Hypertension: empirical evidence and implications in 2014.
High blood pressure (HBP) or hypertension (HTN) is one of the leading causes of cardiovascular (CV) morbidity and mortality throughout the world. Despite this fact, there is widespread agreement that the treatment of HBP, over the last half century, has been a great achievement. However, after the release of the new Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure-8 (JNC-8) guidelines, there have been heated debates with regard to what are the most evidence-based blood pressure goals. While JNC-8 claims that the goal blood pressure for otherwise healthy patients with mild hypertension (systolic blood pressure ≥140-159 mm Hg and diastolic blood pressure ≥90-99 mm Hg) should be <140/90 mm Hg; a recent Cochrane meta-analysis is in direct conflict with these recommendations. Indeed, a 2012 Cochrane meta-analysis indicated that there is no evidence that treating otherwise healthy mild hypertension patients with antihypertensive therapy will reduce CV events or mortality. Additionally, the Cochrane meta-analysis showed that antihypertensive therapy was associated with a significant increase in withdrawal due to adverse events. Thus, the current evidence in the literature does not support the goals set by the JNC-8 guidelines. In this review we discussed the strengths and limitations of both lines of evidence and why it takes an evidence-based medication to reduce CV events/mortality (eg, how a goal blood pressure is achieved is more important than getting to the goal). As medications inherently cause side effects and come at a cost to the patient, the practice of evidence-based medicine becomes exceedingly important. Although the majority of HTN studies claim great advantages by lowering HBP, this review finds severe conflicts in the findings among the various HTN studies, as well as serious epistemological, methodological and statistical problems that cast doubt to such claims.


QM/MM simulations as an assay for carbapenemase activity in class A β-lactamases.
Carbapenems, 'last resort' antibiotics for many bacterial infections, can now be broken down by several class A β-lactamases (i.e. carbapenemases). Here, carbapenemase activity is predicted through QM/MM dynamics simulations of acyl-enzyme deacylation, requiring only the 3D structure of the apo-enzyme. This may assist in anticipating resistance and future antibiotic design.


The protective effect of 17β-estradiol against hydrogen peroxide-induced apoptosis on mesenchymal stem cell.
This study was designed to investigate the function of 17β-estradiol (17β-E2) against oxidative stress on the cell death of mice bone marrow mesenchymal stem cells (BMSCs) induced by hydrogen peroxide (H₂O₂). BMSCs were treated with 17β-E2 for 24h and then treated with 100μM H₂O₂ for 1h. Cell viability, apoptosis, caspase-9 mRNA, JNKs (Jun N-terminal kinases) and c-Jun protein expression in BMSCs were evaluated. Cell apoptosis of BMSCs were increased in a dose-dependent manner after treated with H₂O₂ compared to control group. But pretreatment with 17β-E2 can inhibit apoptosis of BMSCs, preserve the mitochondrial transmembrane potential, decrease caspase-9 mRNA, JNK1/2 and c-Jun protein expression. In conclusion, 17β-E₂ exerts antiapoptotic effects in BMSCs which related to the mitochondria death pathway and JNKs pathway. The study revealed that 17β-E₂ can reduce the donor stem cells damage.


Efficacy of the investigational echinocandin ASP9726 in a guinea pig model of invasive pulmonary aspergillosis.
ASP9726 is an investigational echinocandin with in vitro activity against Aspergillus species. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1 → 3)-β-D-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1 → 3)-β-D-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.


Machine Learning and Natural Language Processing for Geolocation-Centric Monitoring and Characterization of Opioid-Related Social Media Chatter.
Automatic curation of consumer-generated, opioid-related social media big data may enable real-time monitoring of the opioid epidemic in the United States. To develop and validate an automatic text-processing pipeline for geospatial and temporal analysis of opioid-mentioning social media chatter. This cross-sectional, population-based study was conducted from December 1, 2017, to August 31, 2019, and used more than 3 years of publicly available social media posts on Twitter, dated from January 1, 2012, to October 31, 2015, that were geolocated in Pennsylvania. Opioid-mentioning tweets were extracted using prescription and illicit opioid names, including street names and misspellings. Social media posts (tweets) (n = 9006) were manually categorized into 4 classes, and training and evaluation of several machine learning algorithms were performed. Temporal and geospatial patterns were analyzed with the best-performing classifier on unlabeled data. Pearson and Spearman correlations of county- and substate-level abuse-indicating tweet rates with opioid overdose death rates from the Centers for Disease Control and Prevention WONDER database and with 4 metrics from the National Survey on Drug Use and Health for 3 years were calculated. Classifier performances were measured through microaveraged F1 scores (harmonic mean of precision and recall) or accuracies and 95% CIs. A total of 9006 social media posts were annotated, of which 1748 (19.4%) were related to abuse, 2001 (22.2%) were related to information, 4830 (53.6%) were unrelated, and 427 (4.7%) were not in the English language. Yearly rates of abuse-indicating social media post showed statistically significant correlation with county-level opioid-related overdose death rates (n = 75) for 3 years (Pearson r = 0.451, P < .001; Spearman r = 0.331, P = .004). Abuse-indicating tweet rates showed consistent correlations with 4 NSDUH metrics (n = 13) associated with nonmedical prescription opioid use (Pearson r = 0.683, P = .01; Spearman r = 0.346, P = .25), illicit drug use (Pearson r = 0.850, P < .001; Spearman r = 0.341, P = .25), illicit drug dependence (Pearson r = 0.937, P < .001; Spearman r = 0.495, P = .09), and illicit drug dependence or abuse (Pearson r = 0.935, P < .001; Spearman r = 0.401, P = .17) over the same 3-year period, although the tests lacked power to demonstrate statistical significance. A classification approach involving an ensemble of classifiers produced the best performance in accuracy or microaveraged F1 score (0.726; 95% CI, 0.708-0.743). The correlations obtained in this study suggest that a social media-based approach reliant on supervised machine learning may be suitable for geolocation-centric monitoring of the US opioid epidemic in near real time.


Effects of chlordecone on 20-hydroxyecdysone concentration and chitobiase activity in a decapod crustacean, Macrobrachium rosenbergii.
Chlordecone (CLD) is an organochlorine insecticide abundant in aquatic environment of the French West Indies. However, few studies have investigated its impact on freshwater invertebrates. Whereas CLD is suspected of inducing endocrine disruption, this work aimed to study the effects of environmentally relevant concentrations of CLD on the 20-hydroxyecdysone (20-HE) hormone concentration and on the chitobiase activity, both having key roles in the molting process of crustaceans. In addition, the bioaccumulation of CLD was measured in the muscle tissue of Macrobrachium rosenbergii to underline potential dose-response relationship. The results have shown that CLD was bioaccumulated in exposed organisms according to a trend to a dose-response relationship. Moreover, it was observed that CLD decreased the 20-HE concentration in exposed prawns when compared to control, whatever the duration of exposure, as well as it inhibited the chitobiase activity after 30days of exposure. The present study indicates that CLD could interfere with molting process of M. rosenbergii by disturbing the 20-HE concentration and the activity of chitobiase, suggesting consequences at the long term on the shrimp development. This study also confirmed that CLD could be an endocrine disruptor in decapod crustaceans, as it was already observed in vertebrates.


Dimensional and Structural Control of Silica Aerogel Membranes for Miniaturized Motionless Gas Pumps.
With growing public interest in portable electronics such as micro fuel cells, micro gas total analysis systems, and portable medical devices, the need for miniaturized air pumps with minimal electrical power consumption is on the rise. Thus, the development and downsizing of next-generation thermal transpiration gas pumps has been investigated intensively during the last decades. Such a system relies on a mesoporous membrane that generates a thermomolecular pressure gradient under the action of an applied temperature bias. However, the development of highly miniaturized active membrane materials with tailored porosity and optimized pumping performance remains a major challenge. Here we report a systematic study on the manufacturing of aerogel membranes using an optimized, minimal-shrinkage sol-gel process, leading to low thermal conductivity and high air conductance. This combination of properties results in superior performance for miniaturized thermomolecular air pump applications. The engineering of such aerogel membranes, which implies pore structure control and chemical surface modification, requires both chemical processing know-how and a detailed understanding of the influence of the material properties on the spatial flow rate density. Optimal pumping performance was found for devices with integrated membranes with a density of 0.062 g cm(-3) and an average pore size of 142.0 nm. Benchmarking of such low-density hydrophobic active aerogel membranes gave an air flow rate density of 3.85 sccm·cm(-2) at an operating temperature of 400 °C. Such a silica aerogel membrane based system has shown more than 50% higher pumping performance when compared to conventional transpiration pump membrane materials as well as the ability to withstand higher operating temperatures (up to 440 °C). This study highlights new perspectives for the development of miniaturized thermal transpiration air pumps while offering insights into the fundamentals of molecular pumping in three-dimensional open-mesoporous materials.


Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior?
Paracetamol formulations provide effective analgesia after surgery [Duggan ST, Scott LJ. Intravenous paracetamol (acetominophen). Drugs 2009; 69: 101-13; Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev 2008: CD004602]. I.V. paracetamol is superior to oral for pain rescue (Jarde O, Boccard E. Parenteral versus oral route increases paracetamol efficacy. Clin Drug Invest 1997; 14: 474-81). By randomized, double-blinded trial, we aimed to determine whether preoperative oral paracetamol provides inferior postoperative analgesia to preoperative i.v. paracetamol. One hundred and thirty participants received either oral paracetamol and i.v. placebo (Group OP), or oral placebo and i.v. paracetamol (Perfalgan™) (Group IP). Oral preparations were given at least 45 min before surgery; i.v. preparations after induction of anaesthesia. Pain was assessed by a 100 mm visual analogue scale (VAS) 1 h from the end of surgery. Rescue analgesia was given on request. A total of 128 patients completed the study. There were no significant differences in baseline characteristics or intraoperative variables between the groups. The study was designed to reveal whether OP is inferior to IP, with an inferiority margin of 20%. The number of patients reporting satisfactory analgesia at 1 h with VAS ≤ 30 mm were 15 (OP) and 17 (IP), respectively. The secondary outcome measure of the mean (standard deviation) VAS (mm) for the whole of each group was 52 (22) for OP and 47 (22) for IP. Analysis of confidence intervals indicates that oral paracetamol is not inferior to i.v. paracetamol. The median survival (90% CI) to rescue analgesia request was 54.3 (51.2-57.4) min in Group OP and 57.3 (55.4-59.2) min in Group IP; there was no significant difference in this measure. In this study of lower third molar extraction, oral paracetamol is not inferior to i.v. for postoperative analgesia. ISRCTN Registration http://www.controlled-trials.com/ISRCTN77607163.


Psychosocial predictors of children's oral health-related quality of life during transition to secondary school.
Dental conditions have the potential to impact negatively on children's oral health-related quality of life (OHRQoL). However, little attempt has been made to investigate how psychosocial variables and significant life events affect children's OHRQoL. This research aimed to explore how children's dental status, coping, and self-esteem influenced OHRQoL during transition to secondary school. All patients were undergoing treatment at a UK Dental Hospital. Self-report questionnaires obtained psychosocial data on self-esteem, coping styles and OHRQoL and were completed by children 3 months prior to secondary school entry and 3 months following educational transition. Data were extracted from the clinical records of the paediatric patients who agreed to participate in the research. A total of 92 children aged between 10 and 11 years participated at baseline (43% response rate) and 71 of these children participated in the follow-up investigation (77% response rate). Multiple lagged regression analyses revealed that clinical variables and children's self-perception of their physical appearance were significant predictors of OHRQoL following transition to secondary school. Children who were satisfied with their physical appearance reported fewer impacts on their OHRQoL. The mechanisms through which this domain of self-esteem impacts on OHRQoL warrants further investigation.


Strength and body composition changes in recreationally strength-trained individuals: comparison of one versus three sets resistance-training programmes.
The purpose of this study was to determine the effects of increasing the volume of weight-training from one to three sets upon body composition and muscular strength. Sixteen male weight-trainers volunteered to act as subjects and were randomly assigned to one of two training groups. Supervised weight-training targeting the upper body was conducted three times per week for eight weeks using one set (n = 8) or three sets (n = 8) of six repetitions to fatigue. Subjects were measured before and after the training intervention for (1) strength performance (N and kg) and (2) adiposity (sum of seven skinfold thicknesses in mm). Both training groups improved significantly (20.7%) in terms of muscular strength (P < 0.05) with no differences being observed between the one set (21.98% increase) and three set group (20.71% increase) after the training interventions (P > 0.05). Significant decreases were also observed for skinfold measures in the one set group (P < 0.05). One set of high intensity resistance training was as effective as three sets for increasing the strength of muscle groups in the upper body. The one set protocol also produced significantly greater decreases in adiposity.


Statistics of time-dependent rupture of single ds-DNA.
Double-stranded (ds-) DNA molecules were stretched and ruptured on molecularly modified graphite surfaces with a scanning force microscope (SFM) exerting a force parallel to the surface. The stretching force was either large enough to break the molecule immediately or compensated by the elastic restoring force of the DNA backbone, which stabilized the molecular length. However, the size-stabilized molecules broke gradually from longer molecules to shorter ones with time. The breakage of different lengths of stabilized molecules was recorded in order to study time-dependent mechanical properties of the molecules under constant forces. From these data, a relatively high rate constant, k0 = (2.2 ± 0.1) × 10(-7) s(-1), was calculated. Moreover, we found a nonlinear stress-strain dependence of DNA on the surface which we attributed to DNA conformational transition. Assuming that the structural transition on the surface is similar to that in solution we estimated the forces needed to stretch the molecules and thereby verify the estimation of the activation energy barrier.


Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain.
A novel mouse homeobox-containing gene, Nkx-2.2, has been isolated. Nkx-2.2 is a member of a family of genes whose homeodomains are homologous to that of the Drosophila NK-2 gene. Nkx-2.2 transcripts are found in localized domains of the brain during mouse embryogenesis. Nkx-2.2 expression in the brain abuts and partially overlaps with the expression domains of two other related homeobox-containing genes, TTF-1 and Dlx. The expression domains of the three genes in the developing prosencephalon coincide with anatomical boundaries, particularly apparent in the diencephalon. This result raises the possibility that these genes may specify regional differentiation of the developing diencephalon into its anatomically and functionally defined subregions. Nkx-2.2 may be involved in specifying diencephalic neuromeric boundaries.


Characterization of soybean genomic features by analysis of its expressed sequence tags.
We analyzed 314,254 soybean expressed sequence tags (ESTs), including 29,540 from our laboratory and 284,714 from GenBank. These ESTs were assembled into 56,147 unigenes. About 76.92% of the unigenes were homologous to genes from Arabidopsis thaliana ( Arabidopsis). The putative products of these unigenes were annotated according to their homology with the categorized proteins of Arabidopsis. Genes corresponding to cell growth and/or maintenance, enzymes and cell communication belonged to the slow-evolving class, whereas genes related to transcription regulation, cell, binding and death appeared to be fast-evolving. Soybean unigenes with no match to genes within the Arabidopsis genome were identified as soybean-specific genes. These genes were mainly involved in nodule development and the synthesis of seed storage proteins. In addition, we also identified 61 genes regulated by salicylic acid, 1,322 transcription factor genes and 326 disease resistance-like genes from soybean unigenes. SSR analysis showed that the soybean genome was more complex than the Arabidopsis and the Medicago truncatula genomes. GC content in soybean unigene sequences is similar to that in Arabidopsis and M. truncatula. Furthermore, the combined analysis of the EST database and the BAC-contig sequences revealed that the total gene number in the soybean genome is about 63,501.


A methodological study for the multifactorial assessment of motor adaptation: Integration of kinematic and neural factors.
The aim of this work was to design a multimodal approach for the investigation of the different factors Motor Learning involves (e.g. planning, execution, correction, …). Attention was focused onto the issue of Motor Adaptation (MA), which takes place when learning of a partially (but not completely) new motor strategy is needed. We hereby present a report about the methodological set-up which has been developed and tested for the investigation of motor adaptation during repetitive pointing tasks. We exploited the potentialities of the combined use of electroencephalographic and motion analysis techniques to find possible relation between the activity of the central nervous system and the neuro-musculo-skeletal one. The adaptation-related changes in oscillatory brain activity and movement kinematics were monitored during a visually-guided, feedback-controlled, sequence of pointing tasks. Our preliminary results suggest that the proposed protocol: (i) can discern modifications of brain activity in the alpha and beta frequency bands; (ii) is sensible to kinematic alterations; and, (iii), allows a quantitative evaluation of performance in terms of both final result and motor patterns. In this work we identified a bunch of possible neuro-motor biomarkers, which we propose as possible indicators of adaptation.


Tissue dynamics spectroscopy for phenotypic profiling of drug effects in three-dimensional culture.
Coherence-gated dynamic light scattering captures cellular dynamics through ultra-low-frequency (0.005-5 Hz) speckle fluctuations and Doppler shifts that encode a broad range of cellular and subcellular motions. The dynamic physiological response of tissues to applied drugs is the basis for a new type of phenotypic profiling for drug screening on multicellular tumor spheroids. Volumetrically resolved tissue-response fluctuation spectrograms act as fingerprints that are segmented through feature masks into high-dimensional feature vectors. Drug-response clustering is achieved through multidimensional scaling with simulated annealing to construct phenotypic drug profiles that cluster drugs with similar responses. Hypoxic vs. normoxic tissue responses present two distinct phenotypes with differentiated responses to environmental perturbations and to pharmacological doses.


pH dependent octanol-water partitioning coefficients of microcystin congeners.
Hazardous algal blooms can generate toxic compounds with significant health impacts for exposed communities. The ubiquitous class of algal toxins known as microcystins exhibits significant heterogeneity in its peptide structure, which has been minimally studied, given the significant impact this has on hydrophobicity, acid/base character and related environmental fate and health effects. Octanol-water partition coefficients for the microcystin congeners MCLR, MCRR, MCLY, MCLF, and MCLA were calculated over an environmentally and physiologically relevant pH range. Microcystin-LR log(Kow) partition coefficient values were found to be consistent with previously established literature values, 1.67 to -1.41 between pH 1 and 8. Microcystin RR was found to be pH insensitive with a log(Kow) of -0.7. The remaining congeners exhibit similar pH dependence as MCLR, with systematic increases in hydrophobicity driven by the introduction of more hydrophobic residues to their variable amino acid region. The variation in pH dependent hydrophobicity suggests increased propensity for bioaccumulation and alternate environmental fates for differing microcystin forms, requiring further investigation.


