Levels of bisphenol-A in different paper products in Guangzhou, China, and assessment of human exposure via dermal contact.
Bisphenol A (BPA) is a chemical widely used both in plastics production as a food and beverage container and in thermal papers as a color developer. Dietary consumption is the main route of human exposure to BPA, but dermal absorption through handling different papers might be underestimated or ignored. In this study, BPA in different paper products, including different types of papers, receipts and Chinese currencies, were investigated. BPA was detected in receipts (n = 87) and Chinese currencies (n = 46) with concentrations of 0.17-2.675 × 10(4) μg per g paper and 0.09-288.55 μg per g paper, respectively. Except for parchment papers (n = 3), copy papers (n = 3) and food contact papers (n = 3), BPA was measured in all of the other paper products, with levels of 0.01-6.67 μg per g paper. BPA transferred from thermal papers to common papers increased with the increasing contact pressure. Compared with that in water, the migration speed of BPA was doubled in the synthetic sweat. Washing hands could reduce BPA dermal exposure, and washing hands with lotion was the most efficient way. However, about 19-47% of BPA was still found on hands after different washing methods. Dermal absorption via handling of receipts and papers was estimated to be 36.45 ng per day for the general population and 1.54 × 10(-3) to 248.73 μg per day for a cashier. These values are below the maximum doses recommended by the U.S. Environmental Protection Agency and the European Food Safety Authority. However, due to its uncertain adverse effects on human beings, long-term BPA exposure through dermal absorption should be paid more attention, particularly for some occupational populations.


Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure.
Indoleamine 2,3-dioxygenase (IDO) suppresses the functions of CD4(+) T cells through its ability to metabolize the essential amino acid tryptophan. Although the activity of IDO is required for the immunosuppression of allergic airway disease by the Toll-Like-Receptor 9 (TLR9) agonist, oligonucleotides comprised of cytosine and guanine nucleotides linked by phosphodiester bonds (CpG) DNA, it is unclear whether IDO expression by resident lung epithelial cells is sufficient to elicit these effects. Therefore, we created a transgenic mouse inducibly overexpressing IDO within nonciliated airway epithelial cells. Upon inhalation of formalin-fixed Aspergillus fumigatus hyphal antigens, the overexpression of IDO from airway epithelial cells of these mice reduced the number of CD4(+) T cells within the inflamed lung and impaired the capacity of antigen-specific splenic CD4(+) effector T cells to secrete the cytokines IL-4, IL-5, IL-13, and IFN-γ. Despite these effects, allergic airway disease pathology was largely unaffected in mice expressing IDO in airway epithelium. In support of the concept that dendritic cells are the major cell type contributing to the IDO-inducing effects of CpG DNA, mice expressing TLR9 only in the airway epithelium did not augment IDO expression subsequent to the administration of CpG DNA. Furthermore, the systemic depletion of CD11c(+) cells rendered mice incapable of CpG DNA-induced IDO expression. Our results demonstrate that an overexpression of IDO within the airway epithelium represents a novel mechanism by which the number of CD4(+) T cells recruited to the lung and their capacity to produce cytokines can be diminished in a model of allergic airway disease, and these results also highlight the critical role of dendritic cells in the antiasthmatic effects of IDO induction by CpG DNA.


A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3.
The use of small molecules to 'chemically direct' differentiation represents a powerful approach to promote specification of embryonic stem cells (ESCs) towards particular functional cell types for use in regenerative medicine and pharmaceutical applications. Here, we demonstrate a novel route for chemically directed differentiation of human ESCs (hESCs) into definitive endoderm (DE) exploiting a selective small-molecule inhibitor of glycogen synthase kinase 3 (GSK-3). This GSK-3 inhibitor, termed 1m, when used as the only supplement to a chemically defined feeder-free culture system, effectively promoted differentiation of ESC lines towards primitive streak (PS), mesoderm and DE. This contrasts with the role of GSK-3 in murine ESCs, where GSK-3 inhibition promotes pluripotency. Interestingly, 1m-mediated induction of differentiation involved transient NODAL expression and Nodal signalling. Prolonged treatment of hESCs with 1m resulted in the generation of a population of cells displaying hepatoblast characteristics, that is expressing α-fetoprotein and HNF4α. Furthermore, 1m-induced DE had the capacity to mature and generate hepatocyte-like cells capable of producing albumin. These findings describe, for the first time, the utility of GSK-3 inhibition, in a chemically directed approach, to a method of DE generation that is robust, potentially scalable and applicable to different hESC lines.


Reduction of verotoxigenic Escherichia coli by process and recipe optimisation in dry-fermented sausages.
Outbreaks of verotoxigenic Escherichia coli (VTEC) linked to dry-fermented sausages (DFSs) have emphasized the need for DFS manufacturers to introduce measures to obtain enhanced safety and still maintain the sensory qualities of their products. To our knowledge no data have yet been reported on non-O157:H7 VTEC survival in DFS. Here, the importance of recipe and process variables on VTEC (O157:H7 and O103:H25) reductions in two types of DFS, morr and salami, was determined through three statistically designed experiments. Linear regression and ANOVA analyses showed that no single variable had a dominant effect on VTEC reductions. High levels of NaCl, NaNO(2), glucose (low pH) and fermentation temperature gave enhanced VTEC reduction, while high fat and large casing diameter (a(w)) gave the opposite effect. Interaction effects were small. The process and recipe variables showed similar effects in morr and salami. In general, recipes combining high batter levels of salt (NaCl and NaNO(2)) and glucose along with high fermentation temperature that gave DFS with low final pH and a(w), provided approximately 3 log(10) reductions compared to approximately 1.5 log(10) reductions obtained for standard recipe DFS. Storage at 4 degrees C for 2 months provided log(10) 0.33-0.95 additional VTEC reductions and were only marginally affected by recipe type. Sensory tests revealed only small differences between the various recipes of morr and salami. By optimisation of recipe and process parameters, it is possible to obtain increased microbial safety of DFS while maintaining the sensory qualities of the sausages.


Hormonal therapy in advanced or recurrent endometrial cancer.
Endometrial cancer is a cancer of the lining of the womb and worldwide is the seventh most common cancer in women. Treatment with hormones is thought to be beneficial in patients with endometrial cancer. To assess the indications, effectiveness and safety of hormone therapy for advanced or recurrent epithelial endometrial cancer. We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE up to May 2009 and and CENTRAL (Issue 2, 2009). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies, and contacted experts in the field. Randomised controlled trials (RCTs) that studied hormonal therapy in adult women diagnosed with advanced or recurrent endometrial cancer. Two review authors independently abstracted data and assessed risk of bias. Comparisons were restricted to single-trial analyses so we did not synthesise data in meta-analyses. We found six trials (542 participants) that met our inclusion criteria. These trials assessed the effectiveness of hormonal therapy in women with advanced or recurrent endometrial cancer as a single agent, as part of combination therapy and as low versus high dose. All comparisons were restricted to single-trial analyses, where we found no evidence that hormonal therapy as a single agent or as a combination treatment prolonged overall or five-year disease-free survival of women with advanced or recurrent endometrial cancer. However, low-dose hormonal therapy may have had a benefit in terms of overall and progression-free survival (PFS) compared to high-dose hormonal therapy (HR 1.31, 95% CI 1.04 to 1.66 and HR 1.35, 95% CI 1.07 to 1.71 for overall and PFS, respectively). We found insufficient evidence that hormonal treatment in any form, dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer. However, a large number of patients would be needed to demonstrate an effect on survival and none of the included RCTs had a sufficient number of patients to demonstrate a significant difference. In the absence of a proven survival advantage and the heterogeneity of patient populations, the decision to use any type of hormonal therapy should be individualised and with the intent to palliate the disease. It is debatable whether outcomes such as quality of life, treatment response or palliative measures such as relieving symptoms should take preference over overall and PFS as the major objectives of future trials.


Enzyme intermediates captured "on the fly" by mix-and-inject serial crystallography.
Ever since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases. Here, we demonstrate a general method for capturing enzyme catalysis "in action" by mix-and-inject serial crystallography (MISC). Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis β-lactamase with the third-generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation from 30 ms to 2 s. MISC is a versatile and generally applicable method to investigate reactions of biological macromolecules, some of which are of immense biological significance and might be, in addition, important targets for structure-based drug design. With megahertz X-ray pulse rates expected at the Linac Coherent Light Source II and the European X-ray free-electron laser, multiple, finely spaced time delays can be collected rapidly, allowing a comprehensive description of biomolecular reactions in terms of structure and kinetics from the same set of X-ray data.


Imaging single-stranded DNA, antigen-antibody reaction and polymerized Langmuir-Blodgett films with an atomic force microscope.
The combination of an (AFM) atomic force microscope together with microfabricated cantilevers that have integrated tips opens many possibilities for imaging systems of great importance in biology. We have imaged single-stranded 25mer DNA that was adsorbed on treated mica or that was covalently bound with a crosslinker to a polymerized Langmuir-Blodgett (LB) film, the top monolayer of a bilayer system. At low magnification the AFM shows cracks between solid domains, like in an image taken with a fluorescence microscope. At higher magnification, however, the AFM reveals much finer cracks and at still higher magnification it reveals rows of individual molecules in the polymerized LB film with a spacing of 0.45 nm. We have also imaged a LB film consisting of lipids in which 4% of the lipids had hapten molecules chemically bound to the lipid headgroups. Specific antibodies can then bind to these hapten molecules and be imaged with the AFM. This points to the possibility of using the AFM to monitor selective antibody binding.


