First Report of Resistance of Wheat Line Avocet 'S' to Stripe Rust Caused by Puccinia striiformis f. sp. tritici (Pst) in Syria.
Seedling assays and field-based assessments are common approaches used in monitoring pathogenic variability of Puccinia striiformis f. sp. tritici (Pst). Due to the many candidate genes for resistance, and the occasional presence of uncharacterized or unexpected resistance genes, interpretation of seedling and adult plant responses of stripe rust differential genotypes can be confounded. To facilitate data interpretation and overcome growth habit differences, a set of near-isogenic lines (NILs) based on a susceptible selection of the widely susceptible Australian spring wheat cultivar Avocet was developed in Plant Breeding Institute, University of Sydney. During the 2011 rust survey of major wheat growing areas in Syria, we collected and recovered two isolates, one from bread wheat and one from durum, using susceptible cultivar Morocco. Fresh urediniospores collected from inoculated seedlings of cultivar Morocco under greenhouse conditions were used to infect a differential set of seedlings comprising the Avocet S NIL series with Yr1, 5, 6, 7, 8, 9, 10, 15, 17, 27, 32, A, SP and a supplementary set of Kalyansona (Yr2), Fielder (Yr6, Yr20), Thatcher (Yr7), Federation*4/Kavkaz (Yr9), TP1295 and TP981 (Yr25), Ciano 79 and Opata 85 (Yr27), Lemhi (Yr21), Anza (YrA), Tres/6*Avocet 'S', Cook, Avocet S, and Federation following standard protocol (1). Seedling infection types (IT) were recorded 15 to 17 days post-inoculation using a 0, ;(fleck), 1 to 4 scale, with ITs 3 and 4 considered to be high. According to European race nomenclature (1), these isolates would be classified as 6 E0 and assumes that differential cultivars Lee (Yr7) and Heines Kolben should be susceptible. A low infection of ;N (necrotic areas without sporulation) was observed on Avocet S and Avocet NILs Yr1, 5, 8, 10, 15, 17, 32, A, and SP. NILs Yr6, 7, and 9 responded with high infection types. Among the supplementary set, IT ;N was recorded for Anza, Cook, Tres/6*Avocet S, Opata 85, and Ciano 79 whereas IT 3+4 occurred on Kalyansona, Fielder, Thatcher, Federation*4/Kavkaz, TP1295 and TP981, and Lemhi. Federation and Morocco were susceptible to both isolates. Based on these data we concluded that 1) Avocet S carries at least one effective gene for resistance to the two isolates (temporarily designated as YrAvS and perhaps the same as the gene(s) in Anza and Cook); and 2) since Avocet S was resistant, it was expected that all the NILs should also be resistant unless one of the selected resistance genes was closely linked in repulsion with the gene in Avocet S. Since such a situation is possible for only one line, other explanations are that the recurrent parent, Avocet S, was not genetically homogeneous, or more likely, that the genetic background of Avocet S was not fully regenerated during the six backcross and subsequent selfing generations. This work illustrates the problems that can arise when sets of differential genotypes that perform in a satisfactory way in a particular (limited) geographical area are applied globally. Pst races carrying avirulence genes that are not present in the original area where a differential cultivar is characterized for its susceptibility may be present in other areas. Consequently, a differential cultivar which was susceptible in the original area may unexpectedly exhibit resistance in a new region. Therefore, host lines considered to be "universally susceptible" in one region may not be susceptible globally. The resistance of Avocet S is yet to be characterized. Reference: (1) R. Johnson et al. Trans. Br. Mycol. Soc. 58:475, 1972.


The draft genome of tropical fruit durian (Durio zibethinus).
Durian (Durio zibethinus) is a Southeast Asian tropical plant known for its hefty, spine-covered fruit and sulfury and onion-like odor. Here we present a draft genome assembly of D. zibethinus, representing the third plant genus in the Malvales order and first in the Helicteroideae subfamily to be sequenced. Single-molecule sequencing and chromosome contact maps enabled assembly of the highly heterozygous durian genome at chromosome-scale resolution. Transcriptomic analysis showed upregulation of sulfur-, ethylene-, and lipid-related pathways in durian fruits. We observed paleopolyploidization events shared by durian and cotton and durian-specific gene expansions in MGL (methionine γ-lyase), associated with production of volatile sulfur compounds (VSCs). MGL and the ethylene-related gene ACS (aminocyclopropane-1-carboxylic acid synthase) were upregulated in fruits concomitantly with their downstream metabolites (VSCs and ethylene), suggesting a potential association between ethylene biosynthesis and methionine regeneration via the Yang cycle. The durian genome provides a resource for tropical fruit biology and agronomy.


Identification of FAP locus genes from chromosome 5q21.
Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.


Visible light guidance in silica capillaries by antiresonant reflection.
Hollow silica capillaries are examined as optical waveguides evaluating the antiresonant reflecting optical waveguide (ARROW) effect by sequentially reducing the wall thickness through etching and measuring the optical transmission. It is found that the periodicity of the transmission bands is proportional to the wall thickness and that the propagation loss is of the order of a few dB/m.


Loss of the mammalian DREAM complex deregulates chondrocyte proliferation.
Mammalian DREAM is a conserved protein complex that functions in cellular quiescence. DREAM contains an E2F, a retinoblastoma (RB)-family protein, and the MuvB core (LIN9, LIN37, LIN52, LIN54, and RBBP4). In mammals, MuvB can alternatively bind to BMYB to form a complex that promotes mitotic gene expression. Because BMYB-MuvB is essential for proliferation, loss-of-function approaches to study MuvB have generated limited insight into DREAM function. Here, we report a gene-targeted mouse model that is uniquely deficient for DREAM complex assembly. We have targeted p107 (Rbl1) to prevent MuvB binding and combined it with deficiency for p130 (Rbl2). Our data demonstrate that cells from these mice preferentially assemble BMYB-MuvB complexes and fail to repress transcription. DREAM-deficient mice show defects in endochondral bone formation and die shortly after birth. Micro-computed tomography and histology demonstrate that in the absence of DREAM, chondrocytes fail to arrest proliferation. Since DREAM requires DYRK1A (dual-specificity tyrosine phosphorylation-regulated protein kinase 1A) phosphorylation of LIN52 for assembly, we utilized an embryonic bone culture system and pharmacologic inhibition of (DYRK) kinase to demonstrate a similar defect in endochondral bone growth. This reveals that assembly of mammalian DREAM is required to induce cell cycle exit in chondrocytes.


Novel redox potential-based screening strategy for rapid isolation of Klebsiella pneumoniae mutants with enhanced 1,3-propanediol-producing capability.
This report describes a novel redox potential (oxidoreduction potential [ORP])-based screening strategy for the isolation of mutants of Klebsiella pneumoniae which have an increased ability to produce 1,3-propanediol (1,3-PD). This method can be described as follows: first, to determine an ORP range which is preferred for the wild-type strain to grow and to produce 1,3-PD; second, to subject a chemically mutagenized culture to a reduced ORP level which is deleterious for the wild-type strain. Colonies that showed high specific growth rates at deleterious ORP levels were selected, and their abilities to produce 1,3-PD were investigated. In an ORP-based screening experiment where the ORP was controlled at -280 mV, 4 out of 11 isolated strains were recognized as positive mutant strains. A mutant which is capable of producing higher concentrations of 1,3-PD was subjected to fed-batch fermentations for further characterization. Its preferred ORP level (-280 mV) was significantly lower than that of its parent (-190 mV). The highest 1,3-PD concentration of the mutant was 915 mmol liter(-1), which was 63.1% higher than that of the parent. Metabolic-flux analysis suggested that the intracellular reductive branch of the mutant was strengthened, which improved 1,3-PD biosynthesis. The procedure and results presented here provide a novel method of screening for strains with improved product formation.


Neural circuitry underlying pain modulation: expectation, hypnosis, placebo.
The ability to predict the likelihood of an aversive event is an important adaptive capacity. Certainty and uncertainty regarding pain cause different adaptive behavior, emotional states, attentional focus, and perceptual changes. Recent functional neuroimaging studies indicate that certain and uncertain expectation are mediated by different neural pathways-the former having been associated with activity in the rostral anterior cingulate cortex and posterior cerebellum, the latter with activation changes in the ventromedial prefrontal cortex, mid-cingulate cortex and hippocampus. Expectation plays an important role not only in its modulation of acute and chronic pain, but also in other disorders which are characterized by certain expectation (specific phobias) or uncertain expectation (generalized anxiety disorder) of aversive events.


Draft genome sequence of Streptomyces strain S4, a symbiont of the leaf-cutting ant Acromyrmex octospinosus.
Streptomyces spp. are common symbionts of the leaf-cutting ant species Acromyrmex octospinosus, which feeds on basidiomycete fungus leaf matter and harvests the lipid- and carbohydrate-rich gongylidia as a food source. A. octospinosus and other ant genera use antifungal compounds produced by Streptomyces spp. and other actinomycetes in order to help defend their fungal gardens from parasitic fungi. Herein, we report the draft genome sequence of Streptomyces strain S4, an antifungal-producing symbiont of A. octospinosus.


