Enhanced ozonation of selected pharmaceutical compounds by sonolysis.
In search of new options to achieve removal of pharmaceuticals in the environment, combined ultrasound and ozonation has become a focus of intense investigation for wastewater treatment. In this study, three pharmaceuticals were selected as model compounds for degradation experiments: diclofenac (DCF), sulfamethoxazole (SMX) and carbamazepine (CBZ). Comparison of the degradation rates for both ozonation and combined ultrasound/ozonation treatments was performed on single synthetic solutions as well as on a mixture of the selected pharmaceuticals, under different experimental conditions. For single synthetic solutions, the efficiency removal for ozonation reached 73%, 51% and 59% after 40 min for DCF, SMX and CBZ, respectively. Comparable results were obtained for pharmaceuticals in mixture. However, the combined ultrasound/ozone treatment was found to increase degradation efficiencies for both DCF and SMX single solutions up to 94% and 61%, respectively, whereas lower removal yields, up to 56%, was noted for CBZ. Likewise, when the combined treatment was applied to the mixture, relatively low removal efficiencies was found for CBZ (44%) and 90% degradation yield was achieved for DCF.


Impact of Abiotic Stresses on Grain Composition and Quality in Food Legumes.
Grain quality and composition in food legumes are influenced by abiotic stresses. This review discusses the influence of abiotic stresses on grain composition and quality in food grains. Grain protein declines under salt stress due to the restricted absorption of nitrate from the soil solution. Grain phosphorus, nitrogen, and potassium contents declined whereas sodium and chloride increased. However, under drought, grain protein increased whereas the oil contents were decreased. For example, among fatty acids, oleic acid content increased; however, linoleic and/or linolenic acids were decreased under drought. Heat stress increased grain oil content whereas grain protein was decreased. Low temperature during late pod-filling reduced starch, protein, soluble sugar, fat, and fiber contents. However, an elevated CO2 level improved omega-3 fatty acid content at the expense of omega-6 fatty acids. Crop management and improvement strategies, next generation sequencing, and gene manipulation can help improve quality of food legumes under abiotic stresses.


Association Between Previous Use of Antiplatelet Therapy and Intracerebral Hemorrhage Outcomes.
Although the use of antiplatelet therapy (APT) is associated with the risk of intracerebral hemorrhage (ICH), there are limited data on prestroke APT and outcomes, particularly among patients on combination APT (CAPT). We hypothesized that the previous use of antiplatelet agents is associated with increased mortality in ICH. We analyzed data of 82 576 patients with ICH who were not on oral anticoagulant therapy from 1574 Get with the Guidelines-Stroke hospitals between October 2012 and March 2016. Patients were categorized as not on APT, on single-APT (SAPT), and CAPT before hospital presentation with ICH. We described baseline characteristics, comorbidities, hospital characteristics and outcomes, overall and stratified by APT use. Before the diagnosis of ICH, 65.8% patients were not on APT, 29.5% patients were on SAPT, and 4.8% patients were on CAPT. There was an overall modest increased in-hospital mortality in the APT group versus no APT group (24% versus 23%; adjusted odds ratio, 1.05; 95% confidence interval, 1.01-1.10). Although patients on SAPT and CAPT were older and had higher risk profiles in terms of comorbidities, there was no significant difference in the in-hospital mortality among patients on SAPT versus those not on any APT (23% versus 23%; adjusted odds ratio, 1.01; 95% confidence interval, 0.97-1.05). However, in-hospital mortality was higher among those on CAPT versus those not on APT (30% versus 23%; adjusted odds ratio, 1.50; 95% confidence interval, 1.39-1.63). Our study suggests that among patients with ICH, previous use of CAPT, but not SAPT, was associated with higher risk for in-hospital mortality.


Zebrafish hox genes: expression in the hindbrain region of wild-type and mutants of the segmentation gene, valentino.
The developing hindbrain is organized into a series of segments termed rhombomeres which represent lineage restricted compartments correlating with domains of gene expression and neuronal differentiation. In this study, we investigate the processes of hindbrain segmentation and the acquisition of segmental identity by analyzing the expression of zebrafish hox genes in the hindbrains of normal fish and fish with a loss-of-function mutation in the segmentation gene valentino (val, the homologue of mouse kreisler; Moens, C. B., Cordes, S. P. Giorgianni, M. W., Barsh, G. S. and Kimmel, C. B. (1998). Development 125, 381-391). We find that zebrafish hox genes generally have similar expression profiles to their murine and avian counterparts, although there are several differences in timing and spatial extent of expression which may underlie some of the functional changes that have occurred along the separate evolutionary lineages of teleosts and tetrapods. Our analysis of hox gene expression in val- embryos confirms that the val gene product is important for subdivision of the presumptive rhombomere 5 and 6 territory into definitive rhombomeres, suggests that the val gene product plays a critical role in regulating hox gene transcription, and indicates that some neural crest cells are inappropriately specified in val- embryos. Our analysis of gene expression at several developmental stages has allowed us to infer differences between primary and secondary defects in the val mutant: we find that extended domains of expression for some hox genes are secondary, late phenomena potentially resulting from inappropriate cell mixing or lack of normal inter-rhombomeric interactions in the caudal hindbrain.


Automated quantitative spectroscopic analysis combining background subtraction, cosmic ray removal, and peak fitting.
An integrated concept for post-acquisition spectrum analysis was developed for in-line (real-time) and off-line applications that preserves absolute spectral quantification; after the initializing parameter setup, only minimal user intervention is required. This spectral evaluation suite is composed of a sequence of tasks specifically addressing cosmic ray removal, background subtraction, and peak analysis and fitting, together with the treatment of two-dimensional charge-coupled device array data. One may use any of the individual steps on their own, or may exclude steps from the chain if so desired. For the background treatment, the canonical rolling-circle filter (RCF) algorithm was adopted, but it was coupled with a Savitzky-Golay filtering step on the locus-array generated from a single RCF pass. This novel only-two-parameter procedure vastly improves on the RCF's deficiency to overestimate the baseline level in spectra with broad peak features. The peak analysis routine developed here is an only-two-parameter (amplitude and position) fitting algorithm that relies on numerical line shape profiles rather than on analytical functions. The overall analysis chain was programmed in National Instrument's LabVIEW; this software allows for easy incorporation of this spectrum analysis suite into any LabVIEW-managed instrument control, data-acquisition environment, or both. The strength of the individual tasks and the integrated program sequence are demonstrated for the analysis of a wide range of (although not necessarily limited to) Raman spectra of varying complexity and exhibiting nonanalytical line profiles. In comparison to other analysis algorithms and functions, our new approach for background subtraction, peak analysis, and fitting returned vastly improved quantitative results, even for "hidden" details in the spectra, in particular, for nonanalytical line profiles. All software is available for download.