Electromagnetic acoustic imaging.
Electromagnetic acoustic imaging (EMAI) is a new imaging technique that uses long-wavelength RF electromagnetic (EM) waves to induce ultrasound emission. Signal intensity and image contrast have been found to depend on spatially varying electrical conductivity of the medium in addition to conventional acoustic properties. The resultant conductivity- weighted ultrasound data may enhance the diagnostic performance of medical ultrasound in cancer and cardiovascular applications because of the known changes in conductivity of malignancy and blood-filled spaces. EMAI has a potential advantage over other related imaging techniques because it combines the high resolution associated with ultrasound detection with the generation of the ultrasound signals directly related to physiologically important electrical properties of the tissues. Here, we report the theoretical development of EMAI, implementation of a dual-mode EMAI/ultrasound apparatus, and successful demonstrations of EMAI in various phantoms designed to establish feasibility of the approach for eventual medical applications.


The Relationship Between State Mental Health Agency and Medicaid Spending with Outcomes.
Little is known about relationships between state mental health expenditures and outcomes. This analysis evaluated relationships between spending and income across the states and mental health outcomes. Relationships between state per capita SMHA and Medicaid mental health spending, as well as median household income, percent of residents on Medicaid and Mental Health America (MHA) ranking, suicide and incarceration rates were assessed using correlations and multiple regressions. Median household income predicted MHA overall and youth ranking. Per capita Medicaid mental health spending predicted MHA prevalence ranking. Median household income and Medicaid spending predicted access to care ranking and incarcerations. Median income, Medicaid spending and percent receiving Medicaid predicted suicide rate. The findings suggest median household income may, in some cases, predict mental health treatment quality and outcomes more strongly than spending. However, the relationship with per capita mental health Medicaid spending on outcomes is also noteworthy.


Microbial profile and antibiotic susceptibility of Campylobacter spp. and Salmonella spp. in broilers processed in air-chilled and immersion-chilled environments.
Carcass chilling is considered a critical step for inhibiting bacterial growth during poultry processing. The objective of this study was to compare microbiological loads and the incidence of Salmonella spp. and Campylobacter spp. on broiler carcasses subjected to immersion chilling and air chilling. Additionally, the antibiotic resistance patterns of pathogen isolates were determined. The results of this study indicated that the incidence of Salmonella spp. and Campylobacter spp. tends to be significantly lower in air-chilled broilers, suggesting that cross-contamination may be more prevalent for immersion-chilled broilers. No significant differences were detected between chilling treatments for total aerobic populations or for generic E. coli or coliform counts. Psychrotrophic populations were significantly larger (P < 0.05) in immersion-chilled broilers than in their air-chilled counterparts. Campylobacter isolates from immersion-chilled broilers had a higher incidence of resistance to nalidixic acid (NAL) and related fluoroquinolones than isolates from air-chilled broilers did. Additionally, Campylobacter isolates from air-chilled broilers had a higher frequency of resistance to tetracycline than isolates from immersion-chilled broilers did. With regard to Salmonella, isolates from immersion-chilled broilers had a higher incidence of resistance to NAL than isolates from air-chilled samples did. No Salmonella isolates from immersion- or air-chilled broilers were resistant to the fluoroquinolones tested. The chilling method used during processing may influence the microbial profile of postchilled broilers.


Strain variation and morphogenesis of yeast- and mycelial-phase Candida albicans in low-sulfate, synthetic medium.
A low-sulfate synthetic medium was developed in which pure cultures of yeast- and mycelial-phase Candida albicans could be cultivated for investigations of the molecular biology of dimorphism. The medium contained ammonium ions, phosphate buffer, salts, glucose, and biotin. Morphogenesis was found to be dependent upon the strain of C. albicans. Of six strains tested in the low-sulfate medium at 37 degrees C, three formed mixed cultures of yeasts, true mycelium and pseudomycelium, two formed pure cultures of true mycelium, and one maintained yeast growth. All six strains produced pure cultures of yeasts at 24 degrees C. The buffering capacity of the medium maintained the pH at 6.9 even at high-density cell growth. The low concentration of sulfate and the absence of amino acids in the medium provided conditions in which to radiolabel cellular constituents with [35S]sulfate. For molecular investigations, the use of two strains is suggested, one forming yeasts and one forming true mycelium in low-sulfate medium at 37 degrees C, thus providing controls for both strain variation and for molecular changes induced by environmental change but unrelated to morphogenesis.


Moderate ocean warming mitigates, but more extreme warming exacerbates the impacts of zinc from engineered nanoparticles on a marine larva.
There is growing concern about the combined effects of multiple human-induced stressors on biodiversity. In particular, there are substantial knowledge gaps about the combined effects of existing stressors (e.g. pollution) and predicted environmental stress from climate change (e.g. ocean warming). We investigated the impacts of ocean warming and engineered nanoparticles (nano-zinc oxide, nZnO) on larvae of a cosmopolitan tropical sea urchin, Tripneustes gratilla. Larval T. gratilla were exposed to all combinations of three temperatures, 25, 27 and 29 °C (current SST and near-future predicted warming of +2 and + 4 °C) and six concentrations of nZnO (0, 0.001, 0.01, 0.1, 1 and 10 mg nZnO·L-1). These stressors had strong interactive effects on fertilization, gastrulation and normal development of 5 day old larvae. High concentrations of nZnO had a negative effect, but this impact was less pronounced for sea urchins reared at their preferred temperature of 27 °C compared to 25 or 29 °C. Larval growth was also impacted by combined stress of elevated temperature and nZnO. Subsequent measurement of the dissolution and aggregation of nZnO particles and the direct effect of Zn2+ ions on larvae, suggest the negative effects of nZnO on larval development and growth were most likely due to Zn2+ ions. Our results demonstrate that marine larvae may be more resilient to stressors at optimal temperatures and highlight the potential for ocean warming to exacerbate the effects of pollution on marine larvae.


Platelet-activating factor mediates the cytotoxicity induced by W7FW14F apomyoglobin amyloid aggregates in neuroblastoma cells.
W7FW14F apomyoglobin (W7FW14F ApoMb) amyloid aggregates induce cytotoxicity in SH-SY5Y human neuroblastoma cells through a mechanism not fully elucidated. Amyloid neurotoxicity process involves calcium dyshomeostasis and reactive oxygen species (ROS) production. Another key mediator of the amyloid neurotoxicity is Platelet-Activating Factor (PAF), an inflammatory phospholipid implicated in neurodegenerative diseases. Here, with the aim at evaluating the possible involvement of PAF signaling in the W7FW14F ApoMb-induced cytotoxicity, we show that the presence of CV3899, a PAF receptor (PAF-R) antagonist, prevented the detrimental effect of W7FW14F ApoMb aggregates on SH-SY5Y cell viability. Noticeably, we found that the activation of PAF signaling, following treatment with W7FW14F ApoMb, involves a decreased expression of the PAF acetylhydroase II (PAF-AH II). Interestingly, the reduced PAF-AH II expression was associated with a decreased acetylhydrolase (AH) activity and to an increased sphingosine-transacetylase activity (TA(S)) with production of N-acetylsphingosine (C2-ceramide), a well known mediator of neuronal caspase-dependent apoptosis. These findings suggest that an altered PAF catabolism takes part to the molecular events leading to W7FW14F ApoMb amyloid aggregates-induced cell death.


Exploring the genetic variations and population structure of Turkish pepper (Capsicum annuum L.) genotypes based on peroxidase gene markers.
Capsicum is thought as one of the most diverse and significant genera due to its varied uses in different parts of the world. In this study, we worked with a total of 71 pepper genotypes from different locations of Turkey to investigate the level of their diversity using the peroxidase gene polymorphism (POGP) markers to reveal their population structure. For this purpose, 14 peroxidase primer pairs were used. They produced 139 bands (mean = 9.9 bands/primer), of which ~ 85.6% were polymorphic in the all germplasm collection. Polymorphism information content (PIC) ranged between 0.48 and 0.97 with an average of 0.75. Range and mean values for gene diversity (h) were 0.09-0.22 and 0.17, respectively. Shannon's information index (I) per POGP marker ranged from 0.18 to 0.35 with a mean of 0.29. Using three clustering methods (unweighted pair-group method with arithmetic means, principal coordinate analysis, and STRUCTURE) revealed a clear separation of all the C. annuum accessions from C. frutescens and C. chinense accessions in our study. Clusters did not establish an association between the accessions and their geographical origin. This is the first study exploring the population structure through the genetic diversity of Turkish peppers from different regions of the country based on the peroxidase gene markers.