Differential expression of MAG, MBP and L1 in the developing lateral superior olive.
The aim of this study was to investigate whether glial-associated molecules exhibit a pattern of expression that could influence oriented dendrite outgrowth in the gerbil lateral superior olive (LSO). In particular, we have previously noted that axon fascicles are oriented parallel to isofrequency laminae in the medial limb of the LSO, as are LSO dendrites, a phenotype that emerges postnatally. Therefore, we examined the immunocytochemical staining pattern of antibodies directed against three proteins that are found along axons: myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and neuron-glia cell adhesion molecule (L1). MAG staining was first observed at postnatal day (P) 4 on the axon fibers surrounding the LSO. By P7 there was a differential pattern of MAG staining within the LSO, and immunopositive fibers were observed solely in the medial limb (e.g., high frequency projection region). Between P7 and P12, MAG staining was restricted largely to fascicles in the medial limb, and these were oriented parallel to the isofrequency axes. Few positive fibers of irregular orientation were observed in the lateral limb (e.g., low frequency projection region). Significant MAG-staining was not observed in the lateral limb until P15. The MAG immunoreactivity extended throughout the LSO by P21, although it was no longer restricted to axon fascicles. In contrast, MBP-positive fibers were uniformly distributed within the LSO by P12. Finally, L1 was found on oriented axon fascicles at P0, but became sparsely distributed throughout the LSO neuropil after P7, and was restricted to neuron cell bodies in the adult. Taken together, the results suggest that oriented axon fascicles bearing MAG and L1 may contribute to the developmental refinement of dendrite and axon arbors within the LSO.


Lessons learnt from incidents reported by postgraduate trainees in Dutch general practice. A prospective cohort study.
There is an inherent tension between allowing trainees in general practice (GP) to feel comfortable to report and learn from errors in a blame-free environment while still assuring high-quality and safe patient care. Unfortunately, little is known about the types and potential severity of incidents that may confront GP trainees. Furthermore, incident reporting by resident trainees is hindered by their concern that such transparency might result in more negative performance evaluations. To explore the number and nature of incidents that were reported by GP trainees and to determine whether there were differences between the reporters and non-reporters based on their performance evaluations. Prospective cohort study. Confidential and voluntary incident reporting was implemented in GP vocational training of the University Medical Center Utrecht, the Netherlands. Seventy-nine GP trainees were asked to report incidents over 6 months. Mixed methods were used to analyse the data. 24 trainees reported a total of 44 incidents. 23 incidents concerned the work process and 17 concerned problems with diagnosis or therapy. Three-quarters (34/44) of incidents were determined to be not specifically related to the inexperience of the GP trainees. While actual patient harm was determined to be minimal or absent in two-thirds of incidents (29/44), the potential for moderate, major, or catastrophic harm was 89% (39/44). Trainees performing best on their performance assessment in the domain of clinical expertise reported incidents more often (43% vs 18%, p<0.03) than those who performed at a lower level. GP trainees rated highly by their faculty voluntarily reported incidents in the delivery of clinical care when given a safe, blame-free, and confidential reporting process. Most incidents were not found to be directly related to the inexperience of the trainee, but were caused by failing organisational processes in the healthcare delivery system. Moreover, the trainees who tended to report these incidents were those whose performance was highly evaluated in the domain of clinical expertise.


The effects of limiting punitive damage awards.
In response to concerns that jury awards in tort cases are excessive and unpredictable, nearly every state legislature has enacted some version of tort reform that is intended to curb extravagant damage awards. One of the most important and controversial reforms involves capping (or limiting) the maximum punitive damage award. We conducted a jury analogue study to assess the impact of this reform. In particular, we examined the possibility that capping punitive awards would cause jurors to inflate their compensatory awards to satisfy their desires to punish the defendant, particularly in situations where the defendant's conduct was highly reprehensible. Relative to a condition in which punitive damages were unlimited, caps on punitive damages did not result in inflation of compensatory awards. However, jurors who had no option to award punitive damages assessed compensatory damages at a significantly higher level than did jurors who had the opportunity to do so. We discuss the policy implications of these findings.


In-office biopsy of upper airway lesions: safety, tolerance, and effect on time to treatment.
Definitive tissue diagnosis for lesions warranting biopsy is shifting from the operating room to the office. Safety, tolerance, factors related to successful biopsy, and time to treatment are not well-defined. Retrospective review of 116 patients undergoing in-office biopsy of oropharynx, larynx, or hypopharynx were included. Logistic regression determined if demographics, site, T-stage, or approach (transoral/transnasal) were related to success. Time to definitive treatment was also analyzed. Ninety-two transnasal and 24 transoral biopsies were performed on 73 laryngeal, 35 oropharyngeal, and 8 hypopharyngeal lesions. Of those, 97 of 116 diagnoses were made in-office. There were no complications; two patients did not tolerate the procedure. Success was not related to age (P = 0.374), site (P = 0.527), T-stage (P = 0.587), or approach (P = 0.566). Time to treatment was 24.2 ± 13.9 days with successful office biopsy and 48.8 ± 49.4 days without. High procedural completion rate was observed across patients, sites, and approaches. All patients should be considered for in-office biopsy, a more time- and cost-effective option leading to earlier treatment.


Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.
Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.


A Qualitative Study on Gendered Barriers to Livestock Vaccine Uptake in Kenya and Uganda and Their Implications on Rift Valley Fever Control.
Rift Valley fever (RVF) is a zoonotic disease of great public health and economic importance transmitted by mosquitoes. The main method of preventing the disease is vaccination of susceptible livestock before outbreaks occur. Studies on RVF vaccines have focused on the production processes, safety, and efficacy standards but those on uptake and adoption levels are rare. This study sought to understand the barriers faced by men and women farmers in the uptake of livestock vaccines to inform strategies for optimizing the use of vaccines against RVF in East Africa. The cross-sectional qualitative study utilized the pairwise ranking technique in sex disaggregated focus group discussions to identify and rank these barriers. Results indicate that men and women farmers experience barriers to vaccine uptake differentially. The barriers include the direct and indirect cost of vaccines, distances to vaccination points, availability of vaccination crushes, intra-household decision making processes and availability of information on vaccination campaigns. The study concludes that vaccine provision does not guarantee uptake at the community level. Hence, these barriers should be considered while designing vaccination strategies to enhance community uptake because vaccine uptake is a complex process which requires buy-in from men and women farmers, veterinary departments, county/district and national governments, and vaccine producers.


Resonant modes of 12-fold symmetric defect free photonic quasicrystal.
This work investigates the resonant modes of a 12-fold symmetric defect free photonic quasicrystal (PQC) nanorod array using finite difference time domain (FDTD) simulation. Localized modes can exist in PQC without introducing defects due to the lack of translational symmetry. The resonant modes of the unit cell PQC and the one time expanded PQC from unit cell are systematically examined. The resonant spectrum is that of a single rod modified by the interaction among PQC nanorods. The mode confinement is contributed by guided resonance and destructive interference scattering. The self-scaling similarity of resonant spectrum and mode profile are also investigated.


Factors associated with less-than-full-time working in medical practice: results of surveys of five cohorts of UK doctors, 10 years after graduation.
The greater participation of women in medicine in recent years, and recent trends showing that doctors of both sexes work fewer hours than in the past, present challenges for medical workforce planning. In this study, we provide a detailed analysis of the characteristics of doctors who choose to work less-than-full-time (LTFT). We aimed to determine the influence of these characteristics on the probability of working LTFT. We used data on working patterns obtained from long-term surveys of 10,866 UK-trained doctors. We analysed working patterns at 10 years post-graduation for doctors of five graduating cohorts, 1993, 1996, 1999, 2000 and 2002 (i.e. in the years 2003, 2006, 2009, 2010 and 2012, respectively). We used multivariable binary logistic regression models to examine the influence of a number of personal and professional characteristics on the likelihood of working LTFT in male and female doctors. Across all cohorts, 42 % of women and 7 % of men worked LTFT. For female doctors, having children significantly increased the likelihood of working LTFT, with greater effects observed for greater numbers of children and for female doctors in non-primary care specialties (non-GPs). While >40 % of female GPs with children worked LTFT, only 10 % of female surgeons with children did so. Conversely, the presence of children had no effect on male working patterns. Living with a partner increased the odds of LTFT working in women doctors, but decreased the odds of LTFT working in men (independently of children). Women without children were no more likely to work LTFT than were men (with or without children). For both women and men, the highest rates of LTFT working were observed among GPs (~10 and 6 times greater than non-GPs, respectively), and among those not in training or senior positions. Family circumstances (children and partner status) affect the working patterns of women and men differently, but both sexes respond similarly to the constraints of their clinical specialty and seniority. Thus, although women doctors comprise the bulk of LTFT workers, gender is just one of several determinants of doctors' working patterns, and wanting to work LTFT is evidently not solely an issue for working mothers.


Analysis of transcriptional regulation of tetracycline responsive genes in Brugia malayi.
The Wolbachia endosymbiont of the human filarial parasites is necessary for parasite reproduction, making it an attractive chemotherapeutic target. Previous studies have demonstrated that mRNA levels of several nuclearly encoded genes are altered as a result of exposure to antibiotics that eliminate the endosymbiont, suggesting that they may be involved in maintaining the parasite-endosymbiont relationship. Here, we tested the hypothesis that the increase in mRNA levels of certain nuclearly encoded genes of Brugia malayi in response to tetracycline treatment involved specific regulatory elements present in the promoters of these genes. The promoters of three such genes (BmRPL13, BmRPS4 and BmHSP70) were tested for tetracycline responsiveness utilizing a homologous transient transcription system. Reporter gene expression driven by all three promoters was up-regulated in transfected embryos exposed to tetracycline. Substitution mutagenesis was employed to map the cis-acting elements responsible for this response in the BmHSP70 promoter. Tetracycline responsiveness was found to be distinct from the cis-acting elements involved in regulating the stress response from the BmHSP70 promoter; rather, tetracycline responsiveness was mediated by a TATAA-box like element. This study represents the first demonstration of small molecule-mediated gene regulation of a native B. malayi promoter.