Selective regulation of current densities underlies spontaneous changes in the activity of cultured neurons.
We study the electrical activity patterns and the expression of conductances in adult stomatogastric ganglion (STG) neurons as a function of time in primary cell culture. When first plated in culture, these neurons had few active properties. After 1 d in culture they produced small action potentials that rapidly inactivated during maintained depolarization. After 2 d in culture they fired large action potentials tonically when depolarized, and their properties resembled very closely the properties of STG neurons pharmacologically isolated in the ganglion. After 3-4 d in culture, however, their electrical properties changed and they fired in bursts when depolarized. We characterized the currents expressed by these neurons in culture. They included two TTX-sensitive sodium currents, a calcium current, a delayed-rectifier-like current, a calcium-dependent potassium current, and two A-type currents. The changes in firing properties with time in culture were accompanied by an increase in inward and decrease in outward current densities. A single-compartment conductance-based model of an STG neuron was constructed by fitting the currents measured in the biological neurons. When the current densities in the model neuron were matched to those measured for the biological neurons in each activity state, the model neuron closely reproduced each state, indicating that the changes in current densities are sufficient to account for the changes in intrinsic properties. These data indicate that STG neurons isolated in culture change their intrinsic electrical properties by selectively adjusting the magnitudes of their ionic conductances.


Fitness ranking of individual mutants drives patterns of epistatic interactions in HIV-1.
Fitness interactions between mutations, referred to as epistasis, can strongly impact evolution. For RNA viruses and retroviruses with their high mutation rates, epistasis may be particularly important to overcome fitness losses due to the accumulation of deleterious mutations and thus could influence the frequency of mutants in a viral population. As human immunodeficiency virus type 1 (HIV-1) resistance to azidothymidine (AZT) requires selection of sequential mutations, it is a good system to study the impact of epistasis. Here we present a thorough analysis of a classical AZT-resistance pathway (the 41-215 cluster) of HIV-1 variants by fitness measurements in single round infection assays covering physiological drug concentrations ex vivo. The sign and value of epistasis varied and did not predict the epistatic effect on the mutant frequency. This complex behavior is explained by the fitness ranking of the variants that strongly depends on environmental factors, i.e., the presence and absence of drugs and the host cells used. Although some interactions compensate fitness losses, the observed small effect on the relative mutant frequencies suggests that epistasis might be inefficient as a buffering mechanism for fitness losses in vivo. While the use of epistasis-based hypotheses to make general assumptions on the evolutionary dynamics of viral populations is appealing, our data caution their interpretation without further knowledge on the characteristics of the viral mutant spectrum under different environmental conditions.


PCDD/F deposition time trend to Esthwaite Water, U.K., and its relevance to sources.
PCDD/Fs were measured in 16 sections of a sediment core from a freshwater lake in rural England. Each section represented 10 yr of deposition. Concentrations greater than the limit of detection were observed for most homologues in all samples. Three eras of PCDD/F input were identified by their distinct homologue and isomer profiles. sigma(4-8)CDD/F levels in core sections deposited before 1900 were in the order of 100 pg/g dry weight (dw) as compared to 1500 pg/g dw in the most recently deposited sediment. Local industries such as mining, quarrying, charcoal burning, and iron smelting appear to have had a minor impact on the PCDD/F deposition in the lake. Since 1900, two major peaks in PCDD/F input to the lake were evident. The first, reaching a maximum in the 1930s, had an unusual homologue pattern dominated by high molecular weight PCDFs, and the source of this input is unknown. The second, with a maximum in the 1970s, is in keeping with previously reported time trends for Europe and North America. Pre-1900, the TCDD/F isomer pattern was dominated by dimerization products of 2,4-dichlorophenol. Concentrations of P(1-3)CDFs appeared to be connected with the input that peaked in the 1930s, while highest concentrations of P(1-3)CDDs were found in the deepest sediment sections. Concentrations of diCDDs were observed to have increased again over the most recent decades to levels similar to pre-1900 sections. Despite detailed knowledge of the catchment and of industry in the surrounding area, the identity of some sources and the contribution of other known sources remain unclear for each era. This indicates that there remain significant gaps in our understanding of PCDD/F sources and undermines our ability to predict future trends in PCDD/F emissions.


Usefulness of symptoms to screen for celiac disease.
To describe the frequency of symptoms and associated conditions among screening-detected celiac disease (CD) cases and non-CD children and to evaluate questionnaire-based case-finding targeting the general population. In a population-based CD screening of 12-year-olds, children and their parents completed questionnaires on CD-associated symptoms and conditions before knowledge of CD status. Questionnaire data for those who had their CD detected in the screening (n = 153) were compared with those of children with normal levels of CD markers (n = 7016). Hypothetical case-finding strategies were also evaluated. Questionnaires were returned by 7054 (98%) of the children and by 6294 (88%) of their parents. Symptoms were as common among screening-detected CD cases as among non-CD children. The frequency of children with screening-detected CD was similar when comparing the groups with and without any CD-related symptoms (2.1% vs 2.1%; P = .930) or CD-associated conditions (3.6% vs 2.1%; P = .07). Case-finding by asking for CD-associated symptoms and/or conditions would have identified 52 cases (38% of all cases) at a cost of analyzing blood samples for 2282 children (37%) in the study population. The current recommended guidelines for finding undiagnosed CD cases, so-called active case-finding, fail to identify the majority of previously undiagnosed cases if applied in the general population of Swedish 12-year-olds. Our results warrant further studies on the effectiveness of CD case-finding in the pediatric population, both at the clinical and population-based levels.


Functional maturation of isolated neural progenitor cells from the adult rat hippocampus.
Although neural progenitor cells (NPCs) may provide a source of new neurons to alleviate neural trauma, little is known about their electrical properties as they differentiate. We have previously shown that single NPCs from the adult rat hippocampus can be cloned in the presence of heparan sulphate chains purified from the hippocampus, and that these cells can be pushed into a proliferative phenotype with the mitogen FGF2 [Chipperfield, H., Bedi, K.S., Cool, S.M. & Nurcombe, V. (2002) Int. J. Dev. Biol., 46, 661-670]. In this study, the active and passive electrical properties of both undifferentiated and differentiated adult hippocampal NPCs, from 0 to 12 days in vitro as single-cell preparations, were investigated. Sparsely plated, undifferentiated NPCs had a resting membrane potential of approximately -90 mV and were electrically inexcitable. In > 70%, ATP and benzoylbenzoyl-ATP evoked an inward current and membrane depolarization, whereas acetylcholine, noradrenaline, glutamate and GABA had no detectable effect. In Fura-2-loaded undifferentiated NPCs, ATP and benzoylbenzoyl-ATP evoked a transient increase in the intracellular free Ca(2+) concentration, which was dependent on extracellular Ca(2+) and was inhibited reversibly by pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS), a P2 receptor antagonist. After differentiation, NPC-derived neurons became electrically excitable, expressing voltage-dependent TTX-sensitive Na(+) channels, low- and high-voltage-activated Ca(2+) channels and delayed-rectifier K(+) channels. Differentiated cells also possessed functional glutamate, GABA, glycine and purinergic (P2X) receptors. Appearance of voltage-dependent and ligand-gated ion channels appears to be an important early step in the differentiation of NPCs.