A role for GPN-loop GTPase yGPN1 in sister chromatid cohesion.
Sister chromatid cohesion and separation, involving the cohesin complex, are crucial for accurate inheritance of genetic information. This complex is also fundamental for efficient post-replicative repair of DNA double-strand breaks and has a key role in the mechanisms of gene transcription control. Cohesin is subjected to many post-translational modifications but the regulators implicated in the control of its activity have been poorly described. Here, we show that the conserved and essential GPN loop GTPase yGPN1 in Saccharomyces cerevisiae is involved in sister chromatid cohesion mechanisms. Based on a sister chromatid cohesion assay, we found that over-expression of the yGPN1 gene promotes sister chromatid separation during anaphase. The sharp slowdown in progression of the S phase observed in cells where yGPN1 expression is down-regulated strongly suggests that yGPN1 is necessary for DNA replication. Moreover, analysis of yGPN1 protein-protein interaction network highlights the yGPN1 links with DNA replication, sister chromatid cohesion/separation and the gene expression process.


Synthesis and in vitro antitumor activity of new butenolide-containing dithiocarbamates.
Three series of butenolide-containing dithiocarbamates were designed and synthesized. Their anti-tumor activity in vitro was evaluated. Among them compound I-14 exhibited broad spectrum anti-cancer activity against five human cancer cell lines with IC(50) <30 μM. Structure-activity relationship analysis showed that the introduction of dithiocarbamate side chains on the C-3 position of butenolide was crucial for anti-tumor activity.


Toward a CRISPR understanding of gene function in human brain development.
Genome-wide association studies pinpoint genetic risk factors for neurodevelopmental disorders (NDDs), but the next challenge is to understand the mechanisms through which these genes affect brain development. Two recent CRISPR screens in human brain organoids1,2 interrogate the function of risk genes for autism spectrum disorder and other NDDs.


Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.
Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-β) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-β-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF-β1 stimulation. Our study demonstrates a requirement of VASP for TGF-β-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver.


Effectiveness of amitriptyline in the prophylactic management of childhood headaches.
To study the effectiveness of a standardized dose of amitriptyline, 1 mg/kg, for childhood headaches. Amitriptyline has been shown to be effective for the prophylaxis of migraine in adults. Studies in children, however, have been quite limited. In adults, the suggested effective dose range is 10 to 150 mg. In children, a standardized dosage is often not used, resulting in a dosage range in clinical practice that often varies from a very low dose to a dose equivalent to that used in adults. Children with more than three headaches per month were treated with amitriptyline, slowly increasing the dose to 1 mg/kg per day. The frequency, severity, and duration of their headaches were initially evaluated and subsequently measured at each follow-up evaluation. Two hundred seventy-nine children had headaches occurring frequently enough to indicate prophylactic treatment. Of these children, 192 (68.8%) were treated with amitriptyline. The average age at presentation was 12.0 (+/- 3.0) years. The ratio of boys to girls was 1:1.74. The average frequency of headaches was 17.1 (+/- 10.1) days per month. The average severity was 6.84 (+/- 1.67) on a 10-point pain scale. The average duration was 11.5 (+/- 15.0) hours. The most frequent diagnoses using International Headache Society criteria were migraine (60.6%), migraine with aura (7.9%), and tension-type headache (10.4%). Of these children, 146 have been seen for at least one follow-up examination, occurring on average 67.3 (+/- 32.3) days after beginning prophylactic treatment. A total of 84.2% of the children reported an overall perception of being better, while 11.6% reported being the same. The frequency of headaches improved to 9.2 (+/- 10.0) days per month. The average severity was reduced to 5.1 (+/- 2.1), and the average duration was reduced to 6.3 (+/- 11.1) hours. If daily or continuous headaches were excluded, the improvements were more marked. Minimal side effects were reported from these children and their families. Long-term evaluation (156 to 415 days) showed continued sustained improvement. Amitriptyline is an effective prophylactic medication for children with frequent headaches. A standardized dosing regimen results in a significant number of children responding with minimal side effects. The children are able to tolerate this dosing scheme and demonstrate good adherence to a dosing schedule of once a day.


Effect of Direct Glare on Orbicularis Oculi and Trapezius During Computer Reading.
Unfavorable visual conditions during computer work may affect development of both eyestrain and musculoskeletal pain in the neck and shoulder area. The aim of the study was to investigate how direct glare affects symptom development, muscle activity, and muscle blood flow in m. orbicularis oculi and m. trapezius during reading on a computer screen. Fifteen healthy young adults with normal binocular vision read text on a computer screen at an optimized computer workplace, 30 minutes with glare exposure and 30 minutes with appropriate lighting. Postural angles were continuously registered. Development of eye symptoms and musculoskeletal pain in the neck and shoulder area were recorded using VAS scales. Muscle activity and muscle blood flow were measured continuously using electromyography and photoplethysmography, respectively. Glare exposure resulted in significantly more pronounced eye pain, increased orbicularis muscle activity, and increased trapezius blood flow compared to reading with appropriate lighting. There were no significant differences in posture between the two light conditions. There were also significant associations between orbicularis oculi activity and both trapezius blood flow and neck pain during both conditions. Results from the current study show that direct glare conditions cause increased eyestrain and orbicularis oculi contraction during reading on a computer screen. This study also indicates that exposure to direct glare affects the trapezius muscle, possibly by an interaction between the visual system, sympathetic nervous system, and head-stabilizing muscles. In addition, there were associations between the use of orbicularis oculi, trapezius blood flow, and development of neck pain independent of the lighting.


Proteomic and functional consequences of hexokinase deficiency in glucose-repressible Kluyveromyces lactis.
The analysis of glucose signaling in the Crabtree-positive eukaryotic model organism Saccharomyces cerevisiae has disclosed a dual role of its hexokinase ScHxk2, which acts as a glycolytic enzyme and key signal transducer adapting central metabolism to glucose availability. In order to identify evolutionarily conserved characteristics of hexokinase structure and function, the cellular response of the Crabtree-negative yeast Kluyveromyces lactis to rag5 null mutation and concomitant deficiency of its unique hexokinase KlHxk1 was analyzed by means of difference gel electrophoresis. In total, 2,851 fluorescent spots containing different protein species were detected in the master gel representing all of the K. lactis proteins that were solubilized from glucose-grown KlHxk1 wild-type and mutant cells. Mass spectrometric peptide analysis identified 45 individual hexokinase-dependent proteins related to carbohydrate, short-chain fatty acid and tricarboxylic acid metabolism as well as to amino acid and protein turnover, but also to general stress response and chromatin remodeling, which occurred as a consequence of KlHxk1 deficiency at a minimum 3-fold enhanced or reduced level in the mutant proteome. In addition, three proteins exhibiting homology to 2-methylcitrate cycle enzymes of S. cerevisiae were detected at increased concentrations, suggesting a stimulation of pyruvate formation from amino acids and/or fatty acids. Experimental validation of the difference gel electrophoresis approach by post-lysis dimethyl labeling largely confirmed the abundance changes detected in the mutant proteome via the former method. Taking into consideration the high proportion of identified hexokinase-dependent proteins exhibiting increased proteomic levels, KlHxk1 is likely to have a repressive function in a multitude of metabolic pathways. The proteomic alterations detected in the mutant classify KlHxk1 as a multifunctional enzyme and support the view of evolutionary conservation of dual-role hexokinases even in organisms that are less specialized than S. cerevisiae in terms of glucose utilization.


Mutations and deletions of the CBP gene in human lung cancer.
Microarray-based comparative genomic hybridization analysis led us to detect a homozygous deletion at the cyclic AMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive analysis of genetic CBP alterations in human lung cancer. Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene. Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examined. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant reduction in transcription activation activity of CBP protein in vivo. A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.


Gray matter volume and executive functioning correlate with time since injury following mild traumatic brain injury.
Most people who sustain a mild traumatic brain injury (mTBI) will recover to baseline functioning within a period of several days to weeks. A substantial minority of patients, however, will show persistent symptoms and mild cognitive complaints for much longer. To more clearly delineate how the duration of time since injury (TSI) is associated with neuroplastic cortical volume changes and cognitive recovery, we employed voxel-based morphometry (VBM) and select neuropsychological measures in a cross-sectional sample of 26 patients with mTBI assessed at either two-weeks, one-month, three-months, six-months, or one-year post injury, and a sample of 12 healthy controls. Longer duration of TSI was associated with larger gray matter volume (GMV) within the ventromedial prefrontal cortex (vmPFC) and right fusiform gyrus, and better neurocognitive performance on measures of visuospatial design fluency and emotional functioning. In particular, volume within the vmPFC was positively correlated with design fluency and negatively correlated with symptoms of anxiety, whereas GMV of the fusiform gyrus was associated with greater design fluency and sustained visual psychomotor vigilance performance. Moreover, the larger GMV seen among the more chronic individuals was significantly greater than healthy controls, suggesting possible enlargement of these regions with time since injury. These findings are interpreted in light of burgeoning evidence suggesting that cortical regions often exhibit structural changes following experience or practice, and suggest that with greater time since an mTBI, the brain displays compensatory remodeling of cortical regions involved in emotional regulation, which may reduce distractibility during attention demanding visuo-motor tasks.