Nicotine dependence phenotype and lung cancer risk.
A behavioral phenotype that characterizes nicotine dependence, the time to first cigarette after waking, is hypothesized to increase the risk of lung cancer. A case-control study of histologically confirmed lung cancer was conducted. The current analysis included 4775 lung cancer cases and 2835 controls who were regular cigarette smokers. Compared with subjects who smoked their first cigarette > 60 minutes after waking, the pack-years-adjusted odds ratio was 1.31 (95% confidence interval [95% CI], 1.11-1.54) for subjects who smoked 31 minutes to 60 minutes after waking and 1.79 (95% CI, 1.56-2.07) for subjects who smoked within 30 minutes of waking. The risk estimates were similar when smoking was modeled as total years, smoking status (current vs former), number of cigarettes smoked per day, years since quitting, and excess odds ratio. The findings were consistent for all histologic types of lung cancer. The findings of the current study indicate that a specific nicotine dependence phenotype that is associated with the amount of smoke uptake per cigarette is independently associated with lung cancer risk. These findings may help to identify high-risk individuals who would benefit from targeted interventions.


Use of interrupted time series analysis in evaluating health care quality improvements.
Interrupted time series (ITS) analysis is arguably the strongest quasi-experimental research design. ITS is particularly useful when a randomized trial is infeasible or unethical. The approach usually involves constructing a time series of population-level rates for a particular quality improvement focus (eg, rates of attention-deficit/hyperactivity disorder [ADHD] medication initiation) and testing statistically for a change in the outcome rate in the time periods before and time periods after implementation of a policy/program designed to change the outcome. In parallel, investigators often analyze rates of negative outcomes that might be (unintentionally) affected by the policy/program. We discuss why ITS is a useful tool for quality improvement. Strengths of ITS include the ability to control for secular trends in the data (unlike a 2-period before-and-after t test), ability to evaluate outcomes using population-level data, clear graphical presentation of results, ease of conducting stratified analyses, and ability to evaluate both intended and unintended consequences of interventions. Limitations of ITS include the need for a minimum of 8 time periods before and 8 after an intervention to evaluate changes statistically, difficulty in analyzing the independent impact of separate components of a program that are implemented close together in time, and existence of a suitable control population. Investigators must also be careful not to make individual-level inferences when population-level rates are used to evaluate interventions (though ITS can be used with individual-level data). A brief description of ITS is provided, including a fully implemented (but hypothetical) study of the impact of a program to reduce ADHD medication initiation in children younger than 5 years old and insured by Medicaid in Washington State. An example of the database needed to conduct an ITS is provided, as well as SAS code to implement a difference-in-differences model using preschool-age children in California as a comparison group.


Anti-HIV and anti-HBV activity and resistance profile of 2',3'-dideoxy-3'-thiacytidine (3TC) and its arylphosphoramidate derivative CF 1109.
A novel membrane-soluble prodrug of the 5'-monophosphate derivative of 3TC containing a phenyl group and the methyl ester of L-alanine linked to the phosphorus through a phosphoramidate bond with the primary amino moiety (designated Cf 1109) was prepared. The 3TC prodrug proved less potent an inhibitor of HIV-1 and HIV-2 replication in CEM cell cultures than 3TC, but lost only 20-fold antiviral potency in 2'-deoxycytidine kinase-deficient CEM/dCK- cells compared with a more than 2,000-fold decrease of activity of 3TC. In contrast, 3TC and Cf 1109 proved equally highly effective in inhibiting HBV release in supernatants of HBV-transfected Hep G2 2.2.15 cell cultures (50% effective concentration approximately 0.02 microM). Both compounds easily selected for highly resistant HIV-1 strains at a comparable speed of breakthrough. The mutant viruses contained an 184-Ile and/or 184-Val amino acid change in their reverse transcriptase. Our data are suggestive for a relatively poor delivery of 3TC-MP in the intact CEM cells but a remarkably high delivery of 3TC and/or 3TC-MP in the intact Hep G2 2.2.15 cells.


Patient-specific computational modeling of cortical spreading depression via diffusion tensor imaging.
Cortical spreading depression, a depolarization wave originating in the visual cortex and traveling towards the frontal lobe, is commonly accepted as a correlate of migraine visual aura. As of today, little is known about the mechanisms that can trigger or stop such phenomenon. However, the complex and highly individual characteristics of the brain cortex suggest that the geometry might have a significant impact in supporting or contrasting the propagation of cortical spreading depression. Accurate patient-specific computational models are fundamental to cope with the high variability in cortical geometries among individuals, but also with the conduction anisotropy induced in a given cortex by the complex neuronal organisation in the grey matter. In this paper, we integrate a distributed model for extracellular potassium concentration with patient-specific diffusivity tensors derived locally from diffusion tensor imaging data.


Hemotrophic mycoplasmas induce programmed cell death in red blood cells.
Hemotrophic mycoplasmas (HM) are uncultivable bacteria found on and in the red blood cells (RBCs). The main clinical sign of HM infections is the hemolytic anemia. However, anemia-inducing pathogenesis has not been totally clarified. In this work we used the splenectomized pig as animal model and Mycoplasma suis as a representative for hemotrophic mycoplasmas to study anemia pathogenesis. Eryptosis, i.e. programmed cell death of RBCs, is characterized by cell shrinkage, microvesiculation and phosphatidylserine (PS) exposure on the outer membrane. The eryptosis occurrence and its influence on anemia pathogenesis was observed over the time-course of M. suis infections in pigs using 3 M. suis isolates of differing virulence. All 3 isolates induced eryptosis, but with different characteristics. The occurrence of eryptosis could as well be confirmed in vitro: serum and plasma of an acutely ill pig induced PS exposure on erythrocytes drawn from healthy pigs. Since M. suis is able to induce eryptotic processes it is concluded that eryptosis is one anemia-inducing factor during M. suis infections and, therefore, plays a significant role in the pathogenesis of infectious anemia due to HM infection.


Evaluation of penalty design in penalized maximum-likelihood image reconstruction for lesion detection.
Detecting cancerous lesions is a major clinical application in emission tomography. Previously, we developed a method to design a shift-variant quadratic penalty function in penalized maximum-likelihood (PML) image reconstruction to improve the lesion detectability. We used a multiview channelized Hotelling observer (mvCHO) to assess the lesion detectability in three-dimensional images and validated the penalty design using computer simulations. In this study, we evaluate the benefit of the proposed penalty function for lesion detection using real patient data and artificial lesions. A high-count real patient dataset with no identifiable tumor inside the field of view is used as the background data. A Na-22 point source is scanned in air at variable locations and the point source data are superimposed onto the patient data as artificial lesions after being attenuated by the patient body. Independent Poisson noise is introduced to the high-count sinograms to generate 200 pairs of lesion-present and lesion-absent datasets, each mimicking a 5-min scan. Lesion detectability is assessed using a mvCHO and a human observer two-alternative forced choice (2AFC) experiment. The results show improvements in lesion detection by the proposed method compared with the conventional first-order quadratic penalty function and a total variation (TV) edge-preserving penalty function.


[Treatment of chronic hepatitis C].
Chronic infection with HCV represents second most common cause of end-stage liver diseases and hepatocellular carcinoma in Korea. The introduction of new agents and regimens for the treatment of chronic hepatitis C, such as pegylated forms of interferon-alpha (Peg-IFN) and combination with oral ribavirin has resulted in substantial improvement in sustained virologic response (SVR) rates. SVR rate of Peg-IFN and ribavirin combination therapy can be 40-46% of individuals infected with genotype 1 and approximately 75-85% with genotype 2 and 3. Peg-IFN/ribavirin combination therapy represents current standard therapy of chronic hepatitis C. This article reviews the treatment objectives, outcomes, optimal regimens, efficacy and predictors of response, monitoring during treatment, adverse events, retreatment of persons who failed to respond to previous treatments, and treatment of special patient groups in chronic hepatitis C.


Co-infection with Fasciola hepatica may increase the risk of Escherichia coli O157 shedding in British cattle destined for the food chain.
Escherichia coli O157 is a zoonotic bacterium that can cause haemorrhagic diarrhoea in humans and is of worldwide public health concern. Cattle are considered to be the main reservoir for human infection. Fasciola hepatica is a globally important parasite of ruminant livestock that is known to modulate its host's immune response and affect susceptibility to bacterial pathogens such as Salmonella Dublin. Shedding of E. coli O157 is triggered by unknown events, but the immune system is thought to play a part. We investigated the hypothesis that shedding of E. coli O157 is associated with F. hepatica infection in cattle. Three hundred and thirty four cattle destined for the food chain, from 14 British farms, were tested between January and October 2015. E. coli O157 was detected by immunomagnetic separation and bacterial load enumerated. F. hepatica infection status was assessed by copro-antigen ELISA. A significant association (p=0.01) was found between the log percent positivity (PP) of the F. hepatica copro-antigen ELISA and E. coli O157 shedding when the fixed effects of day of sampling and the age of the youngest animal in the group, plus the random effect of farm were adjusted for. The results should be interpreted cautiously due to the lower than predicted level of fluke infection in the animals sampled. Nevertheless these results indicate that control of F. hepatica infection may have an impact on the shedding of E. coli O157 in cattle destined for the human food chain.