Chemical imaging with Fourier transform coherent anti-Stokes Raman scattering microscopy.
We report chemical imaging using Fourier transform coherent anti-Stokes Raman scattering (FTCARS) microscopy. Adding a passively phase-stable local field to amplify the weak FTCARS signal, we also demonstrate interferometric FTCARS microscopy, permitting reduced incident power to be used for imaging. We discuss signal-to-noise considerations and the conditions necessary to effectively suppress background noise, allowing FTCARS microscopy that is limited by the shot noise of the detector. We also discuss differences between the signal-to-noise obtainable by time and frequency domain coherent anti-Stokes Raman scattering (CARS) methods.


Sputum plug selection under inverted microscopy improves microbial identification during exacerbations of airway diseases.
Salivary contamination decreases the yield of identifying potential airway bacterial and fungal pathogens in routine cultures of spontaneous or induced sputum during exacerbations of airway diseases. We investigated the utility of selecting out the squamous cells from sputum using inverted microscopy. Sputum was obtained from fifty subjects, then divided to facilitate parallel processing of paired samples for gram-stain and semi-quantitative cultures, and quantitative cytometry. Selective processing under inverted microscopy allowed for fewer sample rejections (2% vs. 24%) and greater culture positivity (58% vs. 24%) compared with routine practices, with significant yield of fungal organisms. While known pathogens were associated with intense sputum neutrophilia, organisms that were not routinely considered as airway pathogens were also associated with modest neutrophilia indicating that they are capable of inducing a clinically relevant cellular response. Sputum selection under inverted microscopy improves the detection of bacterial pathogens during infective exacerbations. The methods to assign pathogenicity to microbes in the airway needs to be re-visited by assessing the cellular responses that they evoke in the airways.


Structure of taq DNA polymerase shows a new orientation for the structure-specific nuclease domain.
Thermus aquaticus DNA polymerase I consists of the polymerase, the structure-specific nuclease and the vestigial editing nuclease domains. Three-dimensional structures of the native enzyme and its complex with DNA have already been reported. The structure of a complex with an inhibitory antibody has also been determined. The structure of the native enzyme in a different crystal form determined at 2.6 A is reported here. Optimized anomalous diffraction measurements made at the holmium L(III) edge were valuable in validating solutions obtained through molecular replacement. The structure of the polymerase domain is similar to those reported previously, while the relative orientation of the structure-specific nuclease domain is significantly different from those of the native enzyme and the DNA complex; it is, however, identical to that observed in the structure of the Fab complex. In the structures of the native enzyme and of the DNA complex reported previously, the active site of the structure-specific nuclease domain is too far from that of the polymerase domain, making it difficult to propose a structural model for the in vivo primer-excision and nick-translation activities of the enzyme. In the present structure, the two active sites are considerably closer. Taken together, the reported structure of the native enzyme, that of the Fab complex and the present structure imply that the different orientation of the structure-specific nuclease domain is probably a consequence of intrinsically high relative mobility between these two domains in this enzyme.


SCPE work, standardization and definition--an overview of the activities of SCPE: a collaboration of European CP registers.
The main aim of the Surveillance of Cerebral Palsy in Europe (SCPE) network was to develop a central database of cerebral palsy (CP) cases across Europe. Monitoring trends in prevalence rates of CP should contribute to collaborative studies on risk factors or quality of life for children living with CP. A multi-centre collaboration of CP registries used a clear definition of CP to accurately and consistently identify cases of CP. The rate of CP within the collaboration varied from 1.5 to 3 per 1000 live births. For the birth cohort 1980 to 1996 (n=9128), 53.9% of the CP children had a bilateral spastic CP, 31.0% had unilateral spastic CP, 6.6% were dyskinetic and 4.1% ataxic. Among CP children, 20.4% had a birth weight less than 1500 g and 25.5% were born before 32 weeks gestational age. Intellectual impairment corresponding to an IQ<50 was found in 29.5% of CP children. The proportion of CP children unable to walk, even with aids, was 30.3%. Twelve and a half percent of CP children were known to have a severe visual impairment. It was concluded that registers are the best means to implement epidemiological research into CP.


Mapping physicians' admission diagnoses to structured concepts towards fully automatic calculation of acute physiology and chronic health evaluation score.
Objective Acute Physiology and Chronic Health Evaluation (APACHE) is most widely used as a mortality prediction score in US intensive care units (ICUs), but its calculation is onerous. The authors aimed to develop and validate automatic mapping of physicians' admission diagnoses to structured concepts for automated APACHE IV calculation. Methods This retrospective study was conducted in medical ICUs of a tertiary healthcare and academic centre. Boolean-logic text searches were used to map admission diagnoses, and these were compared with conventional APACHE database entry by bedside nurses and a gold-standard physician chart review. The primary outcome was APACHE IV predicted hospital mortality. The tool was developed in a larger cohort of ICU patients. Results In a derivation cohort of 192 consecutive critically ill patients, the diagnosis coefficient coded by three different methods had a positive correlation, highest between manual and gold standard (r(2)=0.95; mean square error (MSE)=0.040) and least between manual and automatic tool (r(2)=0.88; MSE=0.066). The automatic tool had an area under the curve (95% CI) value of 0.82 (0.74 to 0.90) which was similar to the physician gold standard, 0.83 (0.75 to 0.91) and standard manual entry, 0.81 (0.73 to 0.89). The Hosmer-Lemeshow goodness-of-fit test demonstrated good calibration of automatically calculated APACHE IV score (χ(2)=6.46; p=0.6). The automatic tool demonstrated excellent discrimination with an area under the curve value of 0.87 (95% CI 0.83 to 0.92) and good calibration (p=0.58) in the validation cohort of 593 patients. Conclusion A Boolean-logic text search is an efficient alternative to manual database entry for mapping of ICU admission diagnosis to structured APACHE IV concepts.


Measurement of mechanical forces acting on optically trapped dielectric spheres induced by surface-enhanced Raman scattering.
Surface enhanced Raman scattering (SERS) is studied from optically trapped dielectric spheres partially covered with silver colloids in a solution with SERS active molecules. The Raman scattering and Brownian motion of the sphere are simultaneously measured to reveal correlations between the enhancement of the Raman signal and average position of the sphere. The correlations are due to the momenta transfer of the emitted Raman photons from the probe molecules. The addition of a mechanical force measurement provides a different dimension to the study of Raman processes.


A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice.
The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.


Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway.
Oxaliplatin is a major treatment for metastatic colorectal cancer, however its effectiveness is greatly diminished by the development of resistances. Our previous work has shown that oxaliplatin efficacy depends on the reactive oxygen species (ROS) produced by Nox1. In this report, we investigated Nox1 involvement in the survival mechanisms of oxaliplatin resistant cell lines that we have selected. Our results show that basal ROS production by Nox1 is increased in resistant cells. Whereas the transitory Nox1-dependent production of superoxide contributes to the cytotoxicity of oxaliplatin in sensitive cells, oxaliplatin treatment of resistant cells leads to a decrease in the production of superoxide associated with an increase of H2O2 and a decreased cytotoxicity of oxaliplatin. We have shown that calpains regulate differently Nox1 according to the sensitivity of the cells to oxaliplatin. In sensitive cells, calpains inhibit Nox1 by cleaving NoxA1 leading to a transient ROS production necessary for oxaliplatin cytotoxic effects. In contrast, in resistant cells calpain activation is associated with an increase of Nox1 activity through Src kinases, inducing a strong and maintained ROS production responsible for cell survival. Using a kinomic study we have shown that this overactivation of Nox1 results in an increase of p38 MAPK activity allowing the resistant cells to escape apoptosis. Our results show that the modulation of Nox1 activity in the context of anticancer treatment remains complex. However, a strategy to maximize Nox1 activation while inhibiting the p38 MAPK-dependent escape routes appears to be an option of choice to optimize oxaliplatin efficiency.


Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer.
The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8*3, CYP2C8-HapC, and CYP3A5*3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5*3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A5*3/*1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than *3/*3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.


Detecting interacting genetic loci with effects on quantitative traits where the nature and order of the interaction are unknown.
Standard techniques for single marker quantitative trait mapping perform poorly in detecting complex interacting genetic influences. When a genetic marker interacts with other genetic markers and/or environmental factors to influence a quantitative trait, a sample of individuals will show different effects according to their exposure to other interacting factors. This paper presents a Bayesian mixture model, which effectively models heterogeneous genetic effects apparent at a single marker. We compute approximate Bayes factors which provide an efficient strategy for screening genetic markers (genome-wide) for evidence of a heterogeneous effect on a quantitative trait. We present a simulation study which demonstrates that the approximation is good and provide a real data example which identifies a population-specific genetic effect on gene expression in the HapMap CEU and YRI populations. We advocate the use of the model as a strategy for identifying candidate interacting markers without any knowledge of the nature or order of the interaction. The source of heterogeneity can be modeled as an extension.


Regulation of FGF8 expression by the androgen receptor in human prostate cancer.
Fibroblast growth factor 8 (FGF8) has been shown to play a key role in prostate carcinogenesis. It was initially cloned as an androgen induced protein in mouse mammary cancer SC3 cells. In this study, we examined if FGF8 was also regulated by the androgen receptor in human prostate cancer. FGF8b protein expression in resected clinical prostate cancer correlated closely with expression of the androgen receptor (AR). In the androgen sensitive CWR22 prostate xenograft, we observed up-regulation of FGF8b immunoreactivity in testosterone supplemented mice while castration markedly reduced its signal. Furthermore, FGF8b protein expression in AR positive LNCaP cells was similarly enhanced by androgens. The proximal promoter of the human FGF8 gene was cloned into a luciferase reporter construct (FGF8.luc). FGF8.luc activity in AR positive LNCaP and SC3 cells was increased 2.5-fold by androgens. In AR negative DU145 cells, maximal induction of FGF8.luc required both co-transfection of the AR and the presence of androgens. The anti-androgen bicalutamide completely abolished AR mediated FGF8.luc induction. Deletion constructs from FGF8.luc have further defined an active promoter region and an androgen responsive region. Nucleotide analysis of this androgen responsive region has revealed putative androgen response elements. Finally, using ChIP assays we confirmed in vivo interaction between the AR and the androgen responsive region of the FGF8 promoter. Taken together these data provide first evidence that expression of the mitogen FGF8 in prostate cancer is, at least in part, regulated by the androgen receptor at the transcriptional level.


Graft infection after endovascular abdominal aortic aneurysm repair.
Although the natural history and management of infected open abdominal aortic aneurysm (AAA) repair is well described, only sporadic case reports have described the fate of patients with infected endografts placed in the abdominal aorta. The present study describes a tertiary referral center's experience with infected endovascular aneurysm repairs (EVARs). The medical records of 1302 open and endovascular aortic procedures were queried from January 2000 to January 2010. The cases were reviewed for prior aortic procedures, prosthetic implants, and etiology of current open procedure. Demographics, operative details, and perioperative courses were documented. Nine patients (1 woman) with a mean age of 71 years had an EVAR that later required an open procedure for explantation and surgical revision for suspected infection. All grafts were explanted through a midline transperitoneal approach, with a mean time to explant of 33 months. The explanted endografts included 4 Zenith (Cook, Bloomington, Ind), 2 Ancure (Endovascular Technologies, Menlo Park, Calif), 2 Excluders (Gore, Flagstaff, Ariz), and 1 AneuRx (Medtronic, Minneapolis, Minn). Eight of the nine original EVARs were performed at other hospitals; 1 patient had EVAR and open explant at the University of Michigan. All patients had preoperative computed tomography scans, except one who was transferred in extremis with a gastrointestinal hemorrhage. Three patients also had a tagged leukocyte scan, and two had magnetic resonance imaging to further reinforce the suspicion of infection before explantation and bypass planning. Rifampin-soaked Hemashield (Boston Scientific) in situ grafts were used in four patients, with extra-anatomic (axillary-bifemoral) bypass used in the other five. The in situ group had no positive preoperative or postoperative cultures, with the exception of the unstable patient who died the day of surgery. For the other five patients, positive tissue cultures were found for Bacteroides, Escherichia coli, coagulase-negative Staphylococcus, Streptococcus, and Candida. Three patients were found to have aortic-enteric fistula, two of whom died before discharge from the hospital. The remaining seven survived to discharge. Average length of stay was 22 days, with a median follow-up of 11 months. This series of infected EVARs is the largest group of infected AAA endografts reported to date. Because EVAR of AAAs is presently the most common method of repair, development of endograft infection, while rare, can be managed with acceptable mortality rates. Patients presenting with aortic-enteric fistula after EVAR appear to have a more virulent course.


Structure-function relationships of membrane-associated GT-B glycosyltransferases.
Membrane-associated GT-B glycosyltransferases (GTs) comprise a large family of enzymes that catalyze the transfer of a sugar moiety from nucleotide-sugar donors to a wide range of membrane-associated acceptor substrates, mostly in the form of lipids and proteins. As a consequence, they generate a significant and diverse amount of glycoconjugates in biological membranes, which are particularly important in cell-cell, cell-matrix and host-pathogen recognition events. Membrane-associated GT-B enzymes display two "Rossmann-fold" domains separated by a deep cleft that includes the catalytic center. They associate permanently or temporarily to the phospholipid bilayer by a combination of hydrophobic and electrostatic interactions. They have the remarkable property to access both hydrophobic and hydrophilic substrates that reside within chemically distinct environments catalyzing their enzymatic transformations in an efficient manner. Here, we discuss the considerable progress that has been made in recent years in understanding the molecular mechanism that governs substrate and membrane recognition, and the impact of the conformational transitions undergone by these GTs during the catalytic cycle.


Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease.
For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients. The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development. HCC occurred in 27 patients during a mean follow-up of 8.0 ± 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age ≥30 years even with early stage than in patients of age <30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age ≥30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively). HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age ≥30 years.


