks between two subject groups, say between healthy controls and patients. Here we illustrate and compare the performance of several state-of-the-art statistical tests drawn from the neuroimaging, genetics, ecology and high-dimensional data literatures. Both real and simulated data were used to evaluate the methods. We found that Network Based Statistic (NBS) performed well in many but not all situations, and its performance critically depends on the choice of its threshold parameter, which is unknown and difficult to choose in practice. Importantly, two adaptive statistical tests called adaptive sum of powered score (aSPU) and its weighted version (aSPUw) are easy to use and complementary to NBS, being higher powered than NBS in some situations. The aSPU and aSPUw tests can also be applied to adjust for covariates. Between the aSPU and aSPUw tests, they often, but not always, performed similarly with neither one as a uniform winner. On the other hand, Multivariate Matrix Distance Regression (MDMR) has been applied to detect group differences for brain connectivity; with the usual choice of the Euclidean distance, MDMR is a special case of the aSPU test. Consequently NBS, aSPU and aSPUw tests are recommended to test for group differences in functional connectivity. | 25,086,298 | [
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Spreading of β-lactam resistance gene (mecA) and methicillin-resistant Staphylococcus aureus through municipal and swine slaughterhouse wastewaters. | Methicillin-resistant Staphylococcus aureus (MRSA) is a potential zoonotic agent. Municipal wastewater treatment plants (WWTPs) can be reservoirs for MRSA dissemination. It is unclear, however, whether MRSA and its β-lactam resistance gene (mecA) can be spread from WWTPs that treat the wastewater of swine auction markets. The aims of the study were to compare (1) the abundance of the mecA gene in one municipal (M-) and one swine (S-) WWTP and (2) the genotypic and phenotypic characteristics of MRSA isolates from these two types of WWTPs. The concentrations of mecA gene from 96 wastewater samples were quantified using real-time quantitative polymerase chain reaction (real-time qPCR). One hundred and thirteen MRSA isolates were recovered and were characterized by antimicrobial susceptibility testing, minimum inhibitory concentrations (MICs), and staphylococcal cassette chromosome mec (SCCmec) typing. The mecA gene could be detected in all the wastewater samples. A high abundance of recovered mecA gene (2.6 × 10(1) to 1.9 × 10(4) gene copies μg(-1) of total DNA) in swine slaughterhouse wastewater implied a correspondingly high transferring/receiving potential. All MRSA isolates were multidrug resistant (MDR) and showed high MICs to different antimicrobials. The M-WWTP MRSA isolates harbored SCCmec II-IV and VII, whereas those from the S-WWTP harbored SCCmec V and IX. In conclusion, wastewater from swine slaughterhouses can make these slaughterhouses potential hotspots for the dissemination of mecA gene and MRSA, and the high MICs of MRSA from both WWTP origins may pose a health risk not only to workers but also to the general public. | 25,086,302 | [
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Host-defense peptides from skin secretions of the octoploid frogs Xenopus vestitus and Xenopus wittei (Pipidae): insights into evolutionary relationships. | The primary structures of host-defense peptides have proved useful in elucidating the evolution history of frogs. Peptidomic analysis was used to compare the diversity of host-defense peptides in norepinephrine-stimulated skin secretions from the octoploid frogs, Xenopus vestitus (Kivu clawed frog) and Xenopus wittei (De Witte's clawed frog) in the family Pipidae. Structural characterization demonstrated that the X. vestitus peptides belong to the magainin (3 peptides), peptide glycine-leucine-amide (PGLa; 4 peptides), xenopsin-precursor fragment (XPF; 1 peptide), and caerulein-precursor fragment (CPF; 5 peptides) families. The X. wittei peptides comprise magainin (4 peptides), PGLa (1 peptide), XPF (2 peptides), and CPF (7 peptides). In addition, secretions from both species contain caerulein, identical to the peptide from Xenopus laevis, but X. wittei secretions contains the novel peptide [R4K]xenopsin. The variability in the numbers of paralogs in each peptide family indicates a selective silencing of the host-defense peptide genes following the polyploidization events. The primary structures of the peptides provide insight into phylogenetic relationships among the octoploid Xenopus frogs. The data support a sister-group relationship between X. vestitus and Xenopus lenduensis, suggestive of bifurcating speciation after allopolyploidization, whereas X. wittei is more closely related to the Xenopus amieti-Xenopus andrei group suggesting a common tetraploid ancestor. Consistent with previous data, the CPF peptides showed the highest growth inhibitory activity against bacteria with CPF-W6 (GIGSLLAKAAKLAAGLV.NH2) combining high antimicrobial potency against Staphylococcus aureus (MIC=4 μM) with relatively low hemolytic activity (LC50=190 μM). | 25,086,320 | [