Nomogram for Predicting Risk of Cancer Therapy-Related Cardiac Dysfunction in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.
Background Cancer therapy-related cardiac dysfunction (CTRCD) is an important treatment-limiting toxicity for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that adversely affects cancer and cardiovascular outcomes. Easy-to-use tools that incorporate readily accessible clinical variables for individual estimation of CTRCD risk are needed. Methods and Results From 2004 to 2013, 1440 patients with stage I to III HER2-positive breast cancer treated with trastuzumab-based therapy were identified. A multivariable Cox proportional hazards model was constructed to identify risk factors for CTRCD and included the 1377 patients in whom data were complete. Nine clinical variables, including age, race, body mass index, left ventricular ejection fraction, systolic blood pressure, coronary artery disease, diabetes, arrhythmia, and anthracycline exposure were built into a nomogram estimating risk of CTRCD at 1 year. The nomogram was validated for calibration and discrimination using bootstrap resampling. A total of 177 CTRCD events occurred within 1 year of HER2-targeted treatment. The nomogram for prediction of 1-year CTRCD probability demonstrated good discrimination, with a concordance index of 0.687. The predicted and observed probabilities of CTRCD were similar, demonstrating good model calibration. Conclusions A nomogram composed of 9 readily accessible clinical variables provides an individualized 1-year risk estimate of CTRCD among women with HER2-positive breast cancer receiving HER2-targeted therapy. This nomogram represents a simple-to-use tool for clinicians and patients that can inform clinical decision-making on breast cancer treatment options, optimal frequency of cardiac surveillance, and role of cardioprotective strategies.


Maximizing federal Medicaid dollars: nursing home provider tax adoption, 2000-2004.
Since Medicaid is jointly financed by the federal and state governments, state officials have sought to offset state expenditures by maximizing federal contributions. One such strategy is to adopt a provider tax, which enables states to collect revenues from providers; those revenues are then used to pay for services rendered to Medicaid recipients, thereby leveraging federal matching dollars without concomitant increases in state expenditures. The number of states adopting a nursing home tax increased from thirteen to thirty-one between 2000 and 2004. This study seeks to identify the factors that spurred the rapid increase in nursing home provider taxes following implementation of the Balanced Budget Act of 1997. Results indicate that states with more powerful nursing home lobbies, lower proportions of private pay nursing home residents, worse fiscal health, weaker fiscal capacity, broader Medicaid eligibility, and nursing home supply restrictions were more likely to adopt. This implies that state officials react rationally to prevailing fiscal and programmatic circumstances when formulating policy under Medicaid and that providers seek relief, in part, from the adverse fiscal consequences of federal policy changes by promoting policy change at the state level.


Retinoic acid signalling in the zebrafish embryo is necessary during pre-segmentation stages to pattern the anterior-posterior axis of the CNS and to induce a pectoral fin bud.
A number of studies have suggested that retinoic acid (RA) is an important signal for patterning the hindbrain, the branchial arches and the limb bud. Retinoic acid is thought to act on the posterior hindbrain and the limb buds at somitogenesis stages in chick and mouse embryos. Here we report a much earlier requirement for RA signalling during pre-segmentation stages for proper development of these structures in zebrafish. We present evidence that a RA signal is necessary during pre-segmentation stages for proper expression of the spinal cord markers hoxb5a and hoxb6b, suggesting an influence of RA on anteroposterior patterning of the neural plate posterior to the hindbrain. We report the identification and expression pattern of the zebrafish retinaldehyde dehydrogenase2 (raldh2/aldh1a2) gene. Raldh2 synthesises retinoic acid (RA) from its immediate precursor retinal. It is expressed in a highly ordered spatial and temporal fashion during gastrulation in the involuting mesoderm and during later embryogenesis in paraxial mesoderm, branchial arches, eyes and fin buds, suggesting the involvement of RA at different times of development in different functional contexts. Mapping of the raldh2 gene reveals close linkage to no-fin (nof), a newly discovered mutant lacking pectoral fins and cartilaginous gill arches. Cloning and functional tests of the wild-type and nof alleles of raldh2 reveal that nof is a raldh2 mutant. By treating nof mutants with RA during different time windows and by making use of a retinoic acid receptor antagonist, we show that RA signalling during pre-segmentation stages is necessary for anteroposterior patterning in the CNS and for fin induction to occur.


Neurofeedback training in children with ADHD: 6-month follow-up of a randomised controlled trial.
Neurofeedback (NF) could help to improve attentional and self-management capabilities in children with attention-deficit/hyperactivity disorder (ADHD). In a randomised controlled trial, NF training was found to be superior to a computerised attention skills training (AST) (Gevensleben et al. in J Child Psychol Psychiatry 50(7):780-789, 2009). In the present paper, treatment effects at 6-month follow-up were studied. 94 children with ADHD, aged 8-12 years, completed either 36 sessions of NF training (n = 59) or a computerised AST (n = 35). Pre-training, post-training and follow-up assessment encompassed several behaviour rating scales (e.g., the German ADHD rating scale, FBB-HKS) completed by parents. Follow-up information was analysed in 61 children (ca. 65%) on a per-protocol basis. 17 children (of 33 dropouts) had started a medication after the end of the training or early in the follow-up period. Improvements in the NF group (n = 38) at follow-up were superior to those of the control group (n = 23) and comparable to the effects at the end of the training. For the FBB-HKS total score (primary outcome measure), a medium effect size of 0.71 was obtained at follow-up. A reduction of at least 25% in the primary outcome measure (responder criterion) was observed in 50% of the children in the NF group. In conclusion, behavioural improvements induced by NF training in children with ADHD were maintained at a 6-month follow-up. Though treatment effects appear to be limited, the results confirm the notion that NF is a clinically efficacious module in the treatment of children with ADHD.


Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools.
Detecting alleles that confer small increments in susceptibility to disease will require large-scale allelic association studies of single-nucleotide polymorphisms (SNPs) in candidate, or positional candidate, genes. However, current genotyping technologies are one to two orders of magnitude too expensive to permit the analysis of thousands of SNPs in large samples. We have developed and thoroughly validated a highly accurate protocol for SNP allele frequency estimation in DNA pools based upon the SNaPshot (Applied Biosystems) chemistry adaptation of primer extension. Using this assay, we were able to estimate the difference in allele frequencies between pooled cases and controls (Delta) with a mean error of 0.01. Moreover, when we genotyped seven different SNPs in a single multiplex reaction, the results were similar, with a mean error for Delta of 0.008. The assay performed well for alleles of low frequency alleles (f approximately 0.05) and was accurate even with relatively poor quality DNA template extracted from mouthwashes. Our assay conditions are generalisable, universal, robust and, therefore, for the first time, permit high-throughput association analysis at a realistic cost.


Cardiac Proteome Profiling in Ischemic and Dilated Cardiomyopathy Mouse Models.
Heart failure (HF) is a worldwide pandemic with an unacceptable high level of morbidity and mortality. Understanding the different pathophysiological mechanisms will contribute to prevention and individualized therapy of HF. We established mouse models for ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) by inducing myocardial infarction (MI) and Coxsackievirus B3 infection, respectively. Isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry technology was used to identify the protein expression profiles in control and failing hearts. A total of 1,638 proteins were identified and compared in this proteomics analysis. Among them, 286 proteins were differently expressed. Gene ontology, KEGG pathway and ingenuity pathway analysis was performed to systematically assess the potential connections of the differentially expressed proteins to biological functions. Compared with control group, the differentially expressed proteins derived from the hearts of ICM and DCM mice were partially similar and mainly modulated in oxidative phosphorylation, metabolism and protein folding pathways. Moreover, difference still existed, the differentially expressed proteins between DCM and ICM hearts were significantly modulated in oxidative phosphorylation, metabolic and AMPK signaling pathways. Confirmatory western bolt analysis demonstrated that SDHB was down-regulated in both ICM and DCM hearts, while UQCRQ, GLUT4 and adiponectin were up-regulated in ICM hearts. Adenosine triphosphate (ATP) concentration significantly decreased in both DCM and ICM hearts. The protein expression of phospho-AMPKα decreased significantly in DCM hearts, but increased in ICM. In summary, oxidative phosphorylation, cardiac metabolism, and protein folding play critical roles in the pathogenesis of HF. The diverse changes in protein expression profiles between failing hearts induced by either MI or CVB3 infection demonstrated the heterogeneity of HF. Understanding the differences in proteome profiles could offer more precise therapeutic options for HF.


The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.
The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.


A novel coelenterate luciferin-based luminescent probe for selective and sensitive detection of thiophenols.
The first dual bioluminescent and chemiluminescent sensor for detecting highly toxic thiophenols has been developed. Such a probe was designed by using a coelenterazine analogue as the luminophore and dinitrophenyl ether as the recognition moiety. It should be noted that this probe displayed good sensitivity and selectivity toward thiophenols, and has been effectively applied for the quantitative detection of thiophenols in aqueous media and complex biological samples.


Water-soluble interpolyelectrolyte complexes of polyisobutylene-block-poly(methacrylic acid) micelles: formation and properties.
We report on interpolyelectrolyte complexes (IPECs) formed by micelles of ionic amphiphilic diblock copolymers with polyisobutylene (PIB) and poly(sodium methacrylate) (PMANa) blocks interacting with quaternized poly(4-vinylpyridine) (P4VPQ). The interpolyelectrolyte complexation was followed by turbidimetry and small angle neutron scattering (SANS). The data obtained by means of a combination of SANS, dynamic light scattering (DLS), and cryogenic transmission electron microscopy (cryo-TEM) provide evidence on the core-shell-corona structure of the complex species with the shell assembled from fragments of electrostatically bound PMANa and quaternized P4VPQ fragments, original PIBx-b-PMAAy micelles apparently playing a lyophilizing part. The complex formation is followed by potentiometric titration as well. This process is initially kinetically controlled. In the second step larger aggregates rearrange in favor of smaller complexes with core-shell-corona structure, which are thermodynamically more stable. An increase in ionic strength of the solution results in dissociation of the complex species as proven by SANS and analytical ultracentrifugation (AUC). This process begins at the certain threshold ionic strength and proceeds via a salt-induced gradual release of chains of the cationic polyectrolyte from the complex species.