Comparison of two amplification technologies for detection and quantitation of human immunodeficiency virus type 1 RNA in the female genital tract. Division of AIDS Treatment Research Initiative 009 Study Team.
Human immunodeficiency virus type 1 (HIV-1) RNA levels in female genital tract and peripheral blood samples were compared using two commercial amplification technologies: the Roche AMPLICOR HIV-1 MONITOR test and either the Organon Teknika nucleic acid sequence-based amplification (NASBA-QT) assay or the NucliSens assay. Estimates of HIV-1 RNA copy number were derived from internal kit standards and analyzed unadjusted and adjusted to a common set of external standards. We found a discordance rate of approximately 18% between the two technologies for the detection of HIV-1 in either the genital tract or peripheral blood samples. Detection discordance was not consistent among specimens or among women. There were no significant differences in adjusted or unadjusted estimates of HIV-1 RNA copy number in the genital tract samples using the AMPLICOR HIV-1 MONITOR test and either the NASBA-QT assay or the NucliSens assay. In addition, the estimated HIV-1 RNA copy number in peripheral blood samples did not differ when tested with the NucliSens assay and the AMPLICOR HIV-1 MONITOR test using kit standards. However, there was a significant difference in estimated RNA copy number between the NASBA-QT assay and the AMPLICOR HIV-1 MONITOR test for internal kit standards, which, as we have previously shown, was eliminated after adjustment with the external standards. Our results suggest that the Roche and Organon Teknika assays are equivalent for quantifying HIV-1 RNA in female genital tract specimens, although variation in detection does exist.


Characterization of translocation contact sites involved in the import of mitochondrial proteins.
Import of proteins into the mitochondrial matrix requires translocation across two membranes. Translocational intermediates of mitochondrial proteins, which span the outer and inner membrane simultaneously and thus suggest that translocation occurs in one step, have recently been described (Schleyer, M., and W. Neupert, 1985, Cell, 43:339-350). In this study we present evidence that distinct membrane areas are involved in the translocation process. Mitochondria that had lost most of their outer membrane by digitonin treatment (mitoplasts) still had the ability to import proteins. Import depended on proteinaceous structures of the residual outer membrane and on a factor that is located between the outer and inner membranes and that could be extracted with detergent plus salt. Translocational intermediates, which had been preformed before fractionation, remained with the mitoplasts under conditions where most of the outer membrane was subsequently removed. Submitochondrial vesicles were isolated in which translocational intermediates were enriched. Immunocytochemical studies also suggested that the translocational intermediates are located in areas where outer and inner membranes are in close proximity. We conclude that the membrane-potential-dependent import of precursor proteins involves translocation contact sites where the two membranes are closely apposed and are linked in a stable manner.


Effects of oviductal fluid on sperm penetration and cortical granule exocytosis during fertilization of pig oocytes in vitro.
The effects of oviductal fluid on sperm penetration and cortical granule exocytosis in pigs were examined. Cortical granule exocytosis in oocytes matured in vivo and in vitro was observed by staining with fluorescent-labelled lectin and laser-scanning confocal microscopy. Exocytosis of matured oocytes was classified into three categories after in vitro fertilization: complete cortical granule exocytosis and even distribution of exudate in the entire perivitelline space (type I); complete exocytosis and partial distribution of exudate (type II) and incomplete cortical granule exocytosis (type III). The incidence of oocytes with type I exocytosis was higher in oocytes matured in vivo than in those matured in vitro. The addition of oviductal fluid at a concentration of 1% or 10% to the fertilization medium decreased sperm penetration and the mean number of spermatozoa present in penetrated eggs. The distribution of cortical granule exudate was not different in the presence of 1% oviductal fluid after sperm penetration from that of control groups. When oocytes were cultured for 1.5 h in medium containing 10% or 30% oviductal fluid before insemination, the incidence of monospermy increased without a decrease in sperm penetration. Preculture of oocytes in medium containing 30% oviductal fluid increased type I cortical granule reaction and increased resistance of the zona pellucida to dissolution by 0.1% (w/v) pronase at the time of sperm penetration. These results suggest that a factor(s) from the oviductal secretion is required for the complete cortical granule reaction and in the modification of the zona pellucida.


The apple REFPOP-a reference population for genomics-assisted breeding in apple.
Breeding of apple is a long-term and costly process due to the time and space requirements for screening selection candidates. Genomics-assisted breeding utilizes genomic and phenotypic information to increase the selection efficiency in breeding programs, and measurements of phenotypes in different environments can facilitate the application of the approach under various climatic conditions. Here we present an apple reference population: the apple REFPOP, a large collection formed of 534 genotypes planted in six European countries, as a unique tool to accelerate apple breeding. The population consisted of 269 accessions and 265 progeny from 27 parental combinations, representing the diversity in cultivated apple and current European breeding material, respectively. A high-density genome-wide dataset of 303,239 SNPs was produced as a combined output of two SNP arrays of different densities using marker imputation with an imputation accuracy of 0.95. Based on the genotypic data, linkage disequilibrium was low and population structure was weak. Two well-studied phenological traits of horticultural importance were measured. We found marker-trait associations in several previously identified genomic regions and maximum predictive abilities of 0.57 and 0.75 for floral emergence and harvest date, respectively. With decreasing SNP density, the detection of significant marker-trait associations varied depending on trait architecture. Regardless of the trait, 10,000 SNPs sufficed to maximize genomic prediction ability. We confirm the suitability of the apple REFPOP design for genomics-assisted breeding, especially for breeding programs using related germplasm, and emphasize the advantages of a coordinated and multinational effort for customizing apple breeding methods in the genomics era.


Stability of synchrony against local intermittent fluctuations in tree-like power grids.
90% of all Renewable Energy Power in Germany is installed in tree-like distribution grids. Intermittent power fluctuations from such sources introduce new dynamics into the lower grid layers. At the same time, distributed resources will have to contribute to stabilize the grid against these fluctuations in the future. In this paper, we model a system of distributed resources as oscillators on a tree-like, lossy power grid and its ability to withstand desynchronization from localized intermittent renewable infeed. We find a remarkable interplay of the network structure and the position of the node at which the fluctuations are fed in. An important precondition for our findings is the presence of losses in distribution grids. Then, the most network central node splits the network into branches with different influence on network stability. Troublemakers, i.e., nodes at which fluctuations are especially exciting the grid, tend to be downstream branches with high net power outflow. For low coupling strength, we also find branches of nodes vulnerable to fluctuations anywhere in the network. These network regions can be predicted at high confidence using an eigenvector based network measure taking the turbulent nature of perturbations into account. While we focus here on tree-like networks, the observed effects also appear, albeit less pronounced, for weakly meshed grids. On the other hand, the observed effects disappear for lossless power grids often studied in the complex system literature.


Quantitative evaluation on activated property-tunable bulk liquid water with reduced hydrogen bonds using deconvoluted Raman spectroscopy.
Interesting properties of water with distinguishable hydrogen-bonding structure on interfacial phase or in confined environment have drawn wide attentions. However, these unique properties of water are only found within the interfacial phase and confined environment, thus, their applications are limited. In addition, quantitative evaluation on these unique properties associating with the enhancement of water's physical and chemical activities represents a notable challenge. Here we report a practicable production of free-standing liquid water at room temperature with weak hydrogen-bonded structure naming Au nanoparticles (NPs)-treated (AuNT) water via treating by plasmon-induced hot electron transfer occurred on resonantly illuminated gold NPs (AuNPs). Compared to well-known untreated bulk water (deionized water), the prepared AuNT water exhibits many distinct activities in generally physical and chemical reactions, such as high solubilities to NaCl and O2. Also, reducing interaction energy within water molecules provides lower overpotential and higher efficiency in electrolytic hydrogen production. In addition, these enhanced catalytic activities of AuNT water are tunable by mixing with deionized water. Also, most of these tunable activities are linearly proportional to its degree of nonhydrogen-bonded structure (DNHBS), which is derived from the O-H stretching in deconvoluted Raman spectrum.


Generating Causal Relations in Scientific Texts: The Long-Term Advantages of Successful Generation.
A high level of text comprehension can be achieved by engaging learners in processes of organization and integration while reading a cohesive text. In the present study, we investigated the impact of an innovative generative technique on learning with scientific texts. The cohesion generation was implemented by means of explicit cohesion gaps. High school students (n = 199) were randomly assigned to either receive a fully cohesive scientific text (control condition) or a scientific text that required the selection of causal connectives, such as because, although, therefore, or however (generation condition). Learners in the generation condition were required to reflect on causal relations to complete the text. All students were tested immediately (T1) and 2 weeks after the learning phase (T2). Cognitive load was measured by a dual task and self-report measure. Contrary to our expectations, no differences were found in performance on inference questions (situation model). Learners in the generation condition performed worse on text-based questions at T1 but showed less forgetting from T1 to T2. The impact of condition on the situation model was moderated by reading skills. Remarkably, the generation success was highly predictive for learning outcomes even when controlling for learners' proficiencies. Consequently, learners who succeeded to employ effortful processes to overcome the difficulty showed a superior performance on both the text-base and situation-model questions compared to students reading the cohesive text. Moreover, in these learners, generative activity led to a sustainable learning performance 2 weeks later. Poor readers especially took advantage of generative activity, despite struggling to perform the cohesion task as indicated by the cognitive load measures. The results suggest that the activity of generating causal relations can augment inferential processing in learners who are not involved in inferential processing spontaneously. To successfully apply this generative learning technique, students require considerable instructional support.


