Weakened negative effect of Au/TiO2 photocatalytic activity by CdS quantum dots deposited under UV-vis light illumination at different intensity ratios.
Herein, we demonstrate experimentally the coexistence of photocatalytic dual opposite roles of Au nanoparticles in a UV-vis light irradiated Au/TiO2 system. We have investigated that the photocatalytic performance curves of Au/TiO2 and CdS/Au/TiO2 for degradation of methylene blue (MB) all present a V-shape with different radiation power ratios. However, through the comparison of photocatalytic activities of Au/TiO2 and CdS/Au/TiO2 by statistics and mathematical simulation, we propose qualitatively that the deposition of CdS used as a photosensitizer could extend the Au/TiO2 light absorption range and weaken the negative effect of Au/TiO2. Compared with Au/TiO2, it is proven indirectly that the photo-excited electrons of CdS/Au/TiO2 transfer from CdS to Au, and then to TiO2. Furthermore, we discuss the photocatalytic dual opposite roles of Au nanoparticles between CdS and TiO2, the positive effect includes localized surface plasmon resonance (LSPR) and Schottky barrier (SB), and the negative effect is that Au nanoparticles can be used as a new charge-carrier recombination center. In addition, we have analyzed that the dual opposite relationship of Au/TiO2 under the irradiation of mixed-light could be regulated by changing the intensity ratio of visible to UV light as well.


Pitfalls of a Mixed Metabolic Response at PET/CT.
Although the term mixed metabolic response is commonly used in PET/CT reports, it should be a red flag to reconsider the assumptions made by the PET scan reader. Fluorine 18 fluorodeoxyglucose (FDG) PET/CT is recognized as an accurate imaging method for detecting response to cancer therapies. Critical clinical decisions regarding therapy are dependent on accurate interpretation of findings. The use of standardized terminology for response assessment, such as that in the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), is highly recommended. With PERCIST, treatment response is categorized as complete metabolic response, partial metabolic response, stable metabolic disease, or progressive metabolic disease. Mixed metabolic response is not included in PERCIST. Rather, it is used colloquially to describe a scenario in which scanning performed after systemic cancer therapy reveals divergent findings, with some tumor foci responding and others not responding or even seen progressing. In PERCIST, mixed metabolic response should be described as stable metabolic disease or progressive metabolic disease. However, the PET/CT reader may also wish to suggest that individual tumors have heterogeneous genetic and/or other characteristics and consequently a mixed response to therapy. The concept of tumor heterogeneity is gaining momentum in cancer research and thus possibly leading to options for therapy targeted to oligometastases that are not responding. However, the authors suggest exercising extreme caution when PET/CT findings appear at first to reflect what some might call a mixed response. In addition, they have found that FDG PET/CT findings are often confounding owing to the simultaneous presence of two or more unrelated disease processes. Common examples include synchronous neoplasms, inflammatory processes, and treatment-related effects. Thus, an apparent mixed response is a red flag to reconsider whether all of the FDG-avid findings are actually metastases of the same cancer. Common mimics of a mixed metabolic response that do not represent true tumor heterogeneity are highlighted to improve the FDG PET/CT reader's recognition of these lesions.©RSNA, 2019.