The crystal structure of the AF2331 protein from Archaeoglobus fulgidus DSM 4304 forms an unusual interdigitated dimer with a new type of alpha + beta fold.
The structure of AF2331, a 11-kDa orphan protein of unknown function from Archaeoglobus fulgidus, was solved by Se-Met MAD to 2.4 A resolution. The structure consists of an alpha + beta fold formed by an unusual homodimer, where the two core beta-sheets are interdigitated, containing strands alternating from both subunits. The decrease in solvent-accessible surface area upon dimerization is unusually large (3960 A(2)) for a protein of its size. The percentage of the total surface area buried in the interface (41.1%) is one of the largest observed in a nonredundant set of homodimers in the PDB and is above the mean for nearly all other types of homo-oligomers. AF2331 has no sequence homologs, and no structure similar to AF2331 could be found in the PDB using the CE, TM-align, DALI, or SSM packages. The protein has been identified in Pfam 23.0 as the archetype of a new superfamily and is topologically dissimilar to all other proteins with the "3-Layer (BBA) Sandwich" fold in CATH. Therefore, we propose that AF2331 forms a novel alpha + beta fold. AF2331 contains multiple negatively charged surface clusters and is located on the same operon as the basic protein AF2330. We hypothesize that AF2331 and AF2330 may form a charge-stabilized complex in vivo, though the role of the negatively charged surface clusters is not clear.


Inventory analysis and carbon footprint of coastland-hotel services: A Spanish case study.
Tourism is a key industry in the Spanish economy. Spain was in the World top three ranking by international tourist arrivals and by income in 2015. The development of the tourism industry is essential to maintain the established economic system. However, if the environmental requirements were not taken into account, the country would face a negative effect on depletion of local environmental resources from which tourism depends. This case study evaluates, through a life cycle perspective, the average carbon footprint of an overnight stay in a Spanish coastland hotel by analyzing 14 two-to-five-stars hotels. Inventory and impact data are analyzed and presented both for resource use and greenhouse gases emissions, with the intention of helping in the environmental decision-making process. The main identified potential hotspots are electricity and fuels consumption (6 to 30kWh/overnight stay and 24 to 127MJ/overnight stay respectively), which are proportional to the number of stars and unoccupancy rate and they produce more than 75% of the impact. It is also revealed that voluntary implementation of environmental monitoring systems (like EMAS regulation) promotes collection of more detailed and accurate data, which helps in a more efficient use of resources. A literature review on LCA and tourism is also discussed. Spanish hotels inventory data presented here for the first time will be useful for tourism related managers (destination managers, policy makers and hotel managers among others) to calculate sustainability key indicators, which can lead to achieve real sustainable-tourism goals. Further data collection will be needed in future projects to gather representative data from more hotels, other accommodation facilities and also other products/services offered by tourist sector in Spain (like transport of tourists, food and beverage, culture-sports & recreation and others).


Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety.
Ultrasonic neuromodulation is a rapidly growing field, in which low-intensity ultrasound (US) is delivered to nervous system tissue, resulting in transient modulation of neural activity. This review summarizes the findings in the central and peripheral nervous systems from mechanistic studies in cell culture to cognitive behavioral studies in humans. The mechanisms by which US mechanically interacts with neurons and could affect firing are presented. An in-depth safety assessment of current studies shows that parameters for the human studies fall within the safety envelope for US imaging. Challenges associated with accurately targeting US and monitoring the response are described. In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting compared with alternative methods. US neurostimulation has the potential to be used both as a scientific instrument to investigate brain function and as a therapeutic modality to modulate brain activity.


Water Exchange on [Ln(DO3A)(H2O)2] and [Ln(DTTA-Me)(H2O)2](-) Studied by Variable Temperature, Pressure, and Magnetic Field NMR.
Water exchange kinetics of [Ln(L)(H2O)2](x) complexes (Ln = Pr, Nd, Dy, Tm, and Yb; L = DO3A and DTTA-Me) were studied by (17)O NMR spectroscopy as a function of temperature, pressure, and frequency and by (1)H nuclear magnetic relaxation dispersion. Water exchange rate constants of both complexes show a maximum at dysprosium. Water exchange on negatively charged complexes of the acyclic DTTA-Me ligand is much faster than on the neutral complexes of the macrocyclic DO3A. Small activation volumes |ΔV(⧧)| < 1 cm(3) mol(-1) measured for water exchange on [Ln(DO3A)(H2O)2] indicate an interchange type of mechanism (I) for the lanthanide complexes studied. In the case of [Ln(DTTA-Me)(H2O)2](-), a change in mechanism is detected from a dissociative mechanism (D, ΔV(⧧) = 7 cm(3) mol(-1)) for complexes with larger ions (Pr to Gd) to an interchange mechanism (Id, I; ΔV(⧧) = +1.8 and +0.4 cm(3) mol(-1)) for complexes with smaller ions (Dy and Tm).


Bone marrow biopsies performed by both the powered OnControl drill device and the Jamshidi needle produce adequate specimens.
The aim of our study was to evaluate the adequacy and quality of the bone marrow (BM) obtained by OnControl powered drill (P-group) and to compare it with manual procedure (M-group). Retrospective analysis was done on 75 BM specimens; Jamshidi needle (n=44) and OnControl (n=31). Biopsy length after fixation, evaluable marrow length and total area, and fragmentation, aspiration and marrow dropout artefacts were compared. Biopsies were sufficient for diagnosis in 38/44 cases (86%) in the M-group and in 26/31 cases (83%) in the P-group. The most common reason for suboptimal/inadequate biopsies was subcortical specimens (4/6) in the M-group and aspiration artefact (5/5) in the P-group. Average length after fixation, evaluable marrow length, evaluable marrow area was comparable. Aspiration artefact was minimal (<10%) in the majority of BM samples in the M-group (31/44), while 25/31 BM in the P-group showed >10% aspiration artefact, p<0.0001. Our study suggests that quality of biopsy cylinder and adequacy rate of the biopsy is comparable between both devices. OnControl device showed more aspiration artefact.


Dynamics of the His79-heme alkaline transition of yeast iso-1-cytochrome c probed by conformationally gated electron transfer with Co(II)bis(terpyridine).
Alkaline conformers of cytochrome c may be involved in both its electron transport and apoptotic functions. We use cobalt(II)bis(terpyridine), Co(terpy)2(2+), as a reagent for conformationally gated electron-transfer (gated ET) experiments to study the alkaline conformational transition of K79H variants of yeast iso-1-cytochrome c expressed in Escherichia coli , WT*K79H, with alanine at position 72 and Saccharomyces cerevisiae , yK79H, with trimethyllysine (Tml) at position 72. Co(terpy)2(2+) is well-suited to the 100 ms to 1 s time scale of the His79-mediated alkaline conformational transition of these variants. Reduction of the His79-heme alkaline conformer by Co(terpy)2(2+) occurs primarily by gated ET, which involves conversion to the native state followed by reduction, with a small fraction of the His79-heme alkaline conformer directly reduced by Co(terpy)2(2+). The gated ET experiments show that the mechanism of formation of the His79-heme alkaline conformer involves only two ionizable groups. In previous work, we showed that the mechanism of the His73-mediated alkaline conformational transition requires three ionizable groups. Thus, the mechanism of heme crevice opening depends upon the position of the ligand mediating the process. The microscopic rate constants provided by gated ET studies show that mutation of Tml72 (yK79H variant) in the heme crevice loop to Ala72 (WT*K79H variant) affects the dynamics of heme crevice opening through a small destabilization of both the native conformer and the transition state relative to the His79-heme alkaline conformer. Previous pH jump data had indicated that the Tml72→Ala mutation primarily stabilized the transition state for the His79-mediated alkaline conformational transition.


Beneficial effects of apple peel polyphenols on vascular endothelial dysfunction and liver injury in high choline-fed mice.
This study was designed to investigate the preventive effects of Red Fuji apple peel polyphenolic extract (APP) on vascular endothelial dysfunction and liver injury in mice fed a high choline diet. The mice were fed 3% dietary choline in drinking water for 8 weeks and displayed vascular dysfunction and liver damage (p < 0.01). The administration of APP at 600 and 900 mg per kg bw significantly elevated serum NO, HDL and 6-Keto-PGF1a levels and lowered serum TC, TG, LDL, ET-1 and TXB2 levels in the HC-fed mice. Besides, APP also caused the reduction of AST, ALT activities and MDA, CRP, TNF-α levels, and increased the hepatic GSH-Px and SOD activities of the HC-fed mice. Furthermore, the histopathology of the liver by conventional H&E and oil red O staining confirmed the liver steatosis induced by a choline diet and the hepatoprotective effect of APP. The experiment results indicated that the polyphenolic extract from apple peel might be regarded as a preventive and therapeutic product for the amelioration of HC diet-induced vascular dysfunction and hepatic injury.


Identification of QTLs for fruit quality traits in Japanese apples: QTLs for early ripening are tightly related to preharvest fruit drop.
Many important apple (Malus × domestica Borkh.) fruit quality traits are regulated by multiple genes, and more information about quantitative trait loci (QTLs) for these traits is required for marker-assisted selection. In this study, we constructed genetic linkage maps of the Japanese apple cultivars 'Orin' and 'Akane' using F1 seedlings derived from a cross between these cultivars. The 'Orin' map consisted of 251 loci covering 17 linkage groups (LGs; total length 1095.3 cM), and the 'Akane' map consisted of 291 loci covering 18 LGs (total length 1098.2 cM). We performed QTL analysis for 16 important traits, and found that four QTLs related to harvest time explained about 70% of genetic variation, and these will be useful for marker-assisted selection. The QTL for early harvest time in LG15 was located very close to the QTL for preharvest fruit drop. The QTL for skin color depth was located around the position of MYB1 in LG9, which suggested that alleles harbored by 'Akane' are regulating red color depth with different degrees of effect. We also analyzed soluble solids and sugar component contents, and found that a QTL for soluble solids content in LG16 could be explained by the amount of sorbitol and fructose.