Intravenous Administration Errors Intercepted by Smart Infusion Technology in an Adult Intensive Care Unit.
The aim of the study was to investigate the efficacy of intravenous (IV) smart pumps with drug libraries and dose error reduction system (DERS) to intercept programming errors entailing high risk for patients in an adult intensive care unit (ICU). A 2-year retrospective study was conducted in the adult ICU of the Hospital Juárez de México in Mexico City to evaluate the impact of IV smart pump/DERS (Hospira MedNet) technology implementation. We conducted a descriptive analysis of the reports generated by the system's software from April 2014 through May 2016. Our study focused on the upper hard limit alerts and used the systems' variance reports and IV Medication Harm Index methodology to determine the severity of the averted overdoses for medications with the highest number of edits. The system monitored 124,229 infusion programs and averted on 36,942 deviations of the preset safe limits. Upper hard limit alerts accounted for 26.4% of pump reprogramming events. One hundred sixty-six significant administration errors were intercepted and prevented, and IV Medication Harm Index analysis identified 83 of them as highest-risk averted overdoses with insulin accounting for 51.8% of those. The rate of compliance with the safety software during the study period was 69.8%. Our study contributes additional evidence of the impact of IV smart pump/DERS technology. These pumps effectively intercepted severe infusion errors and significantly prevented adverse drug events related to dosing. Our results support the implementation of this technology in ICUs as a minimum safety standard and could help drive an IV infusion safety initiative in Mexico.


Prevalence and histopathological characteristics of corneal stromal dystrophies in Saudi Arabia.
The aim was to determine the frequency and describe the main histopathologic features of corneal stromal dystrophy in Saudi Arabia. A single-center, retrospective analysis of 193 corneal specimens diagnosed with stromal dystrophy. All samples were retrieved from the Histopathology Department at King Khaled Eye Specialist Hospital over a 10-year period (2002 to December 31, 2011). Cases of stromal dystrophy undergoing keratoplasty were included in the study. Routine histopathologic stains and specific stains were used to determine a diagnosis. The corresponding demographic data and basic clinical/surgical information were collected via chart review. The study sample was comprised of 193 eyes. The final diagnoses were macular corneal dystrophy (MCD) in 180 (93.26%) eyes, granular corneal dystrophy (GCD) in 9 (4.66%) and lattice corneal dystrophy (LCD) in 4 (2.07%) eyes. The mean age at presentation was 27.03 years for MCD, 26.33 years for GCD and 53.75 years for LCD. The interval between diagnosis and surgical intervention was not statistically different between the macular and granular groups (P = 0.141). There was a positive family history for the MCD (37.22%) and GCD (44.44%) groups. All eyes underwent penetrating keratoplasty (PKP) except 10 MCD cases that underwent lamellar keratoplasty. Diffuse stromal deposits were present in 87.2% of MCD corneas and 66.67% of GCD corneas. Seventeen eyes with MCD were misdiagnosed as GCD. None of the LCD cases were clinically identified since all of these cases were diagnosed as corneal scarring. In eyes with MCD that underwent PKP, there was diffuse stromal involvement (in 87.22% eyes) and changes in Descemet's membrane (in 53.5% eyes). This pathological study suggested that MCD was the most common corneal stromal dystrophy that required keratoplasty in Saudi Arabia. Patient with MCD and GCD presented at a significantly younger age than LCD. The clinical diagnosis of MCD is not achieved in all cases likely due to a more severe phenotype in the Saudi population or the presence of corneal scarring that is associated with previous trachoma, which obscures the classical appearance of LCD. We believe that PKP is first-line surgical treatment, especially for MCD because it involves all corneal layers. However, deep stromal involvement and changes in Descemet's membrane in MCD should be considered when selecting the surgical procedure.


Fabrication of orderly nanostructured PLGA scaffolds using anodic aluminum oxide templates.
In this research, two simple fabrication methods to fabricate orderly nanostructured PLGA scaffolds using anodic aluminum oxide (AAO) template were conducted. In the vacuum air-extraction approach, the PLGA solution was cast on an AAO template first. The vacuum air-extraction process was then applied to suck the semi-congealed PLGA into the nanopores of the AAO template to form a bamboo sprouts array of PLGA. The surface roughness of the nanostructured scaffolds, ranging from 20 nm to 76 nm, can be controlled by the sucking time of the vacuum air-extraction process. In the replica molding approach, the PLGA solution was cast on the orderly scraggy barrier-layer surface of an AAO membrane to fabricate a PLGA scaffold of concave nanostructure. Cell culture experiments using the bovine endothelial cells (BEC) demonstrated that the nanostructured PLGA membrane can increase the cell growing rate, especially for the bamboo sprouts array scaffolds with smaller surface roughness.


Tsetse challenge, trypanosome and helminth infection in relation to productivity of village Ndama cattle in Senegal.
Data on tsetse fly, and on village Ndama cattle collected over a 4-year period in southern Senegal, were analysed. A total of 431 Ndama cattle in four herds of three villages in the Upper Casamance area of southern Senegal were monitored monthly. Glossina morsitans submorsitans and Glossina palpalis gambiensis are present in the study area. Mean tsetse apparent density was 5.4 flies/trap/day. Trypanosome (Trypanosoma congonlense and Trypanosoma vivax) infection rate in flies was 2.4 (s.e. 0.37)%. Tsetse challenge index was 17.3 (s.e. 4.18). Mean monthly trypanosome prevalence in cattle was 2.5 (s.e. 0.51)%. Highest trypanosome prevalence occurred during the dry season, and animals less than 1-year old were more frequently infected than older animals. The linear relationship between the log10+1 tsetse challenge and the arcsine of the trypanosome prevalence was significant only when mean monthly values of these variables over the 4-year period were used with tsetse challenge preceding infection rate by 3 months. Mean monthly prevalence of strongyle, Strongyloides spp., Toxocara spp. and coccidia were 34.4 (s.e. 0.60), 2.1 (s.e. 0.18), 1.2 (s.e. 0.45) and 15.6 (s.e. 0.47)%, respectively. Calf mortality rate at 1,6 and 12 months of age was 2.1 (s.e. 2.1), 5.2 (s.e. 2.8) and 12.2 (s.e. 3.3)%, respectively. Calving interval (584 s.e. 58 days) was not influenced by trypanosome status of the cow during lactation. Calving interval was shorter by 167 days when the calf died before 1 year of age in comparison to calving intervals for which the calf survived beyond one year. Live weight at birth, 6 and 12 months of age were 15.8 (s.e. 0.54), 48.1 (s.e. 2.56) and 71.1 (s.e. 5.44) kg, respectively. Mean lactation length, total and daily milk offtake were 389 (s.e. 16) days, 231 (s.e. 15) litres and 0.69 (s.e. 0.037) litres, respectively. Trypanosome infection during lactation did not have a significant effect on the amount of milk extracted for human consumption nor did trypanosome status affect calf growth.


Selective estrogen receptor modulators (SERMs) affect cholesterol homeostasis through the master regulators SREBP and LXR.
Selective estrogen receptor modulators (SERMs) are nonsteroidal drugs that display an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs have attracted great clinical interest for the treatment of several pathologies, most notably breast cancer and osteoporosis. There is strong evidence that SERMs secondarily affect cholesterol metabolism, although the mechanism has not been fully elucidated. In this study, we analysed the effect of the SERMs tamoxifen, raloxifene, and toremifene on the expression of lipid metabolism genes by microarrays and quantitative PCR in different cell types, and ascertained the main mechanisms involved. The three SERMs increased the expression of sterol regulatory element-binding protein (SREBP) target genes, especially those targeted by SREBP-2. In consonance, SERMs increased SREBP-2 processing. These effects were associated to the interference with intracellular LDL-derived cholesterol trafficking. When the cells were exposed to LDL, but not to cholesterol/methyl-cyclodextrin complexes, the SERM-induced increases in gene expression were synergistic with those induced by lovastatin. Furthermore, the SERMs reduced the stimulation of the transcriptional activity of the liver X receptor (LXR) by exogenous cholesterol. However, their impact on the expression of the LXR canonical target ABCA1 in the presence of LDL was cell-type dependent. These actions of SERMs were independent of estrogen receptors. We conclude that, by inhibiting the intracellular trafficking of LDL-derived cholesterol, SERMs promote the activation of SREBP-2 and prevent the activation of LXR, two master regulators of cellular cholesterol metabolism. This study highlights the impact of SERMs on lipid homeostasis regulation beyond their actions as estrogen receptor modulators.


The Successful Treatment of Opioid Withdrawal-Induced Refractory Muscle Spasms with 5-HTP in a Patient Intolerant to Clonidine.
Instituting drug holidays for chronic opioid using patients is becoming commonplace for pain practitioners initiating procedures such as intrathecal pump or spinal cord stimulator trials. As such, pain practitioners need to be adept in their management of acute opioid withdrawal. Successfully weaning an opioid dependent patient off of chronic opioids requires a thorough knowledge of the available adjuvants to assist in this process. However, that selection can become exhausted by adjuvant side effects or by ineffective attenuation of opioid withdrawal symptoms. In that case, novel drugs, or novel application of currently available medications must be sought after to assist in the drug holiday. We present a case in which refractory muscle spasms secondary to opioid withdrawal were successfully treated with an over-the-counter supplement that is not typically used for the attenuation of opioid withdrawal symptoms. In a patient intolerant to the side effects of clonidine, we were able to successfully wean chronic opiates by treating refractory muscle spasms with the serotonin precursor, 5-hydroxytryptophan (5-HTP). We hypothesize that our success with this medication gives further credence to the role of serotonin in opioid withdrawal somatic symptomatology, and supports the need for future research to clarify the role of serotonin precursors or serotonin modulating drugs as potential alternatives in those unable to follow standard treatment protocols.