Relative Body Weight and Standardised Brightness-Mode Ultrasound Measurement of Subcutaneous Fat in Athletes: An International Multicentre Reliability Study, Under the Auspices of the IOC Medical Commission.
Fat is a metabolic fuel, but excess body fat is ballast mass, and therefore, many elite athletes reduce body fat to dangerously low levels. Uncompressed subcutaneous adipose tissue (SAT) thickness measured by brightness-mode ultrasound (US) provides an estimate of body fat content. The accuracy for determining tissue borders is about 0.1-0.2 mm and reliability (experienced measurers) was within ± 1.4 mm (95% limit of agreement, LOA). We present here inter- and intra-measurer scores of three experienced US measurers from each of the centres C1 and C2, and of three novice measurers from each of the centres C3-C5. Each of the five centres measured 16 competitive adult athletes of national or international level, except for one centre where the number was 12. The following sports were included: artistic gymnastics, judo, pentathlon, power lifting, rowing, kayak, soccer, tennis, rugby, basketball, field hockey, water polo, volleyball, American football, triathlon, swimming, cycling, long-distance running, mid-distance running, hurdles, cross-country skiing, snowboarding, and ice hockey. SAT contour was detected semi-automatically: typically, 100 thicknesses of SAT at a given site (i.e., in a given image), with and without fibrous structures, were measured. At SAT thickness sums DI (of eight standardised sites) between 6.0 and 70.0 mm, the LOA of experienced measurers was 1.2 mm, and the intra-class correlation coefficient ICC was 0.998; novice measurers: 3.1 mm and 0.988. Intra-measurer differences were similar. The median DI value of all 39 female participants was 51 mm (11% fibrous structures) compared to 17 mm (18%) in the 37 male participants. DI measurement accuracy and precision enables detection of fat mass changes of approximately 0.2 kg. Such reliability has not been reached with any other method. Although females' median body mass index and mass index were lower than those of males, females' median DI was three times higher, and their percentage of fibrous structures was lower. The standardised US method provides a highly accurate and reliable tool for measuring SAT and thus changes in body fat, but training of measurers is important.


Mental health reform in the Russian Federation: an integrated approach to achieve social inclusion and recovery.
To facilitate mental health reform in one Russian oblast (region) using systematic approaches to policy design and implementation. The authors undertook a three-year action-research programme across three pilot sites, comprising a multifaceted set of interventions combining situation appraisal to inform planning, sustained policy dialogue at federal and regional levels to catalyse change, introduction of multidisciplinary and intersectoral-working at all levels, skills-based training for professionals, and support for nongovernmental organizations (NGOs) to develop new care models. Training programmes developed in this process have been adopted into routine curricula with measurable changes in staff skills. Approaches to care improved through multidisciplinary and multisectoral service delivery, with an increase in NGO activities, user involvement in care planning and delivery in all pilot sites. Hospital admissions at start and end of the study fell in two pilot sites, while the rate of readmissions in all three pilot sites by 2006 was below that for the region as a whole. Lessons learned have informed the development of regional and federal mental health policies. A multifaceted and comprehensive programme can be effective in overcoming organizational barriers to the introduction of evidence-based multisectoral interventions in one Russian region. This can help facilitate significant and sustainable changes in policy and reduce institutionalization.


Factors associated with complementary and alternative medicine use among women at midlife.
Hormone replacement therapy (HRT) has been established as the first-line treatment for women experiencing menopausal symptoms. The use of complementary and alternative medicine (CAM), however, is becoming increasingly popular among women at midlife for management of such symptoms. Despite the equivocal evidence of CAM's efficacy in the reduction and alleviation of menopausal symptoms in placebo-controlled, randomized trials, 50% of women at midlife use CAM. To date, several large, population-based studies have focused upon CAM use amongst menopausal women and the factors associated with the adoption of such therapies. By identifying women in the menopausal transition who tend to use CAM, this narrative review highlights evidence that aids women at this stage of life make better and individualized treatment choices to relieve these symptoms. The available evidence suggests that the prevalence of CAM use among menopausal women is high world-wide, but there is a paucity of high-quality studies that adequately assess the factors associated with its use. Further studies are needed to confirm the characteristics of women who employ CAM to manage their night sweats and hot flushes. Results of this study might enable the development of policies catering to the needs of those women and provide a resource to support their decision-making regarding treatment options.


Associations between Use of Antimalarial Medications and Health among U.S. Veterans of the Wars in Iraq and Afghanistan.
Mefloquine (Lariam®; Roche Holding AG, Basel, Switzerland) has been linked to acute neuropsychiatric side effects. This is a concern for U.S. veterans who may have used mefloquine during recent Southwest Asia deployments. Using data from the National Health Study for a New Generation of U.S. Veterans, a population-based study of U.S. veterans who served between 2001 and 2008, we investigated associations between self-reported use of antimalarial medications and overall physical and mental health (MH) using the twelve-item short form, and with other MH outcomes using the post-traumatic stress disorder Checklist-17 and the Patient Health Questionnaire (anxiety, major depression, and self-harm). Multivariable logistic regression was performed to examine associations between health measures and seven antimalarial drug categories: any antimalarial, mefloquine, chloroquine, doxycycline, primaquine, mefloquine plus any other antimalarial, and any other antimalarial or antimalarial combination while adjusting for the effects of deployment and combat exposure. Data from 19,487 veterans showed that although antimalarial use was generally associated with higher odds of negative health outcomes, once deployment and combat exposure were added to the multivariable models, the associations with each of the MH outcomes became attenuated. A positive trend was observed between combat exposure intensity and prevalence of the five MH outcomes. No significant associations were found between mefloquine and MH measures. These data suggest that the poor physical and MH outcomes reported in this study population are largely because of combat deployment exposure.


Relative frequencies of constrained events in stochastic processes: An analytical approach.
The stochastic simulation algorithm (SSA) and the corresponding Monte Carlo (MC) method are among the most common approaches for studying stochastic processes. They relies on knowledge of interevent probability density functions (PDFs) and on information about dependencies between all possible events. Analytical representations of a PDF are difficult to specify in advance, in many real life applications. Knowing the shapes of PDFs, and using experimental data, different optimization schemes can be applied in order to evaluate probability density functions and, therefore, the properties of the studied system. Such methods, however, are computationally demanding, and often not feasible. We show that, in the case where experimentally accessed properties are directly related to the frequencies of events involved, it may be possible to replace the heavy Monte Carlo core of optimization schemes with an analytical solution. Such a replacement not only provides a more accurate estimation of the properties of the process, but also reduces the simulation time by a factor of order of the sample size (at least ≈10(4)). The proposed analytical approach is valid for any choice of PDF. The accuracy, computational efficiency, and advantages of the method over MC procedures are demonstrated in the exactly solvable case and in the evaluation of branching fractions in controlled radical polymerization (CRP) of acrylic monomers. This polymerization can be modeled by a constrained stochastic process. Constrained systems are quite common, and this makes the method useful for various applications.