Cutaneous T-cell lymphoma presenting as benign dermatoses.
Cutaneous T-cell lymphoma, also known as mycosis fungoides, is a malignancy of the T helper (CD4+) cells. Diagnosis is difficult early in the course of this disease because it mimics several benign skin disorders, including eczema, psoriasis and contact dermatitis. Cutaneous T-cell lymphoma is also difficult to identify histologically, and multiple biopsies may be necessary to confirm the diagnosis. Treatment may require a combination of topical and systemic agents. Patients with limited skin disease have a good prognosis, but the prognosis is less hopeful in those with extracutaneous involvement. As the disease progresses, the normal T-cell population is eliminated, and the patient becomes significantly immunosuppressed. Infection is the primary cause of mortality in patients with cutaneous T-cell lymphoma.


Effects of acute glucose overload on histamine H2 receptor-mediated Ca2+ mobilization in bovine cerebral endothelial cells.
[Ca2+]i and whole-cell membrane current were measured in microvascular endothelial cells from bovine brain. The effects of histamine on [Ca2+]i were examined, and the acute effect of changing extracellular glucose concentration on Ca2+ homeostasis was investigated. Application of 10 micromol/l histamine evoked an initially transient and then sustained increase in [Ca2+]i in normal Krebs solution, but only the transient component in Ca2+-free solution, thereby indicating that histamine mobilizes Ca2+ both from intracellular store sites and extracellular space. The effects of histamine on [Ca2+]i were inhibited by the H2 antagonists, ranitidine and cimetidine, but not by the H1 antagonist, pyrilamine. Incubation of the cells for 2 h in solutions containing low (1.1 and 2.3 mmol/l) or high (23 mmol/l) concentrations of glucose did not influence the resting level of [Ca2+]i. Treatment with low concentrations of glucose did not impair histamine-induced Ca2+ mobilization. On the other hand, when histamine was applied to the cells pretreated with 23 mmol/l glucose, it failed to mobilize Ca2+ from both intracellular store sites and extracellular space. The effect of histamine was mimicked by dibutyryl cyclic AMP, but glucose overload failed to inhibit this, suggesting that glucose overload inhibits H2 receptor-mediated cyclic AMP production. Glucose overload-induced impairment of histamine action was reversed by pretreatment with staurosporine and calphostin C and mimicked by phorbol-12,13-dibutyrate, thereby suggesting the involvement of protein kinase C in the high glucose-induced inhibition of Ca2+ mobilization. Whole-cell membrane current measurement showed that there was no difference in the membrane currents between control and high glucose-treated cells. These results indicate that in bovine brain microvascular endothelial cells, histamine induces Ca2+ release from intracellular store sites and subsequent entry from the extracellular space through the activation of H2 receptors. Glucose overload acutely inhibits histamine-induced Ca2+ mobilization by the activation of protein kinase C.


Medical Graduates' Research Practices and Perceptions: A comparative cross-sectional study between 2015 and 2017 graduates of King Abdulaziz University.
This study aimed to compare changes in medical students' research practices and perceptions of two cohorts of graduates. This cross-sectional comparative study was conducted from November 2014 to December 2017 and included the 2015 and 2017 medical graduates of King Abdulaziz University, Jeddah, Saudi Arabia. A validated self-administrated questionnaire, which included questions about participants' age and gender, research activities, and obstacles to and motivators for research involvement was used. A total of 484 graduates were included in this study (response rate: 96.8%). A significant difference was found between the 2015 and 2017 graduates who had not started any research project (48.4% versus 35%; P <0.001) and a 20% increase in the 2017 graduates' confidence in their abilities to start their own projects was observed (P <0.001). Significantly more 2017 graduates were engaged in various research roles, other than 'author', compared to 2015 graduates (71.3% versus 55.4%; P <0.001). Career progression was the main motivator for both the 2015 and 2017 medical graduates to participate in research (79.5%). Reported obstacles to research included a lack of dedicated time for research and methodology training and a shortage of research project opportunities. This study highlights positive changes in attitudes towards and perceptions of research among medical graduates.


Recent perspectives on global epidemiology of asthma in childhood.
New research in asthma epidemiology in children includes the development of the ISAAC programme, which has shown large variations globally in the prevalence of asthma symptoms. Time trends in the prevalence of asthma symptoms have shown a mixed picture of increases in low prevalence centres, and a plateau or even a decrease in high prevalence centres. A range of environmental factors have been studied and some potentially protective associations have been found, as well as potentially aggravating factors. Atopy has less influence on the prevalence of symptoms of asthma in low and middle income countries. Breast feeding exerts a protective effect only on non-atopic asthma in non-affluent countries. Future research should explore these areas further.


Differential effect of mechanical thrombectomy and intravenous thrombolysis in atrial fibrillation associated stroke.
Atrial fibrillation (AF) associated ischemic stroke has worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Limited data exist about the effect of AF on procedural and clinical outcomes after mechanical thrombectomy (MT). To determine whether recanalization efficacy, procedural speed, and clinical outcomes differ in AF associated stroke treated with MT. We performed a retrospective cohort study of the Stroke Thrombectomy and Aneurysm Registry (STAR) from January 2015 to December 2018 and identified 4169 patients who underwent MT for an anterior circulation stroke, 1517 (36.4 %) of whom had comorbid AF. Prospectively defined baseline characteristics, procedural outcomes, and clinical outcomes were reported and compared. AF predicted faster procedural times, fewer passes, and higher rates of first pass success on multivariate analysis (p<0.01). AF had no effect on intracranial hemorrhage (aOR 0.69, 95% CI 0.43 to 1.12) or 90-day functional outcomes (aOR 1.17, 95% CI 0.91 to 1.50) after MT, although patients with AF were less likely to receive IVT (46% vs 54%, p<0.0001). In patients treated with MT, comorbid AF is associated with faster procedural time, fewer passes, and increased rates of first pass success without increased risk of intracranial hemorrhage or worse functional outcomes. These results are in contrast to the increased hemorrhage rates and worse functional outcomes observed in AF associated stroke treated with supportive care and or IVT. These data suggest that MT negates the AF penalty in ischemic stroke.


Reducing the population's sodium intake: the UK Food Standards Agency's salt reduction programme.
To describe the UK Food Standards Agency's (FSA) salt reduction programme undertaken between 2003 and 2010 and to discuss its effectiveness. Relevant scientific papers, campaign materials and evaluations and consultation responses to the FSA's salt reduction programme were used. Adult salt intakes, monitored using urinary Na data collected from UK-wide surveys, indicate a statistically significant reduction in the population's average salt intake from 9·5 g/d in 2000-2001 to 8·6 g/d in 2008, which is likely to have health benefits. Reducing salt intake will have an impact on blood pressure; an estimated 6 % of deaths from CHD in the UK can be avoided if the number of people with high blood pressure is reduced by 50 %. Salt levels in food, monitored using commercial label data and information collected through an industry self-reporting framework, indicated that substantial reductions of up to 70 % in some foods had been achieved. The FSA's consumer campaign evaluation showed increased awareness of the benefits of reducing salt intake on health, with 43 % of adults in 2009 claiming to have made a special effort to reduce salt in their diet compared with 34 % of adults in 2004, before the campaign commenced. The UK's salt reduction programme successfully reduced the average salt intake of the population and increased consumers' awareness. Significant challenges remain in achieving the population average salt intake of 6 g/d recommended by the UK's Scientific Advisory Committee on Nutrition. However, the UK has demonstrated the success of its programme and this approach is now being implemented elsewhere in the world.


Photoadaptation in Neurospora by competitive interaction of activating and inhibitory LOV domains.
Light responses and photoadaptation of Neurospora depend on the photosensory light-oxygen-voltage (LOV) domains of the circadian transcription factor White Collar Complex (WCC) and its negative regulator VIVID (VVD). We found that light triggers LOV-mediated dimerization of the WCC. The activated WCC induces expression of VVD, which then disrupts and inactivates the WCC homodimers by the competitive formation of WCC-VVD heterodimers, leading to photoadaptation. During the day, expression levels of VVD correlate with light intensity, allowing photoadaptation over several orders of magnitude. At night, previously synthesized VVD serves as a molecular memory of the brightness of the preceding day and suppresses responses to light cues of lower intensity. We show that VVD is essential to discriminate between day and night, even in naturally ambiguous photoperiods with moonlight.


The period gene and allochronic reproductive isolation in Bactrocera cucurbitae.
Clock genes that pleiotropically control circadian rhythm and the time of mating may cause allochronic reproductive isolation in the melon fly Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae). Flies with a shorter circadian period (ca. 22 h of locomotor activity rhythm) mated 5 h earlier in the day than those with a longer circadian period (ca. 30 h). Mate-choice tests demonstrated significant pre-mating isolation between populations with short and long circadian periods. Pre-mating isolation did not occur when the mating time was synchronized between the two populations by photoperiodic controls, indicating that reproductive isolation is due to variations in the time of mating and not any unidentified ethological difference between the two populations. We cloned the period (per) gene of B. cucurbitae that is homologous to the per gene in Drosophila. The relative level of per mRNA in the melon fly exhibited a robust daily fluctuation under light : dark conditions. The fluctuation of per expression under dark : dark conditions is closely correlated to the locomotor rhythm in B. cucurbitae. These results suggest that clock genes can cause reproductive isolation via the pleiotropic effect as a change of mating time.


Ginsenoside Ameliorates Cognitive Dysfunction in Type 2 Diabetic Goto-Kakizaki Rats.
BACKGROUND Ginsenoside is the major bioactive component of ginseng, which has been proven to be a neuroprotective drug. The aim of this study was to evaluate the therapeutic effect of ginsenoside in a diabetic Goto-Kakizaki (GK) rat model. MATERIAL AND METHODS Twenty GK rats were randomly divided into a diabetic model (DM) group (n=10) and a ginsenoside + DM group (n=10); Wistar rats with the same age and body weight were used as the control (CON) group (n=10). Food and water intake, body weight, and blood fasting plasma glucose were measured. The Morris water maze test was used to detect learning and memory functions of the rats. Superoxide dismutase (SOD), malondialdehyde (MDA), and inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the hippocampus were analyzed after ginsenoside treatment. RESULTS The blood glucose, body weight, Morris correlation index, SOD, MDA, and other test results were increased in the diabetic rats. Ginsenoside ameliorated diabetic cognitive decline. CONCLUSIONS The possible mechanism was related to inhibiting brain oxidative/nitrosative damage and affecting the expression of the cytokines IL-1β, IL-6, and TNF-α.