Long-term outcome of prosthetic joint infections treated with two-stage revision.
Long-term evaluation of prosthetic joint infection treated with two-stage revision. Retrospective analysis of 102 periprosthetic infections treated with two-stage revision from 2010 to 2012 in Albenga hospital, Italy. During the second stage, samples for microbiological tests were collected. Failure was defined as a persistence of infection during the second stage or as a relapse during follow-up. 102 cases (55 hip, 47 knee) were analyzed. Patients were evaluated for a median of 44 months. 8/102 (8%) had positive cultures at replacement. These patients were treated with long-term antibiotic treatment and in 3/8 (38%) infection was cured. 9 patients were loss to follow-up or died, 6 patients (6%) had a relapse a median of 16,3 months from replanting. Risk factors significantly related to failures were diabetes and infection due to methicillin-resistant staphylococci. Two stage revision requires continued follow up. Screening for infection at replacement suggests prolonged antibiotic treatment.


Comparative Genomic Analyses of Flavobacterium psychrophilum Isolates Reveals New Putative Genetic Determinants of Virulence Traits.
The fish pathogen Flavobacterium psychrophilum is currently one of the main pathogenic bacteria hampering the productivity of salmonid farming worldwide. Although putative virulence determinants have been identified, the genetic basis for variation in virulence of F. psychrophilum is not fully understood. In this study, we analyzed whole-genome sequences of a collection of 25 F. psychrophilum isolates from Baltic Sea countries and compared genomic information with a previous determination of their virulence in juvenile rainbow trout. The results revealed a conserved population of F. psychrophilum that were consistently present across the Baltic Sea countries, with no clear association between genomic repertoire, phylogenomic, or gene distribution and virulence traits. However, analysis of the entire genome of four F. psychrophilum isolates by hybrid assembly provided an unprecedented resolution for discriminating even highly related isolates. The results showed that isolates with different virulence phenotypes harbored genetic variances on a number of consecutive leucine-rich repeat (LRR) proteins, repetitive motifs in gliding motility-associated protein, and the insertion of transposable elements into intergenic and genic regions. Thus, these findings provide novel insights into the genetic variation of these elements and their putative role in the modulation of F. psychrophilum virulence.


Residential treatment for homeless female veterans with psychiatric and substance use disorders: effect on 1-year clinical outcomes.
Limited evidence shows that time-limited residential treatment (RT) is beneficial for homeless people with serious mental illness. The Department of Veterans Affairs has established 11 specialty programs for homeless female veterans. We present data comparing 1-year clinical outcomes in a group of veterans who did and did not receive at least 30 days of RT. Clients of the Homeless Women Veterans Programs were invited to participate in a follow-up study. They were interviewed every 3 months for 1 year. Those who received at least 30 days of RT in the 3 months after program entry (RT group) were compared with other program participants (no or <30 days RT [NRT] group) on measures of community functioning, psychiatric symptoms, and drug and alcohol use during the follow-up. The RT group had better outcomes on employment, social support, housing status, and psychiatric symptoms. They also had significantly increased use of drugs and alcohol compared with the NRT group. Data suggest that RT may have a beneficial effect on mental health outcomes in homeless women. This study, in conjunction with others, suggests that provision of stable housing may be an important element of recovery for homeless women with psychiatric problems, excluding substance use.


Rearrangement of potassium ions and Kv1.1/Kv1.2 potassium channels in regenerating axons following end-to-end neurorrhaphy: ionic images from TOF-SIMS.
The voltage-gated potassium channels Kv1.1 and Kv1.2 that cluster at juxtaparanodal (JXP) regions are essential in the regulation of nerve excitability and play a critical role in axonal conduction. When demyelination occurs, Kv1.1/Kv1.2 activity increases, suppressing the membrane potential nearly to the equilibrium potential of K+, which results in an axonal conduction blockade. The recovery of K+-dependent communication signals and proper clustering of Kv1.1/Kv1.2 channels at JXP regions may directly reflect nerve regeneration following peripheral nerve injury. However, little is known about potassium channel expression and its relationship with the dynamic potassium ion distribution at the node of Ranvier during the regenerative process of peripheral nerve injury (PNI). In the present study, end-to-end neurorrhaphy (EEN) was performed using an in vivo model of PNI. The distribution of K+ at regenerating axons following EEN was detected by time-of-flight secondary-ion mass spectrometry. The specific localization and expression of Kv1.1/Kv1.2 channels were examined by confocal microscopy and western blotting. Our data showed that the re-establishment of K+ distribution and intensity was correlated with the functional recovery of compound muscle action potential morphology in EEN rats. Furthermore, the re-clustering of Kv1.1/1.2 channels 1 and 3 months after EEN at the nodal region of the regenerating nerve corresponded to changes in the K+ distribution. This study provided direct evidence of K+ distribution in regenerating axons for the first time. We proposed that the Kv1.1/Kv1.2 channels re-clustered at the JXP regions of regenerating axons are essential for modulating the proper patterns of K+ distribution in axons for maintaining membrane potential stability after EEN.


RAZA: A Rapid 3D z-crossings algorithm to segment electron tomograms and extract organelles and macromolecules.
Resolving the 3D architecture of cells to atomic resolution is one of the most ambitious challenges of cellular and structural biology. Central to this process is the ability to automate tomogram segmentation to identify sub-cellular components, facilitate molecular docking and annotate detected objects with associated metadata. Here we demonstrate that RAZA (Rapid 3D z-crossings algorithm) provides a robust, accurate, intuitive, fast, and generally applicable segmentation algorithm capable of detecting organelles, membranes, macromolecular assemblies and extrinsic membrane protein domains. RAZA defines each continuous contour within a tomogram as a discrete object and extracts a set of 3D structural fingerprints (major, middle and minor axes, surface area and volume), enabling selective, semi-automated segmentation and object extraction. RAZA takes advantage of the fact that the underlying algorithm is a true 3D edge detector, allowing the axes of a detected object to be defined, independent of its random orientation within a cellular tomogram. The selectivity of object segmentation and extraction can be controlled by specifying a user-defined detection tolerance threshold for each fingerprint parameter, within which segmented objects must fall and/or by altering the number of search parameters, to define morphologically similar structures. We demonstrate the capability of RAZA to selectively extract subgroups of organelles (mitochondria) and macromolecular assemblies (ribosomes) from cellular tomograms. Furthermore, the ability of RAZA to define objects and their contours, provides a basis for molecular docking and rapid tomogram annotation.


Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts.
Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.


Carboxypeptidase A: native, zinc-removed and mercury-replaced forms.
The crystal structure of the zinc-containing exopeptidase bovine carboxypeptidase A (CPA) has been refined to high resolution, based on a data set collected from a single crystal, incorporating new sequence information based on cloning of the bovine gene. In addition, new refined structures are available for the zinc-removed form of the enzyme, apo-CPA, as well as the mercury-replaced form, Hg-CPA. The native structure reveals that the zinc-bound water molecule does not appear to more loosely bound than the rest of the zinc ligands, at least when B-factor values are considered. Nor is there any evidence for a secondary location of this water molecule. The apo-enzyme structure does not show any density in the place of the removed zinc ion. The only significant change appears to be a chi2 rotation of one zinc histidine ligand to form an ion-pair interaction with a glutamic acid side chain. The structure of Hg-CPA reveals a solvent Tris molecule bound to the mercury cation, as well as an unidentified cation bound to Glu270. The location of this citation agrees with previous proposals for the binding side of inhibitory zinc. These observations may explain some of the differences in kinetics observed in metal- replaced CPA.


Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.
The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs.


Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors.
Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression. Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured. Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: -0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: -0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover. Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI.


[Association study between candidate genes on transforming growth factor-β signaling pathway and the risk of non-syndromic cleft lip with or without cleft palate in Chinese populations].
To explore the association between 10 candidate genes on transforming growth factor-β (TGFB) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Chinese populations, and to study the gene-environment interaction. A total of 806 Chinese Han NSCL/P trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affecting risk to NSCL/P. The transmission disequilibrium test (TDT) was used to test for effects of 343 single nucleotide polymorphisms (SNPs) in 10 genes on TGFB signaling pathway including DCN, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, BAMBI, SMAD2, SMAD3 and SMAD4. The conditional regression models were used to test for gene-environment interaction. For TDT, although 19 SNPs showed nominal significant association with NSCL/P, no significant evidence of association was seen for all SNPs in 806 NSCL/P trios after Bonferroni correction. The interactions between genes and maternal smoking, environmental tobacco smoke, alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons. No evidence for SNP effect of genes on TGFB signaling pathway and significant gene-environment interaction was seen in our data.


Renal and Cardiovascular Effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial.
Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study. To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-blind, placebo-controlled, cross-over trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 and 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 and 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio and urinary albumin/creatinine ratio when compared with placebo. Ethics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal. NCT03226457; Pre-results.


Hollow Mesoporous Molybdenum Single-Atom Nanozyme-Based Reactor for Enhanced Cascade Catalytic Antibacterial Therapy.
The remarkable peroxidase-like activity of single-atom nanozymes (SAzymes) allows them to catalyze the conversion of H2O2 to •OH, rendering them highly promising for antibacterial applications. However, their practical in vivo application is hindered by the near-neutral pH and insufficient H2O2 levels present in physiological systems. This study was aimed at developing a SAzyme-based nanoreactor and investigating its in vivo antibacterial activity. We developed a hollow mesoporous molybdenum single-atom nanozyme (HMMo-SAzyme) using a controlled chemical etching approach and pyrolysis strategy. The HMMo-SAzyme not only exhibited excellent catalytic activity but also served as an effective nanocarrier. By loading glucose oxidase (GOx) with HMMo-SAzyme and encapsulating it with hyaluronic acid (HA), a nanoreactor (HMMo/GOx@HA) was constructed as glucose-triggered cascade catalyst for combating bacterial infection in vivo. Hyaluronidase (HAase) at the site of infection degraded HA, allowing GOx to convert glucose into gluconic acid and H2O2. An acid environment significantly enhanced the catalytic activity of HMMo-SAzyme to promote the further catalytic conversion of H2O2 to •OH for bacterial elimination. In vitro and in vivo experiments demonstrated that the nanoreactor had excellent antibacterial activity and negligible biological toxicity. This study represents a significant advancement in developing a cascade catalytic system with high efficiency based on hollow mesoporous SAzyme, promising the advancement of biological applications of SAzyme.


Angiotensinogen-M235T genotype and post-transplant hypertension.
The angiotensinogen gene has been linked to the development of essential hypertension, and a M235T variant of this gene, associated with increased plasma levels of angiotensinogen, is more common in hypertensives than in normotensive controls in various populations. The present study was conducted to examine whether the M235T variant of the angiotensinogen gene may be a risk factor for the development of hypertension in patients undergoing renal transplantation. DNA for genetic analysis was prospectively collected from 269 consecutive patients undergoing kidney transplantation between 1988 and 1993 and their corresponding donors. Presence of hypertension and graft survival was analysed by blinded review of all case records over a follow-up period up to 30 months. Angiotensinogen genotype was determined by a mutagenically separated allele-specific polymerase-chain-reaction technique. While post-transplant hypertension was present in 78% of all patients, no relationship was found between either donor or recipient genotype and the presence or severity of post-transplant hypertension. Furthermore, there was no relationship between angio-tensinogen genotype and graft survival during the course of the study. These findings do not support the hypothesis that the M235T variant of the angiotensinogen gene is a risk factor for the development of post-transplant hypertension.


Management of allergic rhinitis in the era of effective over-the-counter treatments.
Allergic rhinitis (AR) may be regarded as a trivial issue unworthy of the doctor's time, and with the availability of many different over-the-counter (OTC) treatments, up to two thirds of patients self-manage AR before seeking medical care. Yet, AR can have a significant impact on health-related quality of life and is associated with a greater detriment to work productivity than other chronic diseases such as diabetes and hypertension. For many patients, the impact on quality of life is greater than suggested by reported symptoms and should also be a focus of treatment. Although many patients can effectively manage AR symptoms independently, a significant percentage will need direction from a physician to obtain optimal results. The availability of several different classes of treatment - including decongestants, sedating and non-sedating antihistamines, and more recently intranasal corticosteroids (INS) - has increased the complexity of self-management, leaving patients confused about the best approach to treatment. Treatment guidelines universally classify INS as the most effective medical agents available for use in the OTC and primary care settings. Many patients are unaware that INS are available OTC and that they are more effective than other therapies. Patients may have negative perceptions about the safety of INS and may have experienced unpleasant taste, scent, and feel with nasal sprays. Unless a patient volunteers the information, healthcare professionals (HCPs) may be unaware that the patient has significant AR and is using one or more OTC AR therapies. To address this gap in communication, HCPs must be proactive in identifying, assessing, and advising patients with AR, including best strategies to assess allergen trigger symptoms, which treatments are appropriate, and when and how to use them. Proper use of delivery devices is especially important. This article reviews the primary care management of AR in the context of the availability of effective OTC medicines.


Evaluation of team effectiveness and personal empathy for associations with professional quality of life and job satisfaction in companion animal practice personnel.
To examine variables of veterinary team effectiveness and personal empathy for associations with professional quality of life (ie, compassion satisfaction, burnout, and secondary traumatic stress) and job satisfaction in companion animal practice personnel. Cross-sectional survey. Data from 232 surveys completed by personnel from 10 companion animal veterinary practices in 2 regions of the United States between April 7 and December 20, 2016. Online surveys were used to collect practice-level data (eg, practice type, setting, and staffing) and individual-level data (eg, demographics, job position, and years in the position and profession). Instruments used in developing the surveys included the Team Effectiveness Instrument, Davis Interpersonal Reactivity Index, Professional Quality of Life Scale, and a measure for job satisfaction. Data were evaluated for associations with professional quality of life and job satisfaction. Individual engagement was positively associated with job satisfaction, negatively associated with secondary traumatic stress, and moderated by levels of personal distress for compassion satisfaction and burnout. Toxic team environment was positively associated with burnout and negatively associated with job satisfaction. Empathetic concern and personal distress were both positively associated with secondary traumatic stress. Empathetic concern was moderated by team engagement for compassion satisfaction. Results indicated that variables influencing professional quality of life and job satisfaction were multimodal and included aspects of team effectiveness and empathy; therefore, workplace strategies that enhance individual and team engagement and mitigate toxic team environments could potentially improve professional quality of life and job satisfaction in veterinary personnel.


Heart Failure With Mid-Range (Borderline) Ejection Fraction: Clinical Implications and Future Directions.
Heart failure (HF) with borderline ejection fraction was first defined in 2013 in the American College of Cardiology/American Heart Association guidelines as the presence of the typical symptoms of HF and a left ventricular ejection fraction (LVEF) of 41% to 49%. In 2016, the European Society of Cardiology specified HF with mid-range ejection fraction (HFmrEF) as LVEF of 40% to 49%. This range of LVEF is less well studied compared with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Although there are effective, guideline-directed medical therapies for patients with HFrEF, no therapies thus far show measurable benefit in HFpEF. Patients with HFmrEF have a clinical profile and prognosis that are closer to those of patients with HFpEF than those of HFrEF, with certain distinctions. Whether these patients represent a unique and dynamic HF group that may benefit from targeted therapies known to be beneficial in patients with HFrEF, such as neurohormonal blockade, requires further study. This review summarizes what is known about the clinical epidemiology, pathophysiology, and prognosis for patients with HFmrEF and how these features compare with the more well-studied HF groups. Although recommended treatments currently focus on aggressive management of comorbidities, we summarize the studies that identify a potential signal for beneficial therapies. Future studies are needed to not only better characterize the HFmrEF population but to also determine effective management strategies to reduce the high cardiovascular morbidity and mortality burden on this phenotype of patients with HF.


Sex allocation and the emergence of helping in cooperatively breeding species.
In cooperative breeding systems individuals invest in the reproductive success of others. In this paper, we study the emergence of cooperative breeding systems in which reproductively active breeders receive investment from reproductively non-active helpers. Our goal is to understand how the division of an investment between male and female components of breeder fitness (i.e. the helper sex-allocation strategy) influences the emergence of cooperative breeding itself. Using mathematical models, we arrive at expressions for the inclusive-fitness advantage of helpful behaviour that generalize previous work. These expressions assume an ecologically stable environment, and that breeders make evolutionarily stable sex-allocation decisions. We find that, when breeders are extremely resource limited, the sex-allocation strategy used by a helper can be a key determinant in the success of helpful alleles. This finding, however, is restricted to cases in which helpers have access to intermediate levels of resources. Surprisingly, when helpers can make only a small investment in a recipient the division of the investment matters only very little to advantage of help. By contrast when resources are extremely abundant, we obtain the unsurprising result that the manner in which resources are allocated has little influence on the emergence of help. When breeders have access to intermediate levels of resources we find increasing relatedness can, in certain cases, inhibit the emergence of help. We also find that increasing the amount of resources available to a breeder can impede help as well. Both of these counter-intuitive results are mediated by evolutionary responses in breeder sex allocation.


Chronic kidney disease in type 2 diabetes: lessons from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study.
The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study is an ongoing observational survey that examines the role of estimated glomerular filtration rate (eGFR) as an independent predictor of cardiovascular and renal outcomes in 15,773 Italian subjects with type 2 diabetes. The analysis of data collected at the enrollment visit provided a picture of chronic kidney disease (CKD) and its association with other complications, risk factors for cardiovascular disease (CVD) and treatments in a large contemporary cohort. Main results of this analysis were that (a) non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with reduced eGFR; (b) concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions; (c) the non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary vascular bed; (d) CKD is associated with hemoglobin (Hb) A1c variability more than with average HbA1c, whereas retinopathy and CVD are not; (e) in elderly individuals with moderate-to-severe eGFR reduction, use of agents which are not recommended, such as sulphonylureas and metformin, is still frequent; and (f) though complications are generally more prevalent in men (except non-albuminuric renal impairment) women show a less favorable CVD risk profile and achieve therapeutic targets to a lesser extent than men, despite the fact that treatment intensity is not lower. These data update existing information on the natural history of CKD in patients with type 2 diabetes.