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Subchronic toxicity study in vivo and allergenicity study in vitro for genetically modified rice that expresses pharmaceutical protein (human serum albumin). | Genetically modified (GM) crops that express pharmaceutical proteins have become an important focus of recent genetic engineering research. Food safety assessment is necessary for the commercial development of these crops. Subchronic toxicity study in vivo and allergenicity study in vitro were designed to evaluate the food safety of the rice variety expressing human serum albumin (HSA). Animals were fed rodent diets containing 12.5%, 25.0% and 50.0% GM or non-GM rice for 90 days. The composition analysis of the GM rice demonstrated several significant differences. However, most of the differences remained within the ranges reported in the literature. In the animal study, a range of indexes including clinical observation, feed efficiency, hematology, serum chemistry, organ weights and histopathology were examined. Random changes unrelated to the GM rice exposure, within the range of historical control values and not associated with any signs of illness were observed. The results of heat stability and in vitro digestion of HSA indicated no evidence of potential allergenicity of the protein. Overall, the results of these studies suggest that the GM rice appears to be safe as a dietary ingredient when it is used at up to 50% in the diet on a subchronic basis. | 25,086,369 | [
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Physiological control of elaborate male courtship: female choice for neuromuscular systems. | Males of many animal species perform specialized courtship behaviours to gain copulations with females. Identifying physiological and anatomical specializations underlying performance of these behaviours helps clarify mechanisms through which sexual selection promotes the evolution of elaborate courtship. Our knowledge about neuromuscular specializations that support elaborate displays is limited to a few model species. In this review, we focus on the physiological control of the courtship of a tropical bird, the golden-collared manakin, which has been the focus of our research for nearly 20 years. Male manakins perform physically elaborate courtship displays that are quick, accurate and powerful. Females seem to choose males based on their motor skills suggesting that neuromuscular specializations possessed by these males are driven by female choice. Male courtship is activated by androgens and androgen receptors are expressed in qualitatively and quantitatively unconventional ways in manakin brain, spinal cord and skeletal muscles. We propose that in some species, females select males based on their neuromuscular capabilities and acquired skills and that elaborate steroid-dependent courtship displays evolve to signal these traits. | 25,086,380 | [
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Knee arthroscopic surgery is beneficial to middle-aged patients with meniscal symptoms: a prospective, randomised, single-blinded study. | There is no evidence that a knee arthroscopy is more beneficial to middle-aged patients with meniscal symptoms compared to other treatments. This randomised controlled trial aimed to determine whether an arthroscopic intervention combined with a structured exercise programme would provide more benefit than a structured exercise programme alone for middle-aged patients with meniscal symptoms that have undergone physiotherapy. 150 out of 179 eligible patients, aged 45 to 64 (mean:54 ± 5), symptom duration more than 3 months and standing X-ray with Ahlbäck grade 0, were randomised to: (1) a physiotherapy appointment within 2 weeks of inclusion that included instructions for a 3-month exercise programme (non-surgery group); or (2) the same as (1) plus, within 4 weeks of inclusion, knee arthroscopy for resection of any significant meniscal injuries (surgery group). The primary outcome was change in pain at 12 months, assessed with the Knee Injury and Osteoarthritis Outcome Score (KOOSPAIN). In the Intention-To-Treat analysis, pain at 12 months was significantly lower in the surgery than in the non-surgery group. The change in KOOSPAIN was significantly larger in the surgery than in the non-surgery group (between-group difference was 10.6 points of change; 95% CI: 3.4 to 17.7, P = 0.004). The As-Treated analysis results were consistent with the Intention-To-Treat analysis results. Middle-aged patients with meniscal symptoms may benefit from arthroscopic surgery in addition to a structured exercise programme. Patients' age or symptom history (i.e., mechanical symptoms or acute onset of symptoms) didn't affect the outcome. NCT01288768. | 25,086,401 | [