Developing a Set of Core Outcomes for Trials in Hemodialysis: An International Delphi Survey.
Survival and quality of life for patients on hemodialysis therapy remain poor despite substantial research efforts. Existing trials often report surrogate outcomes that may not be relevant to patients and clinicians. The aim of this project was to generate a consensus-based prioritized list of core outcomes for trials in hemodialysis. In a Delphi survey, participants rated the importance of outcomes using a 9-point Likert scale in round 1 and then re-rated outcomes in rounds 2 and 3 after reviewing other respondents' scores. For each outcome, the median, mean, and proportion rating as 7 to 9 (critically important) were calculated. 1,181 participants (202 [17%] patients/caregivers, 979 health professionals) from 73 countries completed round 1, with 838 (71%) completing round 3. Outcomes included in the potential core outcome set met the following criteria for both patients/caregivers and health professionals: median score ≥ 8, mean score ≥ 7.5, proportion rating the outcome as critically important ≥ 75%, and median score in the forced ranking question < 10. Patients/caregivers rated 4 outcomes higher than health professionals: ability to travel, dialysis-free time, dialysis adequacy, and washed out after dialysis (mean differences of 0.9, 0.5, 0.3, and 0.2, respectively). Health professionals gave a higher rating for mortality, hospitalization, decrease in blood pressure, vascular access complications, depression, cardiovascular disease, target weight, infection, and potassium (mean differences of 1.0, 1.0, 1.0, 0.9, 0.9, 0.8, 0.7, 0.4, and 0.4, respectively). The Delphi survey was conducted online in English and excludes participants without access to a computer and internet connection. Patients/caregivers gave higher priority to lifestyle-related outcomes than health professionals. The prioritized outcomes for both groups were vascular access problems, dialysis adequacy, fatigue, cardiovascular disease, and mortality. This process will inform a core outcome set that in turn will improve the relevance, efficiency, and comparability of trial evidence to facilitate treatment decisions.


Curcumin and Intestinal Inflammatory Diseases: Molecular Mechanisms of Protection.
Intestinal inflammatory diseases, such as Crohn's disease, ulcerative colitis, and necrotizing enterocolitis, are becoming increasingly prevalent. While knowledge of the pathogenesis of these related diseases is currently incomplete, each of these conditions is thought to involve a dysfunctional, or overstated, host immunological response to both bacteria and dietary antigens, resulting in unchecked intestinal inflammation and, often, alterations in the intestinal microbiome. This inflammation can result in an impaired intestinal barrier allowing for bacterial translocation, potentially resulting in systemic inflammation and, in severe cases, sepsis. Chronic inflammation of this nature, in the case of inflammatory bowel disease, can even spur cancer growth in the longer-term. Recent research has indicated certain natural products with anti-inflammatory properties, such as curcumin, can help tame the inflammation involved in intestinal inflammatory diseases, thus improving intestinal barrier function, and potentially, clinical outcomes. In this review, we explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its antimicrobial and immunomodulatory properties, as well as its potential to alter the intestinal microbiome. Curcumin may play a significant role in intestinal inflammatory disease treatment in the future, particularly as an adjuvant therapy.


An unusual clinical presentation of lupus erythematosus tumidus localized on the thigh.
A 44-year-old woman with seronegative polyarthritis presented with a 2-year history of a solitary, bluish-red, oedematous, nonscaly, annular and partially reticulated macule on her right thigh. Histopathological findings revealed perivascular and periadnexal lymphocytic infiltrate in the dermis. Alcian blue and colloidal iron stains highlighted mucinous deposit in the upper and mid dermis. Direct immunofluorescence showed a linear deposit of IgG and C3 along the basement membrane zone. Antinuclear antibody was positive at a titre of 1 : 80, with homogenous and speckled patterns. Except for its unusual localization and lack of photosensitivity, our case had the clinical and histopathological features of lupus erythematosus tumidus. These characteristics were also reminiscent of reticular erythematous mucinosis and erythema annulare centrifugum, both of which are considered to be associated with cutaneous lupus erythematosus (CLE). Hydroxychloroquine 200 mg daily led to improvement of the skin lesion. The unusual clinical presentation of our case emphasizes the heterogeneity of clinical manifestations of CLE.


Ginger ingredients inhibit the development of diethylnitrosoamine induced premalignant phenotype in rat chemical hepatocarcinogenesis model.
To investigate the possible antitumor activity of ginger extract against hepatic carcinogenesis initiated by diethylnitrosoamines (DEN) and promoted by carbon tetrachloride (CCl(4) ). A total of 60 male Wistar albino rats were divided into four groups with 15 animals in each group. Rats in group 1 (control group) received a single intraperitoneal (i.p.) injection of normal saline. Animals in group 2 were given ginger (50 mg/kg/day) in drinking water for 8 weeks. Rats in group 3 (DEN group) were injected with a single dose of DEN (200 mg/kg, i.p.), 2 weeks later received a single dose of CCl(4) (2 mL/kg i.g) by gavage as 1:1 dilution in corn oil. Animals in group 4 (DEN-ginger group) received the same carcinogenesis induction protocol as in group 3 plus ginger (50 mg/kg/day) in drinking water for 2 weeks before induction of hepatocarcinogenesis and continued throughout the experimental period. DEN-initiated and CCl(4) -promoted hepatocarcinogenesis in male Wistar rats was manifested biochemically by elevation of serum hepatic tumor markers tested; α-fetoprotein and carcinoembryonic antigen. In addition, hepatocarcinogenesis was further confirmed by a significant increase in hepatic tissue growth factors; vascular endothelial growth factor, basic fibroblast growth factor, and hydroxyproline content. A marked decrease in endostatin and metallothonein were also observed. Long-term ginger extract administration 2 weeks before induction of hepatocarcinogenesis and throughout the experimental period prevented the decrease of the hepatic content of metallothionein and endostatin and the increase in the growth factors induced by the carcinogen. Moreover, ginger extract normalize serum hepatic tumor markers. Histopathological examination of liver tissue also correlated with the biochemical observations. These findings suggest a protective effect of ginger extract against premalignant stages of liver cancer in the DEN-initiated and CCl(4) -promoted hepatocarcinogenesis model in rats.


A facile synthesis of highly luminescent nitrogen-doped graphene quantum dots for the detection of 2,4,6-trinitrophenol in aqueous solution.
A facile bottom-up method for the synthesis of highly fluorescent nitrogen-doped graphene quantum dots (N-GQDs) has been developed via a one-step pyrolysis of citric acid and tris(hydroxymethyl)aminomethane. The obtained N-GQDs emitted strong blue fluorescence under 365 nm UV light excitation with a high quantum yield of 59.2%. They displayed excitation-independent behavior, high resistance to photobleaching and high ionic strength. In addition to the good linear relationship between the fluorescence intensity of the N-GQDs and pH in the range 2-7, the fluorescence intensity of the N-GQDs could be greatly quenched by the addition of a small amount of 2,4,6-trinitrophenol (TNP). A sensitive approach has been developed for the detection of TNP with a detection limit of 0.30 μM, and a linearity ranging from 1 to 60 μM TNP could be obtained. The approach was highly selective and suitable for TNP analysis in natural water samples.


General n-dimensional quadrature transform and its application to interferogram demodulation.
Quadrature operators are useful for obtaining the modulating phase phi in interferometry and temporal signals in electrical communications. In carrier-frequency interferometry and electrical communications, one uses the Hilbert transform to obtain the quadrature of the signal. In these cases the Hilbert transform gives the desired quadrature because the modulating phase is monotonically increasing. We propose an n-dimensional quadrature operator that transforms cos(phi) into -sin(phi) regardless of the frequency spectrum of the signal. With the quadrature of the phase-modulated signal, one can easily calculate the value of phi over all the domain of interest. Our quadrature operator is composed of two n-dimensional vector fields: One is related to the gradient of the image normalized with respect to local frequency magnitude, and the other is related to the sign of the local frequency of the signal. The inner product of these two vector fields gives us the desired quadrature signal. This quadrature operator is derived in the image space by use of differential vector calculus and in the frequency domain by use of a n-dimensional generalization of the Hilbert transform. A robust numerical algorithm is given to find the modulating phase of two-dimensional single-image closed-fringe interferograms by use of the ideas put forward.


Pinus taeda clones and soil nutrient availability: effects of soil organic matter incorporation and fertilization on biomass partitioning and leaf physiology.
The combined effects of intensive management and planting of improved seedlings have led to large increases in productivity on intensively managed pine forests in the southeastern United States. To best match clones to particular site conditions, an understanding of how specific clones respond to changes in nutrition in terms of biomass partitioning, leaf physiology and biochemistry will be necessary. This study measured the response of biomass partitioning, light-saturated net photosynthesis (A(Sat)) and photosynthetic capacity to a range in soil fertility and fertilization between two contrasting Pinus taeda L. clone ideotypes: a 'narrow crown' clone (NC) that allocates more resources to stem growth and a 'broad crown' clone (BC) that allocates more resources to leaf area (LA). Under field conditions, we found consistent clone by environment (i.e., varying nutrient regimes) interactions in biomass as well as leaf physiology. Nutrient limitations induced by logging residue incorporation resulted in a 25% loss in stem growth in BC, while NC showed no response. We postulated that the decrease in BC was due to the differences in canopy architecture leading to a reduced canopy CO(2) assimilation, as well as to increased belowground maintenance costs associated with fine-root production. In contrast, N and P additions resulted in a 21% greater increase in stem volume in NC relative to BC. Fertilization increased A(Sat) temporarily in both clones, but A(Sat) eventually decreased below control levels by the end of the study. Although we found a clone by fertilization interaction in leaf physiology, the greatest genotype by environment interaction was found in the LA that appeared to have a greater influence than A(Sat) on growth. This research demonstrates the potential importance of selecting appropriate clonal material and silvicultural prescription when implementing site-specific silviculture to maximize productivity in intensively managed southern pine forests.