Climate policy implications of nonlinear decline of Arctic land permafrost and other cryosphere elements.
Arctic feedbacks accelerate climate change through carbon releases from thawing permafrost and higher solar absorption from reductions in the surface albedo, following loss of sea ice and land snow. Here, we include dynamic emulators of complex physical models in the integrated assessment model PAGE-ICE to explore nonlinear transitions in the Arctic feedbacks and their subsequent impacts on the global climate and economy under the Paris Agreement scenarios. The permafrost feedback is increasingly positive in warmer climates, while the albedo feedback weakens as the ice and snow melt. Combined, these two factors lead to significant increases in the mean discounted economic effect of climate change: +4.0% ($24.8 trillion) under the 1.5 °C scenario, +5.5% ($33.8 trillion) under the 2 °C scenario, and +4.8% ($66.9 trillion) under mitigation levels consistent with the current national pledges. Considering the nonlinear Arctic feedbacks makes the 1.5 °C target marginally more economically attractive than the 2 °C target, although both are statistically equivalent.


Coronavirus Disease 2019 (COVID-19): A Systematic Review of Pregnancy and the Possibility of Vertical Transmission.
There is a growing need for information regarding maternal and neonatal outcomes during coronavirus pandemic. In this study, a comprehensive investigation was done regarding the possibility of vertical transmission using the available data in the literature. A systematic search was conducted using electronic databases, including PubMed, Scopus, Web of Science, Embase, and Scholar. All studies containing infected COVID-19 pregnant women who had given birth were included, and the search was done up to April 14, 2020. Overall, 21 articles were reviewed, and clinical characteristics of 90 pregnant patients and 92 neonates born to mothers infected with COVID-19 were reviewed. The most common symptoms included fever, cough, and dyspnea. The main laboratory findings included leukocytosis, lymphopenia, thrombocytopenia, and elevated C-reactive protein. The most commonly reported complications were preterm labor and fetal distress. Three mothers were admitted to ICU and required mechanical ventilation; among them, one died, and one was on extracorporeal membrane oxygenation. Overall, 86 neonates were tested for the possibility of vertical transmission and 82 cases were negative in RT-PCR, while 4 were positive. Out of 92 neonates, one died, and one was born dead. Nineteen patients reported having no symptoms, while breathing problems and pneumonia were reported as the most common neonatal complications. There were no differences in the clinical characteristics of pregnant women and non-pregnant COVID-19 patients. COVID-19 infection has caused higher incidence of fetal distress and premature labor in pregnant women. Although the possibility of vertical transmission in infected pregnant women is rare, four neonates' test results for COVID-19 infection were positive in this review.


Supplementing stuttering treatment with online cognitive behavior therapy: An experimental trial.
It is now well established that adults who present to speech clinics for help with stuttering will have an increased risk of having an anxiety disorder, particularly social anxiety disorder. Concomitant psychological problems are known to interfere with the maintenance of the benefits of behavioral speech treatments for stuttering. The current team has developed and trialed a cognitive behavior therapy (CBT) program designed specifically to reduce anxiety in adults who stutter, and trials have shown promise for both an in-clinic version and a standalone internet-based version. The aim of the present study is to determine whether iGlebe, the internet-based version of the team's internet CBT treatment (previously known as CBTPsych), enhances the benefits of behavioral stuttering treatment. Participants were 32 adults seeking treatment for stuttering. The design was a two-arm randomized experimental trial with blinded outcome assessments at 6 and 12 months post-randomization. Both arms received basic speech-restructuring training to reduce stuttering, without any anxiolytic (anxiety reducing) components. The experimental arm also received 5 months access to iGlebe. There was evidence that, at 12 months post-randomization, iGlebe added clinically significant improvements to self-reported stuttering severity and quality of life. The present experimental trial provides the first evidence that the addition of CBT to speech restructuring improves speech outcomes. The present results will be the basis for the development of a comprehensive, internet-based treatment program for anxiety associated with stuttering. Ultimately, it may be possible for such an economical, scalable, and translatable comprehensive treatment model to supplement standard speech-language pathology treatment practices for those who stutter.


Association of cigarette smoking with neuromyelitis optica-immunoglobulin G sero-positivity in neuromyelitis optica spectrum disorder.
Background: Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory demyelinating disease caused by the presence of a highly specific serum autoantibody marker, NMO-immunoglobulin G (NMO-IgG), that reacts against the water channel aquaporin-4 (AQP4). The present study examined the association between NMO-IgG sero-positivity and environmental factors such as cigarette smoking. Methods: A cross-sectional study was conducted in Sina Hospital, a tertiary referral center in Tehran, Iran. All the patients with a definite diagnosis of NMOSD were involved in this study. The enzyme-linked immunosorbent assay (ELISA) was used to examine the AQP4-IgG status. To assess the association between NMO-IgG sero-positivity and cigarette smoking, a researcher-made questionnaire covering patients' lifestyle information on smoking habits was designed and administered using the structured face-to-face interviews with the patients. Results: The positive and negative NMO-IgG results were found in 44 (46.8%) and 50 (53.2%) patients, respectively. The increased NMO-IgG sero-positivity odds were observed among the lifetime smokers [odds ratio (OR) = 3.24, 95% confidence interval (CI): 1.16-9.08], current smokers (OR = 6.08, 95% CI: 1.26-29.39), and passive smokers (OR = 2.22, 95% CI: 1.10-4.50). Conclusion: Lifetime and current smoking as well as passive smoking can be regarded as risk factors for NMO-IgG sero-positivity. Smoking with its immunological effects can lead to the production of autoantibodies such as NMO-IgG.


Disulfuric acid dissociated by two water molecules: ab initio and density functional theory calculations.
We have studied geometries, energies and vibrational spectra of disulfuric acid (H2S2O7) and its anion (HS2O7(-)) hydrated by a few water molecules, using density functional theory (M062X) and ab initio theory (SCS-MP2 and CCSD(T)). The most noteworthy result is found in H2S2O7(H2O)2 in which the lowest energy conformer shows deprotonated H2S2O7. Thus, H2S2O7 requires only two water molecules, the fewest number of water molecules for deprotonation among various hydrated monomeric acids reported so far. Even the second deprotonation of the first deprotonated species HS2O7(-) needs only four water molecules. The deprotonation is supported by vibration spectra, in which acid O-H stretching peaks disappear and specific three O-H stretching peaks for H3O(+) (eigen structure) appear. We have also kept track of variations in several geometrical parameters, atomic charges, and hybrid orbital characters upon addition of water. As the number of water molecules added increases, the S-O bond weakens in the case of H2S2O7, but strengthens in the case of HS2O7(-). It implies that the decomposition leading to H2SO4 and SO3 hardly occurs prior to the 2nd deprotonation at low temperatures.


Assessment of the relative systemic potency of inhaled fluticasone and budesonide.
Studies using dry powder devices have suggested that fluticasone propionate (FP) has a greater systemic effect than budesonide (BUD). The aim of the present study was to investigate and compare the relative systemic potency of FP and BUD from their respective pressurized metered-dose inhalers (pMDIs). A placebo-controlled, open, randomized, cross-over study was conducted in 21 healthy male volunteers. Placebo, BUD (200, 400 and 1,000 micrograms b.i.d.) and FP (200, 375 and 1,000 micrograms b.i.d.) were inhaled for 4 days, with a wash-out period of at least 3 days between treatments. Blood samples for cortisol analysis were drawn during the last 24 h of each treatment period. Cortisol levels, measured as 24 h pooled plasma cortisol, were statistically significantly lower (p = 0.0001) for all dose levels during FP pMDI treatment (21, 39 and 84% suppression from placebo) than during BUD pMDI treatment (1, 3 and 27% suppression from placebo). The relative systemic potency FP:BUD was 3.7:1 (95% confidence interval (95% CI) 2.9-4.8)). The relative systemic potency based on the single 08:00 h samples was 5.2:1 (95% CI 3.0-9.3). In conclusion, in healthy male volunteers using pressurized metered-dose inhalers, fluticasone propionate was shown to have a stronger systemic effect than budesonide.