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A novel micellar per aqueous liquid chromatographic method for simultaneous determination of diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum. | A novel micellar per aqueous liquid chromatographic method was investigated to simultaneously determine diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum. Separation and determination of the analytes were performed on a Pinnacle II Cyano column as the stationary phase using the mobile phase consisted of aqueous solution (4.15×10(-2) mol/L sodium dodecyl sulfate and 0.02 mol/L sodium dihydrogen phosphate) with 10% (v/v) of 1-propanol at pH 7.0. This method was validated by linearity, lower limit of quantification, extraction recovery, stability, precision, and accuracy. The main analytical parameters were linearity (r>0.9950), intra- and inter-day precisions (intra-day RSD 2.2-3.5%, and inter-day RSD 3.7-9.5%), lower limit of quantification (20 ng mL(-1) for isosorbide mononitrate, metoprolol tartrate and diltiazem hydrochloride). The extraction recovery was 63.3% (0.1 μg/mL), 65.6% (1.0 μg/mL), and 69.5% (25 μg/mL) for isosorbide mononitrate; 65.1% (0.1 μg/mL), 69.5% (1.0 μg mL) and 73.5% (2.5 μg/mL) for metoprolol tartrate; 67.1% (0.1 μg/mL), 68.8% (1.0 μg/mL) and 73.8 % (2.5 μg/mL) for diltiazem hydrochloride. The relative error of stability was <6.4% at the room temperature for 24h, <3.8% at 4 °C for 1 week, <4.6% at -20 °C for 1 month, and <6.7% for freeze/thaw cycles (n=3). The results indicated that the proposed method was rapid, sensitive, and accurate for determination of the three antianginal drugs in human serum. The possible separation mechanism of the method was also discussed, and a model of separation mechanism for the analytes was established. | 25,086,418 | [
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Separation of porcine parvovirus from bovine serum albumin using PEG-salt aqueous two-phase system. | Vaccine production faces a challenge in adopting conventional downstream processing steps that can efficiently purify large viral particles. Some major issues that plague vaccine purification are purity, potency, and quality. The industry currently considers 30% as an acceptable virus recovery for a vaccine purification process, including all downstream processes, whereas antibody recovery from CHO cell culture is generally around 80-85%. A platform technology with an improved virus recovery would revolutionize vaccine production. In a quest to fulfill this goal, we have been exploring aqueous two-phase systems (ATPSs) as an optional mechanism to purify virus. ATPS has been unable to gain wide implementation mainly due to loss of virus infectivity, co-purification of proteins, and difficulty of polymer recycling. Non-enveloped viruses are chemically resistant enough to withstand the high polymer and salt concentrations that are required for effective ATPS separations. We used infectious porcine parvovirus (PPV), a non-enveloped, DNA virus as a model virus to test and develop an ATPS separation method. We successfully tackled two of the three main disadvantages of ATPS previously stated; we achieved a high infectious yield of 64% in a PEG-citrate ATPS process while separating out the main contaminate protein, bovine serum albumin (BSA). The most dominant forces in the separation were biomolecule charge, virus surface hydrophobicity, and the ATPS surface tension. Highly hydrophobic viruses are likely to benefit from the discovered ATPS for high-purity vaccine production and ease of implementation. | 25,086,421 | [
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Management and outcomes of malignant posterior reversible encephalopathy syndrome. | Recognition of severe forms of posterior reversible encephalopathy syndrome (PRES) has improved. Management of these patients remains challenging, particularly in patients with the combination of edema and hemorrhage. A prospective inpatient neuro-intensive care database was queried for patients with PRES. Malignant PRES was diagnosed by clinical assessments (GCS less than 8 and clinical decline despite standard medical management for elevated intracranial pressure) and radiographic criteria (edema with associated mass effect; brain hemorrhage exerting mass effect; effacement of basal cisterns, transtentorial, tonsillar, or uncal herniation). Malignant PRES was defined as: radiology studies consistent with PRES; GCS less than 8; and clinical decline despite standard elevated intracranial pressure management. Five cases were identified over a 4 year interval. The following contributing conditions were also present: chemotherapy (1), systemic lupus erythematosis (2), pregnancy (1), and methamphetamines (1). Neurocritical care interventions included: hyperosmolar therapy (5), anticonvulsants (5), management of coagulopathy (5), and ventilatory support (5). Neurosurgical interventions included: craniectomy (5), hematoma evacuation (3), and external ventricular drain (4). Brain biopsy was performed in 5 patients and was negative for vasculitis, demyelinating disease, tumor, or infection. Cyclophosphamide was administered to the two patients with SLE. With long-term follow up, all patients achieved good functional outcomes (modified Rankin score 1-2). In contrast to historical reports of high mortality rates (16-29%) for severe and hemorrhagic PRES variants, we had no fatalities and observed favorable functional outcomes with intracranial pressure monitoring and craniectomy for malignant PRES cases who fail medical ICP management. | 25,086,431 | [
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