Meta-analysis of clinical trials of Cyclo 3 Fort in the treatment of chronic venous insufficiency.
Chronic venous insufficiency (CVI) of the lower limbs is a major cause of morbidity and varicose veins affect 20% to 60% of adults in the western world. The treatment of patients with CVI attempts to reduce both clinical symptoms and the development of chronic venous disease. A meta-analysis using data from all clinical trials and studies of Cyclo 3 Fort, a combination of root extract of the Ruscus aculeatus plant (150 mg per capsule), hesperidin methyl chalcone (150 mg) and ascorbic acid (100 mg), was carried out to estimate the overall effect on the symptoms and severity of chronic venous insufficiency. The meta-analysis included 20 placebo controlled, randomised, double blind studies and 5 randomised studies against a comparator drug. There were 6 single arm studies of Cyclo 3 Fort alone with no placebo arm. In all studies the response to Cyclo 3 Fort was compared to baseline values. In total there was information from 10,246 subjects. On a 4 point symptom severity scale, where 0 corresponds to no symptoms and 3 to severe symptoms, Cyclo 3 Fort significantly reduces the severity of pain by 0.44 (0.12) points; cramps 0.26 (0.08), heaviness 0.53 (0.11), and paraesthesia 0.29 (0.10) compared to placebo. There is also a significant reduction in venous capacity of 0.70 (0.19) ml/100 ml with Cyclo 3 Fort compared to placebo. We also found reductions in the severity of oedema 0.43 (0.20) points, and decreases in calf and ankle circumference, 0.73 (0.37) cms and 1.17 (0.83) cm, respectively, among patients treated with Cyclo 3 Fort compared to placebo which were not statistically significant. Despite questions surrounding the variability of data quality and sample size of some of the studies, we conclude that in patients with CVI Cyclo 3 Fort significantly reduces the severity of the symptoms compared to placebo. This study is a strong and objective demonstration of the clinical efficacy of Cyclo 3 Fort in treating patients with CVI.


The AO Ulnar Shortening Osteotomy System Indications and Surgical Technique.
Ulnar shortening osteotomy is an established and frequently performed surgical procedure in wrist surgery. The technical aspects of the procedure have continued to develop in recent years, with instruments and implants being developed specifically for this purpose. Ulnar shortening osteotomy is required for different clinical indications and situations. These varying indications demand different amounts of shortening, but all must be precise and accurate. Controversy exists as to how this can best be achieved in terms of the location for osteotomy, the surgical approach and geometry of the osteotomy, as well as which implant to use to provide optimal stability. The goal of all techniques (besides successfully resolving the underlying problem) is to achieve reliable and rapid bone union without compromising early functional rehabilitation and also to avoid hardware complications. The AO Hand Expert Group has developed a specialized instrumentation system with dedicated and specifically designed implants to ensure exact and accurate cutting with precise and rigid stabilization of the ulna. The matched drill guides and double-blade saws allow accurate completion of the planned amount of shortening together with precise coaptation of the osteotomy fragments. The specific ulnar osteotomy LCP (locking compression plate) combines maximum stability with minimum bulk and soft tissue irritation. The features of the implant, its surgical technique, and early results are described.


Effects of estradiol and progesterone on gonadotropin LHβ- and FSHβ-subunit promoter activities in gonadotroph LβT2 cells.
Sex steroid hormones play roles in the regulation of pituitary hormone synthesis and secretion. Here we investigated the role of estradiol (E2) and progesterone (P4) on pituitary gonadotropin luteinizing hormone (LH)β- and follicle stimulating hormone (FSH)β-transcriptional activity in a single colony of gonadotroph LβT2 cells. Pituitary gonadotroph cell line, LβT2 cells were used in this study. Cells were transfected with LHβ- or FSHβ-subunit promoter region-linked luciferase vector, and stimulated with gonadotropin-releasing hormone (GnRH) in the presence or absence of sex steroids. Transcriptional activity for LHβ- and FSHβ-subunit were determined by luciferase assay. Effects of sex steroids on cell proliferation was also determined by measurement of 5-bromoe-2'-deoxyuridine (BrdU) incorporation. The basal promoter activity of the LHβ subunit was not modulated by 10 nM E2, but gonadotropin releasing hormone (GnRH)-induced LHβ promoter activity was significantly increased by the same concentration of E2. Similarly, although the basal FSHβ promoter was not modulated by 10 nM E2, GnRH-induced FSHβ promoters were significantly potentiated in the presence of E2. One micromole E2 modulated neither basal nor GnRH-induced LHβ and FSHβ promoters. On the other hand, basal LHβ promoter activity was enhanced by 1 µM P4, but the stimulatory response of GnRH on LHβ promoters was significantly inhibited in the presence of 1 µM P4. Similar to LHβ promoters, the basal activity of the FSHβ promoter was increased by 1 µM P4; however, the response to GnRH was not modulated in the presence of P4. Ten micromoles P4 modified neither basal nor GnRH-induced promoter activity for LHβ and FSHβ. E2 had no antagonistic effect on P4-induced basal promoter activities of LHβ or FSHβ. A cell proliferation assay showed that neither E2 nor P4 modulated the growth of LβT2 cells, even in the presence or absence of GnRH. These observations suggest that both E2 and P4 uniquely modulate basal and GnRH-stimulated gonadotropin promoters without affecting cell growth.


Unique topological nodal line states and associated exceptional thermoelectric power factor platform in Nb3GeTe6 monolayer and bulk.
To date, ideal topological nodal line semimetal (TNLS) candidates in high dynamically stable and high thermally stable two-dimensional (2D) materials are still extremely scarce. Herein, by performing first-principles calculations, on the one hand, we found that three-dimensional Nb3GeTe6 bulk possesses a single closed TNL in the kx = 0 plane and a fourfold TNL in the S-R direction without considering spin-orbit coupling (SOC). Under the SOC effect, a new topological signature, i.e., hourglass-like Dirac nodal line, occurs in Nb3GeTe6 bulk. On the other hand, we found that the 2D Nb3GeTe6 monolayer features a doubly degenerate TNL along surface X-S paths. Importantly, this monolayer enjoys the following advantages: (i) it has high thermal stability at room temperature and above; (ii) its TNL is nearly flat in energy and is very close to the Fermi level (EF), which provides a fantastic maximum value platform of the thermoelectric power factor around the EF; and (iii) no extraneous bands are close to the TNL, near the Fermi level. Moreover, we explore the entanglement between the topological states and thermolectric properties for the 2D Nb3GeTe6 monolayer. Our work not only reports the discovery of a novel TNL material, but also builds the link between the TNL and thermoelectric properties.


Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205.
Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.


In Vivo Morphological Changes of the Femoropopliteal Arteries due to Knee Flexion After Endovascular Treatment of Popliteal Aneurysm.
Purpose: To evaluate morphological changes of the femoropopliteal (FP) arteries due to limb flexion in patients undergoing endovascular treatment of popliteal artery aneurysms (PAAs). Materials and Methods: Seven male patients (mean age 68 years) underwent endovascular treatment of PAA with a Viabahn stent-graft between January 2013 and December 2017. During follow-up, one contrast-enhanced computed tomography angiography (CTA) scan of the lower limbs was acquired for each recruited patient. A standardized CTA protocol for acquisitions in both straight-leg and bent-leg positions was used to visualize changes in artery shape due to limb flexion. Three-dimensional reconstruction of the FP segment was performed to compute mean diameter and eccentricity of the vascular lumen and to measure length, tortuosity, and curvature of the vessel centerline in 3 arterial zones: (A) between the origin of the superficial femoral artery and the proximal end of the stent-graft, (B) within the stent-graft, and (C) from the distal end of the stent-graft to the origin of the anterior tibial artery. Results: After limb flexion, all zones of the FP segment foreshortened: 6% in zone A (p=0.001), 4% in zone B (p=0.001), and 8% in zone C (p=0.07), which was the shortest (mean 4.5±3.6 cm compared with 23.8±5.7 cm in zone A and 23.6±7.4 cm in zone B). Tortuosity increased in zone A (mean 0.03 to 0.05, p=0.03), in zone B (0.06 to 0.15, p=0.005), and in zone C (0.027 to 0.031, p=0.1). Mean curvature increased 15% (p=0.05) in zone A, 27% (p=0.005) in zone B, and 95% (p=0.06) in zone C. In all zones, the mean artery diameter and eccentricity were not significantly affected by limb flexion. Conclusion: Limb flexion induces vessel foreshortening and increases mean curvature and tortuosity of the FP segment both within and outside the area of the stent-graft.


Prevalence and predictors of trichomonas infection in newly incarcerated women.
Trichomonas vaginalis is the most prevalent curable sexually transmitted infection in the United States and may lead to preterm delivery, infertility, and increased HIV transmission. Incarcerated women may be at especially high risk for infection, although few studies have examined routine screening for Trichomonas infection in this population. Women older than 18 years entering the Rhode Island Department of Corrections between September 2009 and May 2011 were recruited to participate. All women submitted a self-collected vaginal swab for APTIMA transcription-mediated amplification testing. Each participant completed a survey addressing demographics, symptoms, sexual behavior, and substance use by audio computer-assisted self-interview. Data analysis was completed using multivariate logistic regression in SAS. Data for 387 women were analyzed. The mean age was 30 years, 60% were white, 18% were Hispanic, 10% were black, and 12% had other race/ethnicity. Forty-four percent reported vaginal symptoms, and 77% reported illicit drug and/or heavy alcohol use in the 30 days before incarceration. The prevalence of Trichomonas was 14% by APTIMA. The strongest predictors of infection included black race (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.9-13.4; P < 0.01), more than 1 year since last Papanicolaou test (OR, 2.5; 95% CI, 1.3-4.8; P < 0.01) and presence of vaginal symptoms (OR, 2.3; 95% CI, 1.2-4.7; P = 0.02). Trichomonas infection is common in incarcerated women, especially among black women, women with vaginal symptoms, and those not receiving routine gynecologic care. Screening for Trichomonas infection in high-risk populations, particularly if using highly sensitive methods such as transcription-mediated amplification, may lead to increased detection and treatment.


Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs.
While the benefits of ascorbic acid (vitamin C, ascorbate) as an essential nutrient are well established, its effects on tumor cells and in tumor treatment are controversial. In particular, conflicting data exist whether ascorbate may increase the cytotoxic effects of antineoplastic drugs or may rather exert adverse effects on drug sensitivity during cancer treatment. Findings are further obscured regarding the distinction between ascorbate and dehydroascorbate (DHA). Thus, the purpose of this study was to evaluate and directly compare the cytotoxic efficacy of ascorbate compared to DHA, and to analyse if ascorbate at pharmacological concentrations affects the efficacy of antineoplastic agents in prostate carcinoma cells. We directly compare the effects of ascorbate (supplied as 'Pascorbin solution for injection') and DHA on tumor cell viability, and determine IC(50) values for various cell lines. At concentrations well below the IC(50), ascorbate effects on cell proliferation and cell cycle are analysed. We furthermore determine changes in cellular sensitivity towards various cytostatic drugs upon pre-treatment of cells with ascorbate. We demonstrate higher therapeutic efficacy of ascorbate over DHA in various cell lines, independent of cell line-specific differences in ascorbate sensitivity, and identify the extracellular generation of H(2)O(2) as critical mechanism of ascorbate action. We furthermore show that, in addition to pro-apoptotic effects described previously, ascorbate treatment already at concentrations well below the IC(50) exerts anti-proliferative effects on tumor cells. Those are based on interference with the cell cycle, namely by inducing a G(0)/G(1) arrest. Pre-treatment of tumor cells with ascorbate leads to increased cellular sensitivity towards Docetaxel, Epirubicin, Irinotecan and 5-FU, but not towards Oxaliplatin and Vinorelbin. For Docetaxel and 5-FU, a linear correlation between this sensitizing effect and the ascorbate dosage is observed. The redox-active form of vitamin C, ascorbate, shows therapeutic efficacy in tumor cells. These antitumor effects of ascorbate are mainly based on its extracellular action and, in addition to the induction of apoptosis, also include an anti-proliferative effect by inducing cell cycle arrest. Furthermore, ascorbate treatment specifically enhances the cytostatic potency of certain chemotherapeutics, which implicates therapeutic benefit during tumor treatment.


Recalcitrant chronic rhinosinusitis: investigation and management.
We discuss the care of patients failing the typical medical and surgical management for chronic rhinosinusitis who need further evaluation to rule out various mimics of sinus disease and other disorders that may require specific treatment plans. We also look at the many treatment options for the recalcitrant sinusitis patient recently published. Work-up of diseases such as gastroesophageal reflux, dental infection and immunodeficiency in the chronic rhinosinusitis patient are discussed. There have been multiple treatment options evaluated in the literature in the past year, including long-term macrolide therapy and various antibiotic, antifungal, and surfactant irrigations. Recommendations regarding these therapies are discussed. Patients with recalcitrant chronic rhinosinusitis offer a significant challenge to the otolaryngologist. This review provides a structured look at both diagnosing and treating the disease processes in these patients, with recently published literature presented.


Google Scholar is not enough to be used alone for systematic reviews.
Google Scholar (GS) has been noted for its ability to search broadly for important references in the literature. Gehanno et al. recently examined GS in their study: 'Is Google scholar enough to be used alone for systematic reviews?' In this paper, we revisit this important question, and some of Gehanno et al.'s other findings in evaluating the academic search engine. The authors searched for a recent systematic review (SR) of comparable size to run search tests similar to those in Gehanno et al. We selected Chou et al. (2013) contacting the authors for a list of publications they found in their SR on social media in health. We queried GS for each of those 506 titles (in quotes ""), one by one. When GS failed to retrieve a paper, or produced too many results, we used the allintitle: command to find papers with the same title. Google Scholar produced records for ~95% of the papers cited by Chou et al. (n=476/506). A few of the 30 papers that were not in GS were later retrieved via PubMed and even regular Google Search. But due to its different structure, we could not run searches in GS that were originally performed by Chou et al. in PubMed, Web of Science, Scopus and PsycINFO®. Identifying 506 papers in GS was an inefficient process, especially for papers using similar search terms. Has Google Scholar improved enough to be used alone in searching for systematic reviews? No. GS' constantly-changing content, algorithms and database structure make it a poor choice for systematic reviews. Looking for papers when you know their titles is a far different issue from discovering them initially. Further research is needed to determine when and how (and for what purposes) GS can be used alone. Google should provide details about GS' database coverage and improve its interface (e.g., with semantic search filters, stored searching, etc.). Perhaps then it will be an appropriate choice for systematic reviews.


Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study.
Subjects with the metabolic syndrome (MetS) have enhanced oxidative stress and inflammation. Dietary fat quality has been proposed to be implicated in these conditions. We investigated the impact of four diets distinct in fat quantity and quality on 8-iso-PGF2α (a major F2-isoprostane and oxidative stress indicator), 15-keto-13,14-dihydro-PGF2α (15-keto-dihydro-PGF2α, a major PGF2α metabolite and marker of cyclooxygenase-mediated inflammation) and C-reactive protein (CRP). In a 12-week parallel multicentre dietary intervention study (LIPGENE), 417 volunteers with the MetS were randomly assigned to one of the four diets: two high-fat diets (38 % energy (%E)) rich in SFA or MUFA and two low-fat high-complex carbohydrate diets (28 %E) with (LFHCC n-3) or without (LFHCC) 1·24 g/d of very long chain n-3 fatty acid supplementation. Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α were determined by RIA and adjusted for urinary creatinine levels. Serum concentration of CRP was measured by ELISA. Neither concentrations of 8-iso-PGF2α and 15-keto-dihydro-PGF2α nor those of CRP differed between diet groups at baseline (P>0·07) or at the end of the study (P>0·44). Also, no differences in changes of the markers were observed between the diet groups (8-iso-PGF2α, P = 0·83; 15-keto-dihydro-PGF2α, P = 0·45; and CRP, P = 0·97). In conclusion, a 12-week dietary fat modification did not affect the investigated markers of oxidative stress and inflammation among subjects with the MetS in the LIPGENE study.


Surface functionalization of thin-film diamond for highly stable and selective biological interfaces.
Carbon is an extremely versatile family of materials with a wide range of mechanical, optical, and mechanical properties, but many similarities in surface chemistry. As one of the most chemically stable materials known, carbon provides an outstanding platform for the development of highly tunable molecular and biomolecular interfaces. Photochemical grafting of alkenes has emerged as an attractive method for functionalizing surfaces of diamond, but many aspects of the surface chemistry and impact on biological recognition processes remain unexplored. Here we report investigations of the interaction of functionalized diamond surfaces with proteins and biological cells using X-ray photoelectron spectroscopy (XPS), atomic force microscopy, and fluorescence methods. XPS data show that functionalization of diamond with short ethylene glycol oligomers reduces the nonspecific binding of fibrinogen below the detection limit of XPS, estimated as > 97% reduction over H-terminated diamond. Measurements of different forms of diamond with different roughness are used to explore the influence of roughness on nonspecific binding onto H-terminated and ethylene glycol (EG)-terminated surfaces. Finally, we use XPS to characterize the chemical stability of Escherichia coli K12 antibodies on the surfaces of diamond and amine-functionalized glass. Our results show that antibody-modified diamond surfaces exhibit increased stability in XPS and that this is accompanied by retention of biological activity in cell-capture measurements. Our results demonstrate that surface chemistry on diamond and other carbon-based materials provides an excellent platform for biomolecular interfaces with high stability and high selectivity.


Segmentation and the Entropic Elasticity of Modular Proteins.
Single-molecule force spectroscopy utilizes polyproteins, which are composed of tandem modular domains, to study their mechanical and structural properties. Under the application of external load, the polyproteins respond by unfolding and refolding domains to acquire the most favored extensibility. However, unlike single-domain proteins, the sequential unfolding of the each domain modifies the free energy landscape (FEL) of the polyprotein nonlinearly. Here we use force-clamp (FC) spectroscopy to measure unfolding and collapse-refolding dynamics of polyubiquitin and poly(I91). Their reconstructed unfolding FEL involves hundreds of kB T in accumulating work performed against conformational entropy, which dwarfs the ∼30 kB T that is typically required to overcome the free energy difference of unfolding. We speculate that the additional entropic energy caused by segmentation of the polyprotein to individual proteins plays a crucial role in defining the "shock absorber" properties of elastic proteins such as the giant muscle protein titin.


The incidence and magnitude of fibrinolytic activation in trauma patients.
Trauma is a global disease, with over 2.5 million deaths annually from hemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma, and is associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. A prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009 was performed. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis of > 15%. Fibrinolytic activation (FA) was determined according to plasmin-antiplasmin (PAP) complex and D-dimer levels. Data were collected on demographics, mechanism, severity of injury, and baseline vital signs. The primary outcome measure was 28-day mortality. The secondary outcome measures were 28-day ventilator-free days and 24-h transfusion requirement. Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of 'moderate' fibrinolysis, with PAP complex levels elevated to over twice normal (> 1500 μg L(-1)) without lysis on TEM. TEM detected clot lysis only when PAP complex levels were increased to 30 times normal (P < 0.001) and antiplasmin levels were < 75% of normal. Patients with FA had increased 28-day mortality as compared with those with no FA (12% vs. 1%, P < 0.001), fewer ventilator-free days, and longer hospital stay. FA occurs in the majority of trauma patients, and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional TEM, which is an insensitive measure of endogenous fibrinolytic activity.