ATLAS-BASED FIBER CLUSTERING FOR MULTI-SUBJECT ANALYSIS OF HIGH ANGULAR RESOLUTION DIFFUSION IMAGING TRACTOGRAPHY.
High angular resolution diffusion imaging (HARDI) allows in vivo analysis of the white matter structure and connectivity. Based on orientation distribution functions (ODFs) that represent the directionality of water diffusion at each point in the brain, tractography methods can recover major axonal pathways. This enables tract-based analysis of fiber integrity and connectivity. For multi-subject comparisons, fibers may be clustered into bundles that are consistently found across subjects. To do this, we scanned 20 young adults with HARDI at 4 T. From the reconstructed ODFs, we performed whole-brain tractography with a novel Hough transform method. We then used measures of agreement between the extracted 3D curves and a co-registered probabilistic DTI atlas to select key pathways. Using median filtering and a shortest path graph search, we derived the maximum density path to compactly represent each tract in the population. With this tract-based method, we performed tract-based analysis of fractional anisotropy, and assessed how the chosen tractography algorithm influenced the results. The resulting method may expedite population-based statistical analysis of HARDI and DTI.


Is zinc a neuromodulator?
The vesicles of certain glutamatergic terminals in the mammalian forebrain are replete with ionic zinc. It is believed that during synaptic transmission zinc is released, binds to receptors on the pre- or postsynaptic membranes, and hence acts as a neuromodulator. Although exogenous zinc modulates a wide variety of channels, whether synaptic zinc transits across the synaptic cleft and alters the response of channels has been difficult to establish. We will review the evidence for zinc as a neuromodulator and propose diagnostic criteria for establishing whether it is indeed one. Moreover, we will delineate alternative ways in which zinc might act at synapses.


Engaging the public in healthcare decision-making: results from a Citizens' Jury on emergency care services.
Policies addressing ED crowding have failed to incorporate the public's perspectives; engaging the public in such policies is needed. This study aimed at determining the public's recommendations related to alternative models of care intended to reduce crowding, optimising access to and provision of emergency care. A Citizens' Jury was convened in Queensland, Australia, to consider priority setting and resource allocation to address ED crowding. Twenty-two jurors were recruited from the electoral roll, who were interested and available to attend the jury from 15 to 17 June 2012. Juror feedback was collected via a survey immediately following the end of the jury. The jury considered that all patients attending the ED should be assessed with a minority of cases diverted for assistance elsewhere. Jurors strongly supported enabling ambulance staff to treat patients in their homes without transporting them to the ED, and allowing non-medical staff to treat some patients without seeing a doctor. Jurors supported (in principle) patient choice over aspects of their treatment (when, where and type of health professional) with some support for patients paying towards treatment but unanimous opposition for patients paying to be prioritised. Most of the jurors were satisfied with their experience of the Citizens' Jury process, but some jurors perceived the time allocated for deliberations as insufficient. These findings suggest that the general public may be open to flexible models of emergency care. The jury provided clear recommendations for direct public input to guide health policy to tackle ED crowding.


Glycemic control in Kuwaiti diabetes patients treated with glucose-lowering medication.
Diabetes is prevalent in Kuwait. We aimed to assess the level of glycemic control in Kuwaiti adults with diabetes. The World Health Organization's STEPS non-communicable disease risk factor survey was conducted in Kuwait in 2014. Participants' demographics, medical history, physical measurements and blood biochemistry were assessed. A total of 2561 Kuwaiti men and women aged 18-69 years completed all three survey steps. Glycemic control in 278 individuals with diabetes who were on glucose-lowering medication was determined using the US National Institutes of Health guidelines of fasting plasma glucose (FPG) ≤7.2mmol/l and the American Diabetes Association guidelines of glycated hemoglobin (HbA1c) <7% (53mmol/mol). Adequate glycemic control in people with drug-treated diabetes was 34.5% when determined by HbA1c, 37.8% when determined by FPG level, and 24.5% when both criteria were met. Mean body-mass index and fasting serum triglycerides were significantly higher and serum high-density lipoprotein-cholesterol significantly lower in individuals with an inadequate glycemic control than in those with adequate control. Women with diabetes were almost twice as likely to have inadequate HbA1c levels as men with diabetes (OR, 1.9, [95% CI, 1.03, 3.5]). Glycemic control in Kuwaiti adults with treated diabetes is low. A systemic, multi-disciplinary public health approach is needed to improve diabetes education and adherence to treatment.


Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat.
Fenoprofen (FN), a member of the 2-arylpropionic acid (2-APA) class of nonsteroidal anti-inflammatory drugs is administered clinically as a racemate. In humans, FN has been shown to rapidly undergo substantial in vivo unidirectional chiral inversion with the inactive R-isomer converted to its active antipode. As with any p.o. administered drug, before reaching the systemic circulation. FN may undergo first-pass metabolism, the major organs involved being the gastrointestinal tract and/or the liver. The site(s) of inversion for the 2-APAs have been a subject of debate, with presystemic intestinal metabolism in humans and hepatic systemic metabolism in rats receiving the most attention. The inversion of R-FN was studied in the male Sprague-Dawley rat 1) in vivo after p.o. and i.v. administration of racemic-FN and R-FN, 2) after perfusion of R-FN into isolated liver (single-pass and recirculation) and 3) after a 2-hr incubation with everted intestinal tissue (duodenum, jejunum, ileum and colon) and noneverted stomach pouch. The enantiomers and their acyl-glucuronides were quantitated using a previously developed stereospecific assay. With the isolated liver, R-FN was shown to invert in both the single-pass and recirculation systems, with a first-pass extraction ratio of 0.3. A significant but variable inversion in all intestinal segments was observed. Substantial inversion by the duodenum was observed (serosal S:R ratio, 1.2) with maximal inversion by the jejunum (serosal S:R ratio, 2.2), whereas inversion of R-FN was absent in the stomach. Considerable glucuronidation was observed in all tissues studied including first-pass glucuronidation of both enantiomers after single-pass perfusion through the isolated liver and stereoselective glucuronidation in intestinal tissue segments. The results indicate that, in the male Sprague-Dawley rat, R-FN undergoes presystemic inversion by both the gastrointestinal tract and liver. These results, however, must be viewed with caution as they may not necessarily be extrapolated to other 2-APAs or species.