Molecular Toxicology and Cancer Prevention.
Molecular toxicology is a field that investigates the interactions between chemical or biological molecules and organisms at the molecular level [...].


Molecular de-novo design through deep reinforcement learning.
This work introduces a method to tune a sequence-based generative model for molecular de novo design that through augmented episodic likelihood can learn to generate structures with certain specified desirable properties. We demonstrate how this model can execute a range of tasks such as generating analogues to a query structure and generating compounds predicted to be active against a biological target. As a proof of principle, the model is first trained to generate molecules that do not contain sulphur. As a second example, the model is trained to generate analogues to the drug Celecoxib, a technique that could be used for scaffold hopping or library expansion starting from a single molecule. Finally, when tuning the model towards generating compounds predicted to be active against the dopamine receptor type 2, the model generates structures of which more than 95% are predicted to be active, including experimentally confirmed actives that have not been included in either the generative model nor the activity prediction model. Graphical abstract .


Circadian rhythms in the pineal organ persist in zebrafish larvae that lack ventral brain.
The mammalian suprachiasmatic nucleus (SCN), located in the ventral hypothalamus, is a major regulator of circadian rhythms in mammals and birds. However, the role of the SCN in lower vertebrates remains poorly understood. Zebrafish cyclops (cyc) mutants lack ventral brain, including the region that gives rise to the SCN. We have used cyc embryos to define the function of the zebrafish SCN in regulating circadian rhythms in the developing pineal organ. The pineal organ is the major source of the circadian hormone melatonin, which regulates rhythms such as daily rest/activity cycles. Mammalian pineal rhythms are controlled almost exclusively by the SCN. In zebrafish and many other lower vertebrates, the pineal has an endogenous clock that is responsible in part for cyclic melatonin biosynthesis and gene expression. We find that pineal rhythms are present in cyc mutants despite the absence of an SCN. The arginine vasopressin-like protein (Avpl, formerly called Vasotocin) is a peptide hormone expressed in and around the SCN. We find avpl mRNA is absent in cyc mutants, supporting previous work suggesting the SCN is missing. In contrast, expression of the putative circadian clock genes, cryptochrome 1b (cry1b) and cryptochrome 3 (cry3), in the brain of the developing fish is unaltered. Expression of two pineal rhythmic genes, exo-rhodopsin (exorh) and serotonin-N-acetyltransferase (aanat2), involved in photoreception and melatonin synthesis, respectively, is also similar between cyc embryos and their wildtype (WT) siblings. The timing of the peaks and troughs of expression are the same, although the amplitude of expression is slightly decreased in the mutants. Cyclic gene expression persists for two days in cyc embryos transferred to constant light or constant dark, suggesting a circadian clock is driving the rhythms. However, the amplitude of rhythms in cyc mutants kept in constant conditions decreased more quickly than in their WT siblings. Our data suggests that circadian rhythms can be initiated and maintained in the absence of SCN and other tissues in the ventral brain. However, the SCN may have a role in regulating the amplitude of rhythms when environmental cues are absent. This provides some of the first evidence that the SCN of teleosts is not essential for establishing circadian rhythms during development. Several SCN-independent circadian rhythms have also been found in mammalian species. Thus, zebrafish may serve as a model system for understanding how vertebrate embryos coordinate rhythms that are controlled by different circadian clocks.


Indicators for Monitoring Water, Sanitation, and Hygiene: A Systematic Review of Indicator Selection Methods.
Monitoring water, sanitation, and hygiene (WaSH) is important to track progress, improve accountability, and demonstrate impacts of efforts to improve conditions and services, especially in low- and middle-income countries. Indicator selection methods enable robust monitoring of WaSH projects and conditions. However, selection methods are not always used and there are no commonly-used methods for selecting WaSH indicators. To address this gap, we conducted a systematic review of indicator selection methods used in WaSH-related fields. We present a summary of indicator selection methods for environment, international development, and water. We identified six methodological stages for selecting indicators for WaSH: define the purpose and scope; select a conceptual framework; search for candidate indicators; determine selection criteria; score indicators against criteria; and select a final suite of indicators. This summary of indicator selection methods provides a foundation for the critical assessment of existing methods. It can be used to inform future efforts to construct indicator sets in WaSH and related fields.


Cooperative switching events in azobenzene foldamer denaturation.
Insight into the mechanism of photoswitchable foldamer denaturation was gained by incorporating two azobenzene switching units (see figure; orange) into the helix backbone. Optimizing the location of the units leads to cooperative photoisomerization events, causing complete unfolding. The switching cooperativity coupled with the cooperative unfolding transition enables the design of highly photosensitive systems.


Hydrogen-bonded clusters of ferrocenecarboxylic acid on Au(111).
Self-assembled monolayers of ferrocenecarboxylic acid (FcCOOH) contain two fundamental units, both stabilized by intermolecular hydrogen bonding: dimers and cyclic five-membered catemers. At surface coverages below a full monolayer, however, there is a significantly more varied structure that includes double-row clusters containing two to twelve FcCOOH molecules. Statistical analysis shows a distribution of cluster sizes that is sharply peaked compared to a binomial distribution. This rules out simple nucleation-and-growth mechanisms of cluster formation, and strongly suggests that clusters are formed in solution and collapse into rows when deposited on the Au(111) surface.


The antidepressant drug carbamazepine induces differential transcriptome expression in the brain of Atlantic salmon, Salmo salar.
Concerns are being expressed recently over possible environmental effects of human pharmaceuticals. Although the likelihood of acute toxicity is low, the continuous discharge of pharmaceuticals into the aquatic environment means that sublethal effects on non-target organisms need to be seriously considered. One-year-old Atlantic salmon parr were exposed to 7.85±0.13μgL(-1) of the antidepressant drug Carbamazepine (CBZ) for five days to investigate changes of mRNA expression in the brain by means of a custom 17k Atlantic salmon cDNA microarray. The selected concentration is similar to upper levels that can be found in hospital and sewage treatment plant effluents. After treatment, 373 features were differently expressed with 26 showing up- or down-regulation of ≥2-fold (p≤0.05). Among the mRNAs showing the highest change were the pituitary hormones encoding features somatolactin, prolactin and somatotropin, or growth hormone. Functional enrichment and network analyses of up- and down-regulated genes showed that CBZ induced a highly different gene expression profile in comparison to untreated organisms. CBZ induced expression of essential genes of the focal adhesion and extracellular matrix - receptor interaction pathways most likely through integrin alpha-6 (itga6) activation. Negative regulation of apoptotic process, extracellular matrix organization and heme biosynthesis were the most enriched biological process related GO-terms, with the simultaneous enrichment of collagen and extracellular region related cellular component GO-terms, and extracellular matrix structural constituent, hormone activity and chromatin binding molecular function related GO-terms. These results show that relatively low doses of CBZ may affect brain physiology in exposed salmon parr, targeting similar processes as in human, indicating a high degree of conservation of targets of CBZ action. However, and since the mRNAs showing most changes in expression are critical for adaptation to different stressors and life history transitions in Atlantic salmon, more research should be undertaken to assess CBZ effects to avoid impairment of normal development and maintenance of natural populations.


Prognostic impact of lipoprotein(a) levels during lipid management with statins after ST-elevation acute myocardial infarction.
The causal relationship of lipoprotein(a) with cardiovascular disease has been established. However, clinical impacts of lipoprotein(a) levels on adverse vascular events in patients with established coronary artery disease who are undergoing statin treatment have not been fully elucidated. We measured lipoprotein(a) levels of 668 consecutive patients with ST-elevated myocardial infarction upon admission and reevaluated lipoprotein(a) of 189 of these patients during statin treatment at least 6 months later than the date of index ST-elevated myocardial infarction. Changes in lipoprotein(a) and associations between lipoprotein(a) levels and the incidence of major adverse cardiac and cerebrovascular event for 3 years were examined. Lipoprotein(a) at baseline was an independent predictor of 3-year major adverse cardiac and cerebrovascular event after ST-elevated myocardial infarction. Levels of lipoprotein(a) at follow-up were slightly but significantly elevated despite improvements in other lipid parameters due to statin treatment. Furthermore, higher levels of lipoprotein(a) achieved with statin treatment were also associated with the subsequent incidence of major adverse cardiac and cerebrovascular event over 3 years, regardless of whether or not the LDL-cholesterol levels were below 100 mg/dl. In conclusion, lipoprotein(a) levels during lipid management by statin are also predictive of adverse vascular events in Japanese patients with ST-elevated myocardial infarction.


Types of motivating operations in interventions with problem behavior: a systematic review.
A motivating operation (MO) alters both the effectiveness of a stimulus as a reinforcer and the current frequency of all behavior that has been reinforced by that particular stimulus. This article reviews studies that have manipulated a MO during interventions with school-age participants with intellectual disabilities and problem behavior. A systematic review was conducted using the following major electronic databases: PsychInfo, Education Resources Information Center, Science Direct, Blackwell, SAGE, and Medline. A total of 31 published articles representing 55 participants was examined. Findings from this study suggest that the modification of a MO usually has an effect on the problem behavior by either establishing or abolishing its motivation. Furthermore, a relationship was found between the type of MO and the behavioral function identified. The theoretical and practical implications of these findings, limitations of this study and potential issues for future research are discussed.


Immunocompetent cells of the chicken. I. Specific surface antigenic markers on bursa and thymus cells.
Specific antisera to chicken thymus and to bursa of Fabricius were obtained in rabbits. After appropriate absorption and dilution all four anti-thymus sera, in the presence of guinea pig C', killed >90% of thymus and <==12% of bursa cells. They were cytotoxic for approximately 50% of spleen cells and did not affect antibody-forming cells. The surface antigen detected by these antisera was named chicken T-lymphocyte antigen (CTLA). Two of four anti-bursa sera, under similar conditions, killed >90% of bursa cells and <==10% of thymus cells. These antisera were cytotoxc for a large percentage of antibody-forming cells and killed approximately 30% of spleen cells The other two anti-bursa sera were somewhat less potent but showed similar specificity. The surface antigen detected by these antisera was named chicken bursa-derived lymphocyte antigen (CBuLA). Rabbit antisera to chicken immunoglobulin were cytotoxic for bursa but not for thymus cells and killed a similar percentage of spleen cells as did anti-bursa sera. They were also cytotoxic for antibody-forming cells.


Early effectiveness of endoscopic posterior urethra primary alignment.
Posterior urethra primary realignment (PUPR) after complete transection may decrease the gap between the ends of the transected urethra, tamponade the retropubic bleeding, and optimize urinary drainage without the need of suprapubic catheter facilitating concurrent pelvic orthopedic and trauma procedures. Historically, the distorted anatomy after pelvic trauma has been a major surgical challenge. The purpose of the study was to assess the relationship of the severity of the pelvic fracture to the success of endoscopic and immediate PUPR following complete posterior urethral disruption using the Young-Burgess classification system. A review of our Level I trauma center database for patients diagnosed with pelvic fracture and complete posterior urethral disruption from January 2005 to April 2012 was performed. Pelvic fracture severity was categorized according to the Young-Burgees classification system. Management consisted of suprapubic catheter insertion at diagnosis followed by early urethral realignment when the patient was clinically stable. Failure of realignment was defined as inability to achieve urethral continuity with Foley catheterization. Clinical follow-up consisted of radiologic, pressure studies and cystoscopic evaluation. A total of 481 patients with pelvic trauma from our trauma registry were screened initially, and 18 (3.7%) were diagnosed with a complete posterior urethral disruption. A total of 15 primary realignments (83.3%) were performed all within 5 days of trauma. The success rate of early realignment was 100%. There was no correlation between the type of pelvic ring fracture and the success of PUPR. Postoperatively, 8 patients (53.3%) developed urethral strictures, 3 patients (20.0%) developed incontinence, and 7 patients (46.7%) reported erectile dysfunction after the trauma. The mean follow-up of these patients was 31.8 months. Endoscopic PUPR may be an effective option for the treatment of complete posterior urethral disruption and enables urinary drainage to best suit the multispecialty surgical team. The success rate of achieving primary realignment did not appear to be related to the complexity and type of pelvic ring fracture.


An Economic Analysis of Tourism Contribution for Urban Poverty Reduction in Major Tourist Towns of North Shewa Zone, Amhara Region, Ethiopia.
Tourism has a significant contribution to the livelihood diversification of the communities and supporting economic development efforts. This study aimed at an economic analysis of tourism's contribution to urban poverty reduction in Major Tourist Towns of North Shewa Zone, Amhara Region, Ethiopia. A multistage simple random sampling and purpose sampling were used to select sample respondents from the population in the study area. Hence, a total of 286 valid observations from 385 sample respondents were used for the analysis of the collected data. Both descriptive and inferential statistics were used to analyze the data. The finding of this study revealed that tourism has a significant and positive contribution to poverty reduction in urban areas, but the level of contribution is minimal. Besides, it exhibited that funding aids and government concern for tourism-targeted programs and access to credit infrastructure, tourism education, and policy were the significant factors that affect tourism's role in urban poverty reduction. Thus, to enhance its contributions and overcome industry bottlenecks, the government shall put tourism as a valuable development pillar, develop pro-poor strategies linking tourism with the urban poor, develop urban tourism development programs, and assign tourism-trained professional leaders to the sector.


Effects of tennis training on lipid metabolism and lipoproteins in recreational players.
To investigate the short term effects of tennis training on lipid metabolism and to find out if a typical tennis training programme has positive longitudinal effects on cardiovascular risk factors in recreational players. The experimental design consisted of an exercise study and a subsequent longitudinal study. In the exercise study the short term metabolic effects of a two hour technically orientated tennis training (TT) session and a running intensive tennis training (RIT) session were investigated in 16 recreational tennis players (eight men: 46 (SD 7) years, 177 (6) cm, 81 (10) kg; and eight women: 44 (5) years, 165 (5) cm, 64 (6) kg). In the longitudinal study the long term effects of a six week RIT programme in 22 players (11 men and 11 women) of similar characteristics were compared with those in 16 control subjects (eight men and eight women). The results of the exercise study (higher lipolytic activity and cardiopulmonary demand, as well as acceptance by the players) led to the RIT method being chosen for all training sessions in the longitudinal study. In RIT, significantly higher values for heart rate (148 (SD 10) v 124 (11) beats/minute) and lactate (2.8 (1.1) v 1.5 (0.6) mmol/l), significantly higher post exercise concentrations of serum glycerol (0.37 (0.15) v 0.29 (0.14) mmol/l) and high density lipoprotein cholesterol (1.31 (0.55) v 1.20 (0.50) mmol/l) and a higher acceptance than in TT (15 of the 16 players preferred RIT) were found. During the six week tennis training programme the changes in body weight (-1.41 (1.56) v 0.00 (1.50) kg) and anaerobic threshold (1.04 (0.84) v -0.08 (0.92) km/h) were significantly different between the training and control group. In the training group several parameters of the lipoprotein profile tended to change in an antiatherosclerotic direction. The results indicate that typical regular tennis training influences cardiovascular risk factors in a positive manner and can be suggested as an attractive alternative to other current health orientated sports programmes. A more frequent use of running intensive exercises during tennis training is recommended.


Detection of K-ras and p53 mutations in sputum samples of lung cancer patients using laser capture microdissection microscope and mutation analysis.
Mutations in the p53 tumor suppressor gene and the K-ras oncogene have been frequently found in sputum and bronchoalveolar lavage (BAL) samples of lung cancer patients and other patients prior to presenting clinical symptoms of lung cancer, suggesting that they may provide useful biomarkers for early lung cancer diagnosis. However, the detection of these gene mutations in sputum and BAL samples has been complicated by the fact that they often occur in only a small fraction of epithelial cells among sputum cells and, in the case of p53 gene, at many codons. In this study, sputum cells were collected on a filter membrane by sputum cytocentrifugation and morphologically analyzed. Epithelial cells were selectively taken by using a laser capture microdissection microscope and analyzed by polymerase chain reaction (PCR) and single-stranded conformational polymorphism (SSCP) for p53 mutations and by PCR and denaturing gradient gel electrophoresis (DGGE) for K-ras mutations. This method was used to analyze sputum of 15 Chinese women with lung cancer from Xuan Wei County, China and detected mutations in sputum of 7 (46.7%) patients, including 5 patients with p53 mutations, 1 patient with a K-ras mutation, and 1 patient with K-ras and p53 mutations. For comparison, only two of the mutations were detected by conventional methods. Therefore, the laser capture/mutation analysis method is sensitive and facilitates the detection of low-fraction mutations occurring throughout the p53 and K-ras genes in sputum of lung cancer patients. This method may be applicable to the analysis of epithelial cells from clinically normal sputum or BAL samples from individuals with a high risk for developing lung cancer.


Corolla chirality does not contribute to directed pollen movement in Hypericum perforatum (Hypericaceae): mirror image pinwheel flowers function as radially symmetric flowers in pollination.
Corolla chirality, the pinwheel arrangement of petals within a flower, is found throughout the core eudicots. In 15 families, different chiral type flowers (i.e., right or left rotated corolla) exist on the same plant, and this condition is referred to as unfixed/enantiomorphic corolla chirality. There are no investigations on the significance of unfixed floral chirality on directed pollen movement even though analogous mirror image floral designs, for example, enantiostyly, has evolved in response to selection to direct pollinator and pollen movement. Here, we examine the role of corolla chirality on directing pollen transfer, pollinator behavior, and its potential influence on disassortative mating. We quantified pollen transfer and pollinator behavior and movement for both right and left rotated flowers in two populations of Hypericum perforatum. In addition, we quantified the number of right and left rotated flowers at the individual level. Pollinators were indifferent to corolla chirality resulting in no difference in pollen deposition between right and left flowers. Corolla chirality had no effect on pollinator and pollen movement between and within chiral morphs. Unlike other mirror image floral designs, corolla chirality appears to play no role in promoting disassortative mating in this species.


Droperidol-fentanyl inhibits mast cell histamine release in rat synovium, but not skin, after immunologic activation: evidence for mast cell heterogeneity.
The characteristics of mast cell heterogeneity include differences in mast cell staining, cellular structure, content of proteoglycans and vasoactive amines, and in vitro responses to secretagogues. We have found that the anesthetic agent, droperidol-fentanyl, significantly decreased rat synovial vascular permeability after selective synovial mast cell degranulation. In contrast, there was no effect on skin mast cell-induced vascular permeability. To address the possibility that this difference in response represents mast cell heterogeneity and uniqueness of synovial mast cells, we investigated the effects of three different anesthetic agents on synovial mast cells. In these studies we examined whether (1) the drugs affect synovial mast cells and (2) whether the drugs affect synovial mast cells differently from mast cells in skin. Our data indicate that, compared to inhaled methoxyflurane and ethyl ether, subcutaneous droperidol-fentanyl had a significant inhibitory effect on synovial, but not skin, mast cell-mediated vascular permeability, which was associated with a significant inhibition of synovial mast cell histamine release. Thus, the permeability differences were not due only to effects on histamine receptors. Our data suggest the possibility that there are significant functional differences between synovial and skin mast cells, a phenomenon that may have important therapeutic implications for treatment of mast cell-mediated synovial inflammation.


Perceptions and sociodemographic factors influencing vaccination uptake and precautionary behaviours in response to the A/H1N1 influenza in Sweden.
In response to the 2009 outbreak of A/H1N1 influenza, Swedish authorities decided on a programme for universal vaccination. Over 60% of the population received at least one dose of vaccine. This study examines demographic factors and perceptions related to the decision whether or not to become vaccinated. A combined web/postal survey was conducted (n = 1587, response rate 53%) in late spring 2010. Questions reported here concerned perceptions, precautionary behaviours and vaccination decision. Main reasons for becoming vaccinated were concerns about spreading the disease to relatives or in the community and confidence in the good effect of vaccination. Vaccination rates were higher among women, those with young children or belonging to a risk group. Main reasons for abstaining were belief that the flu was not a serious threat, low risk of spreading the disease, concern about side-effects and perceived uncertainties in information. Three profiles representing different patterns of thought and beliefs were identified by cluster analysis, respectively labelled as a vulnerable, a trusting and a sceptical group. Vaccination rates and precautionary behaviours were demonstrated to differ between these groups. Perceptions relating to the 2009 pandemic are likely to influence uptake of vaccination in the future. Authorities need to be aware of different patterns of beliefs and attitudes among the public, and that these may vary in different phases. Communication of risk needs to be dynamic and prepared to engage with the public before, during and even for some time after the acute risk period.


Relationship Between Nutrition Intake and Outcome After Subarachnoid Hemorrhage: Results From the International Nutritional Survey.
A previous study suggested an association between low caloric intake(CI), negative nitrogen balance, and poor outcome after subarachnoid hemorrhage(SAH). Objective of this multinational, multicenter study was to investigate whether clinical outcomes vary by protein intake(PI) or CI in SAH patients adjusting for the nutritional risk as judged by the modified NUTrition Risk in the Critically Ill (mNUTRIC) score. The International Nutrition Survey(INS) 2007-2014 was utilized to describe the characteristics, outcomes and nutrition use. A subgroup of patients from 2013 and 2014(when NUTRIC score was captured) examined the association between CI and PI and time to discharge alive(TTDA) from hospital using Cox regression models, adjusting for nutrition risk classified by the mNUTRIC score as low(0-4) or high(5-9). There were 489 SAH patients(57% female with a mean ± SD age 57.5 ± 13.9 years, BMI of 25.9 ± 5.3 kg/m2 and APACHE-2 score 19.4 ± 7.0. Majority(85%) received enteral nutrition(EN) only, with a time to initiation of EN of 35.4 ± 35.2 hours. 64% had EN interrupted. Patients received a CI of 14.6 ± 7.1 calories/kg/day and PI 0.7 ± 0.3 grams/kg/day corresponding to 59% and 55% of total prescribed CI and PI respectively. In the 2013 and 2014 subgroup there were 226 SAH patients with a mNUTRIC score of 3.4 ± 1.8. Increased CI and PI were associated with faster TTDA among high mNUTRIC patients(HR per 20% of prescription received = 1.34[95% CI,1.03 -1.76] for CI and 1.44[1.07 -1.93] for PI), but not low mNUTRIC patients(CI: HR = 0.95[0.77 -1.16] PI:0.95[0.78 -1.16]). Results from this multicenter study found that SAH patients received under 60% of their prescribed CI and PI. Further, achieving greater CI and PI in hi risk SAH patients was associated with improved TTDA. mNUTRIC serves to identify SAH patients that benefit most from artificial nutrition and efforts to optimize protein and caloric delivery in this subpopulation should be maximized.


Sensory axonopathy in mild to moderate peripheral arterial disease.
The effect of mild to moderate arterial occlusive disease on peripheral nervous system conduction was prospectively investigated in 18 subjects and 18 control subjects, aged 40 to 85 years. Experimental and control subjects underwent a thorough history and physical followed by vascular and electrophysiologic studies. The primary outcome measure was the sensory nerve action potential. Although 33% of the subjects with peripheral arterial disease had experienced paresthesias, the clinical evaluation of sensation was relatively unaffected. Sensory conduction studies revealed 30% absent sural responses and 56% absent superficial peroneal nerve responses in subjects with peripheral arterial disease compared with 3 and 14% absent responses in control subjects, respectively (P = 0.044; 0.025). There were no differences in distal latency or sensory amplitude, although the superficial peroneal amplitude did approach significance (P = 0.06). No significant differences were found in motor distal latency, amplitude, or conduction velocity. Age, leg length, temperature, disease severity, presence of paresthesias, cholesterol levels, and past alcohol or tobacco ingestion did not account for the difference in sensory responses. These results support the presence of a mild sensory axonopathy in subjects with peripheral arterial disease. Electromyographers should be cognizant of absent distal responses from peripheral arterial disease so as not to ascribe the findings to an alternative pathology and should not attribute abnormal motor conduction results to the presence of this degree of peripheral arterial disease.


[Vaccination in the elderly population].
It is known that the immune systems tend to weaken over time, putting elderly patients at higher risk for chronic diseases such as cardiovascular (CV) diseases, diabetes, chronic renal disorders and their complication as well as infectious disease leading to an increased mortality and morbidity rates in patients over 65 years old. Vaccination, a prophylactic treatment strategy, means that immunogenic materials from pathogens (or tumours) are administered to generate an adequate immune response specifically to these antigens. Vaccine-preventable diseases which can affect the elderly population are influenza, pneumococcal disease, tetanus, hepatitis B and zona zoster. It is recommended that all adults over 65 years old, and for adults younger than 65 years who have certain chronic health conditions receive seasonal influenza vaccination annually, pneumococcal vaccines and zoster vaccine. Also tetanus vaccine administration is recommended every 10 years in adults.


The Many Guises of Endometriosis: Giant Abdominal Wall Endometriosis Masquerading as An Incisional Hernia.
Endometriosis is defined by the presence of ectopic endometrial tissue outside the uterine cavity. Although it is a leading cause of chronic pelvic pain and infertility, its clinical presentation can vary, resulting in diagnostic and therapeutic challenges. Extrapelvic endometriosis is particularly difficult to diagnose owing to its ability to mimic other conditions. Endometrial tissue in a surgical scar is uncommon and often misdiagnosed as a granuloma, abscess, or malignancy. Cyclical hemorrhagic ascites due to peritoneal endometriosis is exceptionally rare. We report the case of a pre-menopausal, nulliparous 44-year-old woman who presented with ascites and a large abdominal mass that arose from the site of a lower midline laparotomy scar. Five years previously, she had undergone open myomectomy for uterine fibroids. Soon after her initial operation she developed abdominal ascites, which necessitated percutaneous drainage on multiple occasions. We performed a laparotomy with excision of the abdominal wall mass through an inverted T incision. The extra-abdominal mass consisted of mixed cystic and solid components, and weighed 1.52 kg. It communicated with the abdominopelvic cavity through a 2 cm defect in the linea alba. The abdomen contained a large amount of odourless, brown fluid which drained into the mass. There was a large capsule that covered the small and large bowel, liver, gallbladder, and stomach. Final histology reported a 28×19×5 cm mass of endometrial tissue with no evidence of malignant transformation. The patient recovered well post-operatively and has remained asymptomatic. Our case illustrates that, despite being a common disease, endometriosis can masquerade as several other conditions and be missed or diagnosed late. Delay in diagnosis will not only prolong symptoms but can also compromise reproductive lifespan. It is therefore paramount that endometriosis is to be considered early in the management of premenopausal women who present with an irregular pelvic mass or hemorrhagic ascites.