Uracil-DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed.
Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil-DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histologic subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with upregulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed upregulation of BER as a feature of acquired pemetrexed resistance. Cotreatment with the BER inhibitor methoxyamine overrides pemetrexed resistance in chronically exposed cells, underscoring the use of BER-directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double-strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value.


"The expert and the patient": a discourse analysis of the house of commons' debates regarding the 2007 Mental Health Act.
The Mental Health Act 1983 was amended in 2007. This legislation appears to be predicated on the assumption that an entity of "mental disorder" exists and that people who are designated mentally disordered require medical treatment, administered by force if necessary. To explore the ways in which mental disorder is constructed and the possible practical effects of these constructions in the House of Commons' debates regarding the Mental Health Act 2007. Verbatim transcripts from the House of Commons debates on the Mental Health Act were studied through a discourse analysis. Two primary discursive constructions were identified: "The Expert" and "The Patient." Mental disorder and associated roles, such as "The Expert," were constructed through particular selective rhetoric, which taken together, made particular psychiatric practices and the need for legislation, such as compulsory detention, seem normal, and necessary.


Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer.
To assess the relation between urinary endogenous sex steroid levels and the risk of postmenopausal breast cancer, a nested case-cohort study was conducted within a large cohort (the DOM cohort) in the Netherlands (n=9,349). Until the end of follow-up (1 January 1996), 397 postmenopausal breast cancer cases were identified and a subcohort of 424 women was then taken from all eligible women. Women using hormones were excluded, leaving 364 breast cancer cases and 382 women in the subcohort for the analyses. Concentrations of oestrone, oestradiol, testosterone, 5alpha-androstane-3alpha, 17beta-diol and creatinine were measured in first morning urine samples, which had been stored since enrolment at -20 degrees C. A Cox proportional Hazards model was used, with Barlow's adjustment for case-cohort sampling, to estimate breast cancer risk in quartiles of each of the, creatinine corrected, hormone levels, the lowest quartile being the reference group. Women with higher levels of all four of the hormones were at increased risk for postmenopausal breast cancer (highest vs lowest quartile: incidence rate ratio for oestrone (IRR(oestrone)=2.5, 95% CI: 1.6-3.8; IRR(oestradiol)=1.5, 95% CI: 1.0-2.3; IRR(testosterone)=1.6, 95% CI: 1.0-2.4; IRR(5alpha-androstane-3alpha, 17beta-diol)=1.7, 95% CI: 1.1-2.7). In conclusion, women with higher excretion levels of both oestrogens and androgens have an increased risk of breast cancer.


Is gender policy related to the gender gap in external cause and circulatory disease mortality? A mixed effects model of 22 OECD countries 1973-2008.
Gender differences in mortality vary widely between countries and over time, but few studies have examined predictors of these variations, apart from smoking. The aim of this study is to investigate the link between gender policy and the gender gap in cause-specific mortality, adjusted for economic factors and health behaviours. 22 OECD countries were followed 1973-2008 and the outcomes were gender gaps in external cause and circulatory disease mortality. A previously found country cluster solution was used, which includes indicators on taxes, parental leave, pensions, social insurances and social services in kind. Male breadwinner countries were made reference group and compared to earner-carer, compensatory breadwinner, and universal citizen countries. Specific policies were also analysed. Mixed effect models were used, where years were the level 1-units, and countries were the level 2-units. Both the earner-carer cluster (ns after adjustment for GDP) and policies characteristic of that cluster are associated with smaller gender differences in external causes, particularly due to an association with increased female mortality. Cluster differences in the gender gap in circulatory disease mortality are the result of a larger relative decrease of male mortality in the compensatory breadwinner cluster and the earner-carer cluster. Policies characteristic of those clusters were however generally related to increased mortality. Results for external cause mortality are in concordance with the hypothesis that women become more exposed to risks of accident and violence when they are economically more active. For circulatory disease mortality, results differ depending on approach--cluster or indicator. Whether cluster differences not explained by specific policies reflect other welfare policies or unrelated societal trends is an open question. Recommendations for further studies are made.


Foxp3+ regulatory T cells control persistence of viral CNS infection.
We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+) CD25(+) Foxp3(+) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H(22-30) (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8(+) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.


5-Hydroxytryptamine releases adenosine and cyclic AMP from primary afferent nerve terminals in the spinal cord in vivo.
5-Hydroxytryptamine (5-HT) releases a purine nucleotide, which is subsequently converted to adenosine, from primary afferent nerve terminals in vitro. This release may mediate spinal antinociception by 5-HT. In the present study, we have investigated whether release also occurs from the spinal cord in vivo using an intrathecal perfusion system in rats. Adenosine was quantitated using high performance liquid chromatography (HPLC) with fluorescence detection. Following perfusion of the spinal cord with 50 and 500 microM 5-HT, a 35-50% increase in the release of endogenous adenosine was observed. This release was completely blocked by 50 microM methysergide, and by intrathecal injection with 100 micrograms capsaicin 5-8 days prior to release experiments. Intrathecal perfusion with 50 and 500 microM 5-HT also released a nucleotide which eluted from the HPLC column at a retention time identical to that of cyclic AMP standards, and was reduced following incubation with cyclic AMP phosphodiesterase. This release of cyclic AMP also was eliminated following intrathecal pretreatment with capsaicin. In contrast to 5-HT, noradrenaline (NA, 500 microM and 5 mM) did not release adenosine or cyclic AMP from the intact spinal cord. These data demonstrate that release of nucleotide, probably cyclic AMP, and subsequent metabolism to adenosine, can be induced by 5-HT but not NA in vivo. This strengthens the hypothesis that release of adenosine from the spinal cord may mediate antinociception by intrathecal 5-HT but not NA.


Estrogen synthesis in fetal sheep brain: effect of maternal treatment with an aromatase inhibitor.
The aim of the present study was to determine whether the fetal lamb brain has the capacity to aromatize androgens to estrogens during the critical period for sexual differentiation. We also determined whether administration of the aromatase-inhibitor 1,4,6-androstatriene-3,17-dione (ATD) could cross the placenta and inhibit aromatase activity (AA) in fetal brain. Eight pregnant ewes were utilized. On Day 50 of pregnancy, four ewes were given ATD-filled Silastic implants, and the other four ewes received sham surgeries. The fetuses were surgically delivered 2 wk later (Day 64 of gestation). High levels of AA (0.8-1.4 pmol/h/mg protein) were present in the hypothalamus and amygdala. Lower levels (0.02-0.1 pmol/h/mg protein) were measured in brain stem regions, cortex, and olfactory bulbs. The Michaelis-Menten dissociation constant (K(m)) for aromatase in the fetal sheep brain was 3-4 nM. No significant sex differences in AA were observed in brain. Treatment with ATD produced significant inhibition of AA in most brain areas but did not significantly alter serum profiles of the major sex steroids in maternal and fetal serum. Concentrations of testosterone in serum from the umbilical artery and vein were significantly greater in male than in female fetuses. No other sex differences in serum steroids were observed. These data demonstrate that high levels of AA are found in the fetal sheep hypothalamus and amygdala during the critical period for sexual differentiation. They also demonstrate that AA can be inhibited in the fetal lamb brain by treating the mother with ATD, without harming fetal development.


Complete Genome Sequence of Megasphaera stantonii AJH120T, Isolated from a Chicken Cecum.
A novel bacterium, Megasphaera stantonii (strain AJH120T), was isolated from the cecum of a chicken during a screen for microorganisms using a brain heart infusion (BHI) medium. PacBio and Illumina MiSeq sequencing technologies were used to produce a single contiguous chromosome. The resulting genome sequence is 2,652,760 bp long with a 52.62% GC content.


Reverse Transcription Errors and RNA-DNA Differences at Short Tandem Repeats.
Transcript variation has important implications for organismal function in health and disease. Most transcriptome studies focus on assessing variation in gene expression levels and isoform representation. Variation at the level of transcript sequence is caused by RNA editing and transcription errors, and leads to nongenetically encoded transcript variants, or RNA-DNA differences (RDDs). Such variation has been understudied, in part because its detection is obscured by reverse transcription (RT) and sequencing errors. It has only been evaluated for intertranscript base substitution differences. Here, we investigated transcript sequence variation for short tandem repeats (STRs). We developed the first maximum-likelihood estimator (MLE) to infer RT error and RDD rates, taking next generation sequencing error rates into account. Using the MLE, we empirically evaluated RT error and RDD rates for STRs in a large-scale DNA and RNA replicated sequencing experiment conducted in a primate species. The RT error rates increased exponentially with STR length and were biased toward expansions. The RDD rates were approximately 1 order of magnitude lower than the RT error rates. The RT error rates estimated with the MLE from a primate data set were concordant with those estimated with an independent method, barcoded RNA sequencing, from a Caenorhabditis elegans data set. Our results have important implications for medical genomics, as STR allelic variation is associated with >40 diseases. STR nonallelic transcript variation can also contribute to disease phenotype. The MLE and empirical rates presented here can be used to evaluate the probability of disease-associated transcripts arising due to RDD.