Associations of social, physical, and financial factors with diet quality among older, community-dwelling women.
This analysis examined whether specific social, physical, and financial factors were associated with diet quality among older, community-dwelling women. This cross-sectional analysis was conducted in a subset of 6,094 community-dwelling Women's Health Initiative participants who completed a food frequency questionnaire, administered from 2012 to 2013, and a self-administered supplemental questionnaire, administered approximately 1 year later. The supplemental questionnaire included five questions assessing social, physical, and financial factors related to eating. Diet quality was assessed with the Healthy Eating Index-2010 (HEI-2010; range of 0-100; higher score indicates a higher quality diet). The total HEI-2010 score was calculated by summing individual scores representing the intake of nine adequacy components (beneficial food groups) and three moderation components (food groups to limit). Associations of responses to the five questions on the supplemental questionnaire with HEI-2010 scores were examined with multiple linear regression, adjusting for relevant covariates. Mean ± standard deviation age of participants was 78.8 ± 6.7 years. Reporting eating fewer than two meals per day, having dental or other mouth problems causing problems with eating, and not always being able to shop, cook, or feed oneself were associated with statistically significantly lower HEI-2010 scores, compared with those not reporting these issues, after multivariable adjustment: 5.37, 2.98, and 2.39 lower scores, respectively (all P values <0.0001). Reporting eating alone most of the time and not always having enough money to buy food were not associated with HEI-2010 scores. Among older, community-dwelling women, eating fewer than two meals per day, dental and other mouth problems, and diminished ability to shop for food, prepare meals, and feed oneself were associated with lower diet quality. These are potential targets for interventions to improve diet quality in older women. : Video Summary:http://links.lww.com/MENO/A561.


Structural basis of the 9-fold symmetry of centrioles.
The centriole, and the related basal body, is an ancient organelle characterized by a universal 9-fold radial symmetry and is critical for generating cilia, flagella, and centrosomes. The mechanisms directing centriole formation are incompletely understood and represent a fundamental open question in biology. Here, we demonstrate that the centriolar protein SAS-6 forms rod-shaped homodimers that interact through their N-terminal domains to form oligomers. We establish that such oligomerization is essential for centriole formation in C. elegans and human cells. We further generate a structural model of the related protein Bld12p from C. reinhardtii, in which nine homodimers assemble into a ring from which nine coiled-coil rods radiate outward. Moreover, we demonstrate that recombinant Bld12p self-assembles into structures akin to the central hub of the cartwheel, which serves as a scaffold for centriole formation. Overall, our findings establish a structural basis for the universal 9-fold symmetry of centrioles.


Large spatial scale of the phenotype-environment color matching in two cryptic species of african desert jerboas (dipodidae: jaculus).
We tested the camouflage hypothesis, or the linkage between animal (Saharan rodent) and habitat coloration, on the largest geographical scale yet conducted. We aimed to determine whether phenotypic variation is explained by micro-habitat variation and/or genetic polymorphism to determine 1) the strength of linkage between fur color and local substrate color, and 2) the divergence in fur coloration between two genetic clades, representing cryptic species, throughout the complete range of the African desert jerboas (Jaculus jaculus). We used a combination of museum and field-collected specimens, remote sensing tools, satellite and digital photography and molecular genetic and phylogenetic methods to investigate the above hypotheses. Along with showing that the two divergent genetic clades of jerboas occur sympatrically throughout their African distribution, we showed significant covariation between dorsal fur coloration of the animals and the color of their habitat. We also described significant phenotypic divergence in fur color, consistent with genetic divergence between the sympatric clades. The linkage between environment and phenotype supports the idea that the selection promoting cryptic coloration is persistent in contemporary populations of jerboas, however the phenotypic divergence indicates that it has different strengths (or optima) in the two clades. The mosaic distribution of micro-habitats occupied by geographically sympatric clades suggests that it may influence both ecological and evolutionary dynamics between these two cryptic species.


Interactive proteogenomic exploration of response to Fusarium head blight in oat varieties with different resistance.
Fusarium species are cereal pathogens that cause the Fusarium Head Blight (FHB) disease. FHB can reduce yield, cause mycotoxin accumulation in the grain and reduce germination efficiency of the harvested seeds. Understanding the biochemical interactions between the host plants and the pathogen is crucial for controlling the disease and for the development of cultivars with improved tolerance to FHB. Here, we studied morphological and proteomic differences between the susceptible oat variety Belinda and the more resistant variety Argamak using variety-specific transcriptome assemblies as references. Measurements of deoxynivalenol toxin levels confirmed the partial resistance in Argamak and the susceptibility in Belinda. To jointly investigate the proteomics- and sequence data, we developed an RShiny-based interface for interactive exploration of the dataset using univariate and multivariate statistics. When applying this interface to the dataset, quantitative protein differences between Belinda and Argamak were detected, and eighteen peptides were found uniquely in Argamak during infection, among them several lipoxygenases. Such proteins can be developed as markers for Fusarium resistance breeding. In conclusion, this study provides the first proteogenomic insight on molecular Fusarium-oat interactions at both morphological and molecular levels and the data are openly available through an interactive interface for further inspection. SIGNIFICANCE: Fusarium head blight causes widespread damage to crops, and chronic and acute toxicity to human and livestock due to the accumulation of toxins during infection. In the present study, two oat varieties with differing resistance were challenged with Fusarium to understand the disease better, and studied both at morphological and molecular levels, identifying proteins which could play a role in the defense mechanism. Furthermore, a proteogenomics approach allows joint profiling of expression and sequence level differences to identify potentially functionally differing mutations. Here such analysis is made openly available through an interactive interface which allows other scientists to draw further findings from the data. This study may both serve as a basis for understanding oat disease response and developing breeding markers for Fusarium resistant oat and future proteogenomic studies using the interactive approach described.


En face spectral domain optical coherence tomography analysis of lamellar macular holes.
To analyze the anatomical characteristics of lamellar macular holes using cross-sectional and en face spectral domain optical coherence tomography. Forty-two lamellar macular holes were retrospectively identified for analysis. The location, cross-sectional length, and area of lamellar holes were measured using B-scans and en face imaging. The presence of photoreceptor inner segment/outer segment disruption and the presence or absence of epiretinal membrane formation were recorded. Forty-two lamellar macular holes were identified. Intraretinal splitting occurred within the outer plexiform layer in 97.6% of eyes. The area of intraretinal splitting in lamellar holes did not correlate with visual acuity. Eyes with inner segment/outer segment disruption had significantly worse mean logMAR visual acuity (0.363 ± 0.169; Snellen = 20/46) than in eyes without inner segment/outer segment disruption (0.203 ± 0.124; Snellen = 20/32) (analysis of variance, P = 0.004). Epiretinal membrane was present in 34 of 42 eyes (81.0%). En face imaging allowed for consistent detection and quantification of intraretinal splitting within the outer plexiform layer in patients with lamellar macular holes, supporting the notion that an area of anatomical weakness exists within Henle's fiber layer, presumably at the synaptic connection of these fibers within the outer plexiform layer. However, the en face area of intraretinal splitting did not correlate with visual acuity, disruption of the inner segment/outer segment junction was associated with significantly worse visual acuity in patients with lamellar macular holes.


Types of indwelling urinary catheters for long-term bladder drainage in adults.
Prolonged urinary catheterization is common amongst people in long-term care settings and this carries a high risk of developing a catheter-related urinary tract infection and associated complications. A variety of different kinds of urethral catheters are available. Some have been developed specifically to lower the risk of catheter-associated infection, for example antiseptic or antibiotic impregnated catheters. Ease of use, comfort and handling for the caregivers and patients, and cost-effectiveness are also important factors influencing choice. The primary objective was to determine which type of indwelling urinary catheter is best to use for long-term bladder drainage in adults. We searched the Cochrane Incontinence Group Specialised Register (last searched 31 March 2011), which includes searches of CENTRAL, MEDLINE and handsearching of journals and conference proceedings, and the reference lists of relevant articles. All randomised trials comparing types of indwelling urinary catheters for long-term catheterization in adults. Long-term catheterization was defined as more than 30 days. Data extraction has been undertaken by two review authors working independently and simultaneously. Any disagreement has been resolved by a third review author. The included trial data were handled according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions. Three trials were included, involving 102 adults in various settings. Two trials had a parallel group design and one was a randomised cross-over trial.Only two of the six targeted comparisons were assessed by these trials: antiseptic impregnated catheters versus standard catheters (one trial) and one type of standard catheter versus another standard catheter (two trials).The single small cross-over trial was inadequate to assess the value of silver alloy (antiseptic) impregnated catheters. In the two trials comparing different types of standard catheters, estimates of differences were all imprecise because the trials also had small sample sizes; confidence intervals (CI) were too wide to rule out clinically important differences. One trial did suggest, however, that the use of a hydrogel coated latex catheter rather than a silicone catheter may be better tolerated (risk ratio (RR) for need for early removal 0.41, 95% CI 0.22 to 0.77). The updated search could not reveal any additional evidence. Very few trials have compared different types of catheter for long-term bladder drainage. All trials were small and showed methodological weaknesses. Therefore, the evidence was not sufficient as a reliable basis for practical conclusions. Further, better quality trials are needed to address the current lack of evidence in this clinically important area.