Generation of SNP datasets for orangutan population genomics using improved reduced-representation sequencing and direct comparisons of SNP calling algorithms.
High-throughput sequencing has opened up exciting possibilities in population and conservation genetics by enabling the assessment of genetic variation at genome-wide scales. One approach to reduce genome complexity, i.e. investigating only parts of the genome, is reduced-representation library (RRL) sequencing. Like similar approaches, RRL sequencing reduces ascertainment bias due to simultaneous discovery and genotyping of single-nucleotide polymorphisms (SNPs) and does not require reference genomes. Yet, generating such datasets remains challenging due to laboratory and bioinformatical issues. In the laboratory, current protocols require improvements with regards to sequencing homologous fragments to reduce the number of missing genotypes. From the bioinformatical perspective, the reliance of most studies on a single SNP caller disregards the possibility that different algorithms may produce disparate SNP datasets. We present an improved RRL (iRRL) protocol that maximizes the generation of homologous DNA sequences, thus achieving improved genotyping-by-sequencing efficiency. Our modifications facilitate generation of single-sample libraries, enabling individual genotype assignments instead of pooled-sample analysis. We sequenced ~1% of the orangutan genome with 41-fold median coverage in 31 wild-born individuals from two populations. SNPs and genotypes were called using three different algorithms. We obtained substantially different SNP datasets depending on the SNP caller. Genotype validations revealed that the Unified Genotyper of the Genome Analysis Toolkit and SAMtools performed significantly better than a caller from CLC Genomics Workbench (CLC). Of all conflicting genotype calls, CLC was only correct in 17% of the cases. Furthermore, conflicting genotypes between two algorithms showed a systematic bias in that one caller almost exclusively assigned heterozygotes, while the other one almost exclusively assigned homozygotes. Our enhanced iRRL approach greatly facilitates genotyping-by-sequencing and thus direct estimates of allele frequencies. Our direct comparison of three commonly used SNP callers emphasizes the need to question the accuracy of SNP and genotype calling, as we obtained considerably different SNP datasets depending on caller algorithms, sequencing depths and filtering criteria. These differences affected scans for signatures of natural selection, but will also exert undue influences on demographic inferences. This study presents the first effort to generate a population genomic dataset for wild-born orangutans with known population provenance.


Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element.
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.


Age-related changes in the rat brain mitochondrial antioxidative enzyme ratios: modulation by melatonin.
Oxidative stress is an important factor for aging. The antioxidative enzymes glutathione peroxidase (GPx), glutathione reductase (GRd) and superoxide dismutase (SOD) play a crucial role protecting the organism against the age-dependent oxidative stress. Glutathione (GSH) is present in nearly all living cells. GSH is one of the main antioxidants in the cell and it serves several physiological functions. Our purpose was to evaluate the age-related changes in mitochondrial GPx, GRd and SOD activities, and mitochondrial GSH pool in the brains of young (3 months) and aged rats (24 months). We also investigated whether melatonin administration influences these brain mitochondrial enzyme activities and GSH levels in young and aged rats. The results showed that GPx activity increased with age, whereas melatonin treatment decreased GPx activity in the aged rats at levels similar to those in young and young+melatonin groups. The activities of GRd and SOD, however, did not change with age. But, melatonin treatment increased SOD activity in the aged rats. GSH levels, which also increased with age, were not modified by melatonin treatment. The reduction in the SOD/GPx and GR/GPx ratios with age was prevented by melatonin administration. Together, our results suggest that the age-related oxidative stress in rat brain mitochondria is more apparent when the antioxidant enzyme ratios are analyzed instead of their absolute values. The antioxidative effects of melatonin were also supported by the recovery of the enzyme ratios during aging.


Some conditions apply: Systems for studying Plasmodium falciparum protein function.
Malaria, caused by infection with Plasmodium parasites, remains a significant global health concern. For decades, genetic intractability and limited tools hindered our ability to study essential proteins and pathways in Plasmodium falciparum, the parasite associated with the most severe malaria cases. However, recent years have seen major leaps forward in the ability to genetically manipulate P. falciparum parasites and conditionally control protein expression/function. The conditional knockdown systems used in P. falciparum target all 3 components of the central dogma, allowing researchers to conditionally control gene expression, translation, and protein function. Here, we review some of the common knockdown systems that have been adapted or developed for use in P. falciparum. Much of the work done using conditional knockdown approaches has been performed in asexual, blood-stage parasites, but we also highlight their uses in other parts of the life cycle and discuss new ways of applying these systems outside of the intraerythrocytic stages. With the use of these tools, the field's understanding of parasite biology is ever increasing, and promising new pathways for antimalarial drug development are being discovered.


Contact angle and adsorption energies of nanoparticles at the air-liquid interface determined by neutron reflectivity and molecular dynamics.
Understanding how nanomaterials interact with interfaces is essential to control their self-assembly as well as their optical, electronic, and catalytic properties. We present here an experimental approach based on neutron reflectivity (NR) that allows the in situ measurement of the contact angles of nanoparticles adsorbed at fluid interfaces. Because our method provides a route to quantify the adsorption and interfacial energies of the nanoparticles in situ, it circumvents problems associated with existing indirect methods, which rely on the transport of the monolayers to substrates for further analysis. We illustrate the method by measuring the contact angle of hydrophilic and hydrophobic gold nanoparticles, coated with perdeuterated octanethiol (d-OT) and with a mixture of d-OT and mercaptohexanol (MHol), respectively. The contact angles were also calculated via atomistic molecular dynamics (MD) computations, showing excellent agreement with the experimental data. Our method opens the route to quantify the adsorption of complex nanoparticle structures adsorbed at fluid interfaces featuring different chemical compositions.


Administration of novel dyes for intraocular surgery: an in vivo toxicity animal study.
To investigate the effect of intravitreal injections of new vital dyes on the retina, the retinal pigment epithelium (RPE) and the choroid in an in vivo rat model. Rats were injected intravitreally with four dyes: light-green SF yellowish (LGSF), copper(II)phthalocyanine-tetrasulfonic acid (E68), bromphenol blue (BPB), and Chicago blue (CB) dissolved in physiologic saline solution (PSS) at concentrations of 0.5% and 0.02%. PSS served as the control. Additional animals were treated with single injections of 0.5%, 0.02%, 0.002%, and 0.0002% ICG or 0.002% E68 into one eye. Adverse effects on anterior and posterior segments were evaluated by slit lamp biomicroscopy and ophthalmoscopy. Retinal toxicity was assessed by histology and retinal ganglion cell (RGC) quantification 7 days after dye administration. Eyes treated with 0.5% E68, 0.5% ICG, or 0.5% CB showed discrete staining of both cornea and lens not seen at lower concentrations or with other dyes. Histology revealed dose-dependent reactions after E68 administration. ICG 0.5% induced significant thinning of inner retinal layers compared with PSS. ICG 0.02% caused focal degenerative changes of the outer retina in three of seven eyes, whereas 0.002% and 0.0002% ICG did not. CB led to heterogeneous morphologic alterations. BPB- or LGSF-treated eyes showed normal retinal morphology. ICG at all tested concentrations induced significant RGC loss, as did E68 at 0.5% but not at lower concentrations. BPB or LGSF produced no significantly detectable toxic effects on the retina in vivo. The safety of these new dyes must be established in other models and/or in preclinical studies before the clinical use of any of these dyes.


Effective cooperation of monoclonal antibody and peptide vaccine for the treatment of mouse melanoma.
mAbs binding to tumor-associated surface Ags are therapeutically applied in a range of malignancies. Therapeutic vaccination only recently met with clinical success, and the first cancer vaccine received U.S. Food and Drug Administration approval last year. To improve current protocols, we combined peptide vaccines with mAb to the tyrosinase-related protein (TRP)-1 surface Ag for the treatment of B16F10 skin melanoma. Vaccine formulations with synthetic long peptides failed to elicit strong CD8 T cell responses to self-differentiation Ags gp100 and TRP-2, whereas altered peptide sequences recruited gp100-specific CD8 T cells from the endogenous repertoire with frequencies of 40%. However, these high frequencies were reached too late; large, progressively growing melanomas had already emerged. Addition of the TRP-1-directed mAb TA99 to the treatment protocol mediated eradication of s.c. lesions. The mode of action of the Ab did not depend on complement factor C3 and did not lead to improved Ag presentation and CD8 T cell immunity; rather, it recruited FcγR-bearing innate immune cells during early tumor control, thereby creating a window of time for the generation of protective cellular immunity. These data support the concept of combination therapy, in which passive transfer of mAbs is supplemented with cancer peptide vaccines. Moreover, we advocate that tumor Ag-specific T cell immunity directed against self-proteins can be exploited from the endogenous repertoire.


Stochastic voyages into uncharted chemical space produce a representative library of all possible drug-like compounds.
The "small molecule universe" (SMU), the set of all synthetically feasible organic molecules of 500 Da molecular weight or less, is estimated to contain over 10(60) structures, making exhaustive searches for structures of interest impractical. Here, we describe the construction of a "representative universal library" spanning the SMU that samples the full extent of feasible small molecule chemistries. This library was generated using the newly developed Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS). ACSESS makes two important contributions to chemical space exploration: it allows the systematic search of the unexplored regions of the small molecule universe, and it facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds.


Assessing diversity in canopy architecture, photosynthesis, and water-use efficiency in a cowpea magic population.
Optimizing crops to improve light absorption and CO2 assimilation throughout the canopy is a proposed strategy to increase yield and meet the needs of a growing population by 2050. Globally, the greatest population increase is expected to occur in Sub-Saharan Africa where large yield gaps currently persist; therefore, it is crucial to develop high-yielding crops adapted to this region. In this study, we screened 50 cowpea (Vigna unguiculata (L.) Walp) genotypes from the multi-parent advanced generation inter-cross (MAGIC) population for canopy architectural traits, canopy photosynthesis, and water-use efficiency using a canopy gas exchange chamber in order to improve our understanding of the relationships among those traits. Canopy architecture contributed to 38.6% of the variance observed in canopy photosynthesis. The results suggest that the light environment within the canopy was a limiting factor for canopy CO2 assimilation. Traits favoring greater exposure of leaf area to light such as the width of the canopy relative to the total leaf area were associated with greater canopy photosynthesis, especially in canopies with high biomass. Canopy water-use efficiency was highly determined by canopy photosynthetic activity and therefore canopy architecture, which indicates that optimizing the canopy will also contribute to improving canopy water-use efficiency. We discuss different breeding strategies for future programs aimed at the improvement of cowpea yield for the Sub-Saharan African region. We show that breeding for high biomass will not optimize canopy CO2 assimilation and suggest that selection should include multiple canopy traits to improve light penetration.


miRGen 2.0: a database of microRNA genomic information and regulation.
MicroRNAs are small, non-protein coding RNA molecules known to regulate the expression of genes by binding to the 3'UTR region of mRNAs. MicroRNAs are produced from longer transcripts which can code for more than one mature miRNAs. miRGen 2.0 is a database that aims to provide comprehensive information about the position of human and mouse microRNA coding transcripts and their regulation by transcription factors, including a unique compilation of both predicted and experimentally supported data. Expression profiles of microRNAs in several tissues and cell lines, single nucleotide polymorphism locations, microRNA target prediction on protein coding genes and mapping of miRNA targets of co-regulated miRNAs on biological pathways are also integrated into the database and user interface. The miRGen database will be continuously maintained and freely available at http://www.microrna.gr/mirgen/.


Psychophysiological stress induces heat shock cognate protein 70 messenger RNA in the hippocampus of rats.
Psychophysiological stress has been shown to increase 70,000 mol. wt heat shock protein messenger RNAs with northern blotting in rats. However, its localization is unknown. With in situ hybridization, we tested our hypothesis that restraint water-immersion stress may induce heat shock cognate protein 70 messenger RNA expression simultaneously with some morphological changes selectively in the hippocampus of rats. Stress for 6 h significantly increased heat shock cognate protein 70 messenger RNAs in the hippocampus, with maximal intensity in the CA3 subfield of the Ammon's horn and to a lesser extent in CA2. Stress for 12 h significantly increased heat shock cognate protein 70 messenger RNAs in the whole hemisphere including the cerebral cortex, the thalamus, the hypothalamus, and the hippocampus with the highest density in CA3. Heat shock cognate protein 70 messenger RNA in rats with stress for 6 h followed by recovery for 6 h significantly increased at CA3 and CA2 compared with the controls or rats stressed for 6 h without recovery. No overt histological changes were detected in neuronal or glial cells in the slides of hematoxylin-eosin or Cresyl Violet staining. These results show that psychophysiological stress induces heat shock cognate protein 70 messenger RNA in the most stress-vulnerable brain structure, hippocampal CA3, probably for cytoprotection.


Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics.
Neural plasticity-the ability to change and adapt in response to stimuli-is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens-a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying "chemical imbalances" and place more emphasis on achieving selective modulation of neural circuits.


The gap between law and ethics in human embryonic stem cell research: overcoming the effect of U.S. federal policy on research advances and public benefit.
Key ethical issues arise in association with the conduct of stem cell research by research institutions in the United States. These ethical issues, summarized in detail, receive no adequate translation into federal laws or regulations, also described in this article. U.S. Federal policy takes a passive approach to these ethical issues, translating them simply into limitations on taxpayer funding, and foregoes scientific and ethical leadership while protecting intellectual property interests through a laissez faire approach to stem cell patents and licenses. Those patents and licenses, far from being scientifically and ethically neutral in effect, virtually prohibit commercially sponsored research that could otherwise be a realistic alternative to the federal funding gap. The lack of federal funding and related data-sharing principles, combined with the effect of U.S. patent policy, the lack of key agency guidance, and the proliferation of divergent state laws arising from the lack of Federal leadership, significantly impede ethical stem cell research in the United States, without coherently supporting any consensus ethical vision. Research institutions must themselves implement steps, described in the article, to integrate addressing ethical review with the many legal compliance issues U.S. federal and state laws create.


Postoperative Opiate Use in Urological Patients: A Quality Improvement Study Aimed at Improving Opiate Disposal Practices.
We aimed to determine trends in postoperative opiate management among urological patients, identify associations with opiate keeping and foster appropriate opiate disposal after surgery via introduction of an educational handout. We retrospectively analyzed opiate practices in 68 patients who had undergone urological surgery. In a separate consecutive cohort of 59 patients we distributed a handout detailing FDA (Food and Drug Administration) approved disposal methods. Patient opiate obtainment, use and disposal were assessed via telephone interviews with prescription filling data verified using the Tennessee CSMD (Controlled Substances Monitoring Database). Opiate keeping was defined as possessing any opiates more than 3 weeks after surgery or more than 4 times the duration of the postoperative prescription, whichever was longer. Opiate keeping was observed in 41 patients (72%) in our initial cohort. Of these patients 68% left the medication unsecured at home. Major barriers to opiate disposal included concern for return of disease specific pain in 44% of patients and unrelated pain in 29%. As assessed on a short test, opiate keepers were less knowledgeable about safe disposal practices compared to nonkeepers (72% vs 85%, p = 0.005). Among opiate keepers there was an improvement in knowledge scores after the intervention (66% to 77%, p = 0.03). When comparing pre-education to post-education, there was no detectable improvement in the rate of opiate keeping (72% vs 68%, p = 0.66) or proper disposal (9% vs 8%, p = 1.0). Opiate keeping is common following urological surgery and a major barrier to disposal is concern for the return of disease specific pain. Future interventions aimed at limiting opiate keeping should combine evidence-based prescription practices and targeted patient education.


Influence of the donor size in D-π-A organic dyes for dye-sensitized solar cells.
We report two new molecularly engineered push-pull dyes, i.e., YA421 and YA422, based on substituted quinoxaline as a π-conjugating linker and bulky-indoline moiety as donor and compared with reported IQ4 dye. Benefitting from increased steric hindrance with the introduction of bis(2,4-dihexyloxy)benzene substitution on the quinoxaline, the electron recombination between redox electrolyte and the TiO2 surface is reduced, especially in redox electrolyte employing Co(II/III) complexes as redox shuttles. It was found that the open circuit photovoltages of IQ4, YA421, and YA422 devices with cobalt-based electrolyte are higher than those with iodide/triiodide electrolyte by 34, 62, and 135 mV, respectively. Moreover, the cells employing graphene nanoplatelets on top of gold spattered film as a counter electrode (CE) show lower charge-transfer resistance compared to platinum as a CE. Consequently, YA422 devices deliver the best power conversion efficiency due to higher fill factor, reaching 10.65% at AM 1.5 simulated sunlight. Electrochemical impedance spectroscopy and transient absorption spectroscopy analysis were performed to understand the electrolyte influence on the device performances with different counter electrode materials and donor structures of donor-π-acceptor dyes. Laser flash photolysis experiments indicate that even though the dye regeneration of YA422 is slower than that of the other two dyes, the slower back electron transfer of YA422 contributes to the higher device performance.


Randomized comparative evaluation of endoscopic submucosal dissection self-learning software in France and Japan.
Background and study aim: Endoscopic submucosal dissection (ESD) is currently the reference method to achieve an en bloc resection for large lesions; however, the technique is difficult and risky, with a long learning curve. In order to reduce the morbidity, training courses that use animal models are recommended. Recently, self-learning software has been developed to assist students in their training. The aim of this study was to evaluate the impact of this tool on the ESD learning curve. Methods: A prospective, randomized, comparative study enrolled 39 students who were experienced in interventional endoscopy. Each student was randomized to one of two groups and performed 30 ESDs of 30 mm standardized lesions in a bovine colon model. The software group used the self-learning software whereas the control group only observed an ESD procedure video. The primary outcome was the rate of successful ESD procedures, defined as complete en bloc resection without any perforation and performed in less than 75 minutes. Results: A total of 39 students performed 1170 ESDs. Success was achieved in 404 (70.9 %) in the software group and 367 (61.2 %) in the control group (P = 0.03). Among the successful procedures, there were no significant differences between the software and control groups in terms of perforation rate (22 [4.0 %] vs. 29 [5.1 %], respectively; P = 0.27) and mean (SD) procedure duration (34.1 [13.4] vs. 32.3 [14.0] minutes, respectively; P = 0.52). For the 30th procedure, the rate of complete resection was superior in the software group (84.2 %) compared with the control group (50.0 %; P = 0.01). Conclusion: ESD self-learning software was effective in improving the quality of resection compared with a standard teaching method using procedure videos. This result suggests the benefit of incorporating such software into teaching programs.


Spiral CT with multiplanar and three-dimensional reconstructions accurately predicts tracheobronchial pathology.
This study was designed to evaluate the clinical accuracy of multiplanar reconstructions and three-dimensional shaded surface displays compared with conventional transaxial computed tomography, bronchoscopy, and surgical pathologic findings. Transaxial computed tomographic images, two-dimensional nonstandard multiplanar reconstruction images, and three-dimensional images obtained from patients with tracheobronchial disease were prospectively evaluated for the relationship to adjacent structures, lesion characterization, and surgical anatomic correlation before invasive procedures. Compared with conventional transaxial computed tomographic images, multiplanar reconstructions and three-dimensional shaded surface displays provided a correlative map of bronchoscopic and surgical anatomy in patients with benign and malignant tracheobronchial pathology. The longitudinal extent of abnormalities are better demonstrated on the multiplanar reconstruction and three-dimensional images, whereas the transverse extent of disease and relationships to adjacent structures were better shown on axial computed tomographic sections. Three-dimensional and multiplanar two-dimensional images are additive to transaxial computed tomography for evaluation of diseases involving the central airways. They are beneficial for planning invasive procedures. More importantly, they provide consistent, highly accurate measurements for routine follow-up and for future clinical trials.


Repetitive transcranial magnetic stimulation of the supplementary motor area (SMA) degrades bimanual movement control in humans.
Moving the upper limbs at a common tempo according to an in-phase or anti-phase mode represents elementary coordination dynamics. Previously, the role of the supplementary motor area (SMA) has been emphasized for successful production of these patterns. The objective of this study was to investigate whether repetitive transcranial magnetic stimulation (rTMS) of the SMA at 5 Hz can interfere with these isofrequency configurations in the post-stimulation stage. Results showed a deterioration of temporal control as a function of coordinative complexity. This effect was associated with a decrease in the functional coupling between the primary motor cortices, as measured by electroencephalographic coherence. These data suggest that rTMS of the SMA can modify interhemispheric communication and accordingly modulate interlimb behavior.


ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up.
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: Prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.


Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors.
DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G1. We find that deficient replication-coupled de novo nucleosome assembly renders replication forks unstable and highly dependent on the ATR and CHK1 checkpoint kinases, as well as poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) activity, to avoid collapse. Human cancer data revealed frequent up-regulation of TLK genes and an association with poor patient outcome in multiple types of cancer, and depletion of TLK activity leads to increased replication stress and DNA damage in a panel of cancer cells. Our results reveal a critical role for TLKs in chromatin replication and suppression of replication stress and identify a synergistic lethal relationship with checkpoint signaling and PARP that could be exploited in treatment of a broad range of cancers.


Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.
Objectives: Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). Methods: A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested. Results: β-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. β-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to β-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1β, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. RNASEq upon β-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance. Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels.


Adverse Effects of Early Puberty Timing in Girls and Potential Solutions.
Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will discuss the public health implications of early puberty and potential clinical and public health measures. Although the major effect of earlier maturation impacts adolescents' mental health and likelihood of engaging in risky behaviors, there are also effects in adulthood on cardiometabolic health, especially type 2 diabetes, and an increased risk of certain cancers, especially hormone-related cancers such as breast cancer. The paper ends with recommendations for clinical management, especially for girls who should receive further evaluation, as well as recommendations for the patient and her family and public health considerations.


Health Beneficial Properties of Grapevine Seed Extract and Its Influence on Selected Biochemical Markers in the Blood, Liver and Kidneys of Rattus norvegicus.
Cadmium (Cd) is a heavy metal that occurs in all areas of the environment, including the food chain. In the body, it causes oxidative stress by producing free radicals that are harmful to the cells. Grape seed extract (GSE) contains a wide range of biologically active components that help to neutralize the adverse effects of free radicals. In this study, the effects of GSE prepared form semi-resistant grapevine cultivar Cerason, which is rich in phenolics, on biochemical markers of brown rats exposed to the effects of cadmium were monitored. GSE increased the plasma antioxidant activity and, in the kidneys and the liver, Cd content was significantly lowered by GSE co-administration. Accordingly, the increase in creatinine content and alanine aminotransferase activity and the decrease of catalase and superoxide dismutase activities caused by cadmium were slowed down by GSE co-administration. The results of this work reveal that grape seed extract offers a protective effect against the intake of heavy metals into the organism.


Long-term changes of the nonresurfaced patella after total knee arthroplasty.
The most common complications of total knee arthroplasty involve the patellofemoral joint. However, the long-term fate of the nonresurfaced patella after total knee arthroplasty has seldom been reported. The purpose of this study was to evaluate the long-term changes of the nonresurfaced patella after total knee arthroplasty. We retrospectively evaluated the nonresurfaced patella in 227 knees (181 patients) at an average of 8.5 years after total knee arthroplasty. Functional results were correlated with radiographic changes, and risk factors leading to abnormal changes of the patella were analyzed. Preoperatively, 186 (82%) of the patellae tracked centrally, thirty-nine (17%) displaced or tilted laterally, and two (1%) subluxated laterally. At the time of the latest follow-up, 133 (59%) of the patellae still tracked centrally with preservation of the cartilage thickness, fifteen (7%) showed early lateral tilt, sixty-eight (30%) had progressive loss of lateral cartilage thickness with lateral tilt and/or displacement, seven (3%) had progressed to lateral subluxation, and four (2%) tilted medially. An abnormal patellofemoral joint did