Leveraging syntax to better capture the semantics of elliptical coordinated compound noun phrases.
Full-text scientific articles are increasingly available, but capturing the meaning conveyed within an article automatically remains a bottleneck for semantic search and reasoning systems. In this paper we consider elliptical coordinated compound noun phrases that authors use to save space in an article. Systems that do not attend to coordination would incorrectly interpret "breast or lung cancer" as a body part (breast) and a disease (lung cancer) rather than two diseases. The algorithmic approach introduced in this paper uses a generate-and-test strategy where candidate expansions for forward, backward and complex ellipses are generated from syntactic dependencies. Dependencies are also used to create a dictionary of non-coordinated noun phrases that is used during the test phrase. Experiments on 21,280 full-text articles show that more than a million noun phrases were impacted by coordinated ellipses. The system achieves 73.07% precision, 75.38% recall, 74.23% F-score and 94.72% accuracy for new noun phrases in the development set. The precision was higher for backward (82.62 vs. 78.63) and forward expansions (64.82 vs. 60.17) and lower for complex expansions (63.41 vs. 72.59) in a test set. On average 10.79% of all noun phrases would be missed if coordination were not resolved, which corresponds to 48 new noun phrases per article in the journal Carcinogenesis, 52 new phrases per article in Diabetes, and 56 new phrases per article in Endocrinology. Results also show coordinated ellipses are more prevalent in abstracts (12.31% of all noun phrases) than in the body of an article (10.70%). To further test the generalizability of this approach the system (without modification) was used on two new collections.


Sequential use of mushroom body neuron subsets during drosophila odor memory processing.
Drosophila mushroom bodies (MB) are bilaterally symmetric multilobed brain structures required for olfactory memory. Previous studies suggested that neurotransmission from MB neurons is only required for memory retrieval. Our unexpected observation that Dorsal Paired Medial (DPM) neurons, which project only to MB neurons, are required during memory storage but not during acquisition or retrieval, led us to revisit the role of MB neurons in memory processing. We show that neurotransmission from the alpha'beta' subset of MB neurons is required to acquire and stabilize aversive and appetitive odor memory, but is dispensable during memory retrieval. In contrast, neurotransmission from MB alphabeta neurons is only required for memory retrieval. These data suggest a dynamic requirement for the different subsets of MB neurons in memory and are consistent with the notion that recurrent activity in an MB alpha'beta' neuron-DPM neuron loop is required to stabilize memories formed in the MB alphabeta neurons.


Understanding your own and other's minds: the relationship to eating disorder related symptoms.
A study using a cross-sectional survey design examined whether eating disorder (ED) related symptoms are associated with understanding one's own and others' minds. A non-clinical sample of 145 women completed self-report questionnaires and recorded their emotional, cognitive and behavioural responses to descriptions of scenarios (vignettes). Responses to scenarios were made from the perspective of self, an attachment figure and a same sex acquaintance. Data were analysed using multiple regression statistics with ED related symptoms as the dependent variable. High levels of ED related symptoms were associated with 'concretised' understanding of own emotions (i.e. a greater number of food related responses), but sophisticated understanding of same sex acquaintance's emotions. They were associated with fewer positive thoughts for self, fewer negative emotions about their own behaviour, and more food responses for same sex acquaintance's behaviour. Similarities and differences were observed in the different perspectives. Limitations are discussed. Implications for further research related to this topic and relevant to EDs are briefly summarised.


Advantages of microsurgical varicocelectomy over conventional techniques.
Varicocelectomy is the only effective method of treating varicocele. Nowdays, many techniques for varicocelectomy include retroperitoneal, inguinal, and subinguinal varicocele repairs with or without magnification and laparoscopic repair. The advantages of the microsurgical approach to varicocele repairs are reliable identification and preservation of the vascular structures. Thus, our aim is to compare the efficiency of microsurgery over conventional techniques of varicocele repairs. We have evaluated 105 man divided into three groups of 35 patients surgically treated with open varicocelectomy in the first group, microsurgical varicocelectomy in the second, and laparoscopic varicocelectomy in the third group. Sperm test improvement and complications were then compared. The testicular volume shows a significant increase after all three types of surgery, the highest one being after the laparascopic varicocelectomy (14.47 ± 6.76 vs. 21.8 ± 7.52), whereas the lowest increase was recorded in open varicocelectomy (14.90 ± 6.26 vs. 17.46 ± 5.89). Regarding motility of spermatozoids, the highest postoperative increase of values is after microsurgical varicocelectomy (4.30 ± 2.19 vs. 15.88 ± 3.13). Our study shows the lowest degree of postoperative complications among patients treated with microsurgical varicocelectomy, and the most frequent complications in those treated by open varicocelectomy. Sperm test outcomes after microsurgical varicocelectomy was better than those after other conventional techniques: significantly higher improvement of sperm quality, shoter postsurgical clinical treatment, and the lowest rate of postsurgical complications.


Analysis of pointing errors reveals properties of data representations and coordinate transformations within the central nervous system.
The execution of a simple pointing task invokes a chain of processing that includes visual acquisition of the target, coordination of multimodal proprioceptive signals, and ultimately the generation of a motor command that will drive the finger to the desired target location. These processes in the sensorimotor chain can be described in terms of internal representations of the target or limb positions and coordinate transformations between different internal reference frames. In this article we first describe how different types of error analysis can be used to identify properties of the internal representations and coordinate transformations within the central nervous system. We then describe a series of experiments in which subjects pointed to remembered 3D visual targets under two lighting conditions (dim light and total darkness) and after two different memory delays (0.5 and 5.0 s) and report results in terms of variable error, constant error, and local distortion. Finally, we present a set of simulations to help explain the patterns of errors produced in this pointing task. These analyses and experiments provide insight into the structure of the underlying sensorimotor processes employed by the central nervous system.


Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma.
Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg. The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. NCT01425008.


Rapid eradication of Listeria monocytogenes by moxifloxacin in a murine model of central nervous system listeriosis.
Listeriosis is a rare but life-threatening infection. A favorable outcome is greatly aided by early administration of antibiotics with rapid bactericidal activity against Listeria monocytogenes. Moxifloxacin, a new-generation fluoroquinolone with extended activity against gram-positive bacteria, has proved its effectiveness in vitro against intracellular reservoirs of bacteria. The efficacies of moxifloxacin and amoxicillin were compared in vivo by survival curve assays and by studying the kinetics of bacterial growth in blood and organs in a murine model of central nervous system (CNS) listeriosis. We combined pharmacokinetic and pharmacodynamic approaches to correlate the observed efficacy in vivo with plasma and tissue moxifloxacin concentrations. Death was significantly delayed for animals treated with a single dose of moxifloxacin compared to a single dose of amoxicillin. We observed rapid bacterial clearance from blood and organs of animals treated with moxifloxacin. The decrease in the bacterial counts in blood and brain correlated with plasma and cerebral concentrations of antibiotic. Moxifloxacin peaked in the brain at 1.92 +/- 0.32 microg/g 1 hour after intraperitoneal injection. This suggests that moxifloxacin rapidly crosses the blood-brain barrier and diffuses into the cerebral parenchyma. Moreover, no resistant strains were selected during in vivo experiments. Our results indicate that moxifloxacin combines useful pharmacokinetic properties and rapid bactericidal activity and that it may be a valuable alternative for the treatment of CNS listeriosis.