[Pulmonary aspergilloma: results of surgical treatment. Report of a series of 206 cases].
The aim of this retrospective study was to report the results of the surgical treatment in 188 patients operated on for pulmonary aspergilloma in a series of 206 patients observed in Morocco. From 1982 to 1998, 206 patients were treated for pulmonary aspergilloma in the same hospital; 188 were operated on and surgery was contraindicated in the other patients with general or respiratory failure. Hemoptysis was the main symptom, present in 190 patients (92%). Surgery was performed on principle with 108 lobectomies, 38 segmentectomies, 18 lobectomies and segmentectomies, 21 pleuropneumonectomies and 3 thoracoplasties. Postoperative complications occurred in 36% of the patients including: pyothorax (n = 15), hemothorax (n = 10), rehabitation defects (n = 17) and respiratory failure (n = 10). Reoperation was necessary in 6 patients. Postoperative mortality rate was 6.4% (12 patients including 5 treated by pleuro-pneumonectomy). The surgical treatment, in spite of its high morbidity, has to be proposed to all patients with pulmonary aspergilloma, even in asymptomatic patients when there is no surgical contraindication. Pleuropneumonectomy is a very high risk procedure and its indications must be restricted. Thoracoscopy was rarely performed in this series.


Dynamics of nitric oxide synthase-calmodulin interactions at physiological calcium concentrations.
The intracellular Ca²⁺ concentration is an important regulator of many cellular functions. The small acidic protein calmodulin (CaM) serves as a Ca²⁺ sensor and control element for many enzymes. Nitric oxide synthase (NOS) is one of the proteins that is activated by CaM and plays a major role in a number of key physiological and pathological processes. Previous studies have shown CaM to act like a switch that causes a conformational change in NOS to allow for the electron transfer between the reductase and oxygenase domains through a process that is thought to be highly dynamic. We have analyzed the structure and dynamics of complexes formed by peptides based on inducible NOS (iNOS) and endothelial NOS (eNOS) with CaM at Ca²⁺ concentrations that mimic the physiological basal (17 and 100 nM) and elevated levels (225 nM) found in mammalian cells using fluorescence techniques and nuclear magnetic resonance spectroscopy. The results show the CaM-NOS complexes have similar structures at physiological and fully saturated Ca²⁺ levels; however, their dynamics are remarkably different. At 225 nM Ca²⁺, the CaM-NOS complexes show overall an increase in backbone dynamics, when compared to the dynamics of the complexes at saturating Ca²⁺ concentrations. Specifically, the N-lobe of CaM in the CaM-iNOS complex displays a lower internal mobility (higher S²) and higher exchange protection compared to those of the CaM-eNOS complex. In contrast, the C-lobe of CaM in the CaM-eNOS complex is less dynamic. These results illustrate that structures of CaM-NOS complexes determined at saturated Ca²⁺ concentrations cannot provide a complete picture because the differences in intramolecular dynamics become visible only at physiological Ca²⁺ levels.


Honey bee orientation: a backup system for cloudy days.
On cloudy days, honey bees are known to navigate to familiar food sources and orient their dances accurately. This capacity could be based on a magnetic compass sense, an ability to perceive the sun or patterns of polarized light through the clouds, or on the bees' memory of the diurnal course of the sun with respect to local landmarks. Experiments pitting these alternatives against one another demonstrate that the navigational backup system of bees is based on memory.


Temporal dynamics of shape analysis in macaque visual area V2.
The firing rate of visual cortical neurons typically changes substantially during a sustained visual stimulus. To assess whether, and to what extent, the information about shape conveyed by neurons in visual area V2 changes over the course of the response, we recorded the responses of V2 neurons in awake, fixating monkeys while presenting a diverse set of static shape stimuli within the classical receptive field. We analyzed the time course of various measures of responsiveness and stimulus-related response modulation at the level of individual cells and of the population. For a majority of V2 cells, the response modulation was maximal during the initial transient response (40-80 ms after stimulus onset). During the same period, the population response was relatively correlated, in that V2 cells tended to respond similarly to specific subsets of stimuli. Over the ensuing 80-100 ms, the signal-to-noise ratio of individual cells generally declined, but to a lesser degree than the evoked-response rate during the corresponding time bins, and the response profiles became decorrelated for many individual cells. Concomitantly, the population response became substantially decorrelated. Our results indicate that the information about stimulus shape evolves dynamically and relatively rapidly in V2 during static visual stimulation in ways that may contribute to form discrimination.


Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects.
Hydrochlorothiazide (HCTZ) has often been contrasted with chlorthalidone, but relatively little is known about HCTZ versus indapamide (INDAP). This systematic review retrieved 9765 publications, and from these, it identified 14 randomized trials with 883 patients comparing HCTZ with INDAP and chlorthalidone on antihypertensive potency or metabolic effects. To make fair comparisons, the dose of the diuretic in each arm was assigned 1 of 3 dose levels. In random effects meta-analysis, INDAP and chlorthalidone lowered systolic blood pressure more than HCTZ: -5.1 mm Hg (95% confidence interval, -8.7 to -1.6); P=0.004 and -3.6 mm Hg (95% confidence interval, -7.3 to 0.0); P=0.052, respectively. For both comparisons, there was minimal heterogeneity in effect across trials and no evidence for publication bias. The HCTZ-INDAP contrast was biased in favor of greater HCTZ potency because of a much greater contribution to the overall effect from trials in which the HCTZ arm had a higher dose level than the INDAP arm. For the HCTZ-INDAP comparison, no single trial was responsible for the overall result nor was it possible to detect significant modifications of this comparison by duration of follow-up, high- versus low-bias trials, or the presence or absence of background medications. There were no detectable differences between HCTZ and INDAP in metabolic adverse effects, including effects on serum potassium. In conclusion, these head-to-head comparisons demonstrate that, like chlorthalidone, INDAP is more potent than HCTZ at commonly prescribed doses without evidence for greater adverse metabolic effects.


Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension.
We compared dilevalol (an isomer of labetalol), 200-400 mg daily, against atenolol, 50-100 mg daily, in a double-blind, crossover, placebo-controlled trial with respect to effects on arterial distensibility (measured as pulse wave velocity [PWV]) and wave reflection (assessed from carotid pressure wave contour). Twelve patients of mean age 58 years (range 44-73 years) with essential hypertension (supine diastolic blood pressure 95-114 mm Hg) took active therapy for 12 weeks, separated by a 2-4 week placebo period. Carotid pressure waveforms were recorded noninvasively by applanation tonometry with a Millar micromanometer-tipped probe. PWV was measured between carotid and femoral arteries (aortic PWV), carotid and radial arteries (arm PWV), and femoral and pedal arteries (leg PWV). Early wave reflection was calculated from the ratio of the height of the peak of the carotid wave above its shoulder to the pulse pressure and was expressed as an augmentation index. Both drugs were equally effective in reducing brachial sphygmomanometric pressure and PWV in all three regions (active vs. placebo, p less than 0.001), but there was no significant difference between the two active therapies. However, the augmentation index (averaged during the treatment period) was significantly lower with dilevalol (19%) than with atenolol (28%, p less than 0.01), corresponding to a greater decrease of 5-8 mm Hg in carotid systolic pressure compared with the brachial artery. Although both drugs were equally effective in reducing arterial distensibility, the vasodilating action of dilevalol gave added benefit in reducing wave reflection, presumably through its vasodilatory effect on peripheral conduit arteries.


The association between fracture and obesity is site-dependent: a population-based study in postmenopausal women.
The association between obesity and fracture is controversial. We investigated the relationship between body mass index (BMI) and fracture at different skeletal sites in women aged ≥50 years using data from the Sistema d' Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP) database. SIDIAP contains the computerized medical records of >3400 general practitioners in Catalonia (northeastern Spain), with information on a representative 80% of the population (>5 million people). In 2009, 1,039,878 women aged ≥50 years were eligible, of whom 832,775 (80.1%) had a BMI measurement. These were categorized into underweight/normal (302,414 women), overweight (266,798), and obese (263,563). Fractures were ascertained using the International Classification of Diseases, 10th revision (ICD-10) codes. Multivariate Poisson regression models were fitted to adjust for age, smoking, high alcohol intake, type 2 diabetes, and oral corticosteroid use. Hip fractures were significantly less common in overweight and obese women than in normal/underweight women (rate ratio [RR] 0.77 [95% confidence interval (CI) 0.68 to 0.88], RR 0.63 [95% CI 0.64 to 0.79], p < 0.001, respectively). Pelvis fracture rates were lower in the overweight (RR 0.78 [95% CI 0.63 to 0.96], p = 0.017) and obese (RR 0.58 [95% CI 0.47 to 0.73], p < 0.001) groups. Conversely, obese women were at significantly higher risk of proximal humerus fracture than the normal/underweight group (RR 1.28 [95% CI 1.04 to 1.58], p = 0.018). Clinical spine, wrist, tibial, and multiple rib fracture rates were not significantly different between groups. An age-related increase in incidence was seen for all BMI groups at all fracture sites; obese women with hip, clinical spine, and pelvis fracture were significantly younger at the time of fracture than normal/underweight women, whereas those with wrist fracture were significantly older. The association between obesity and fracture in postmenopausal women is site-dependent, obesity being protective against hip and pelvis fractures but associated with an almost 30% increase in risk for proximal humerus fractures when compared with normal/underweight women. The reasons for these site-specific variations are unknown but may be related to different patterns of falls and attenuation of their impact by adipose tissue.


Damage initiation and progression in the cartilage surface probed by nonlinear optical microscopy.
With increasing interest in treating osteoarthritis at its earliest stages, it has become important to understand the mechanisms by which the disease progresses across a joint. Here, second harmonic generation (SHG) microscopy, coupled with a two-dimensional spring-mass network model, was used to image and investigate the collagen meshwork architecture at the cartilage surface surrounding osteoarthritic lesions. We found that minor weakening of the collagen meshwork leads to the bundling of fibrils at the surface under normal loading. This bundling appears to be an irreversible step in the degradation process, as the stress concentrations drive the progression of damage, forming larger bundles and cracks that eventually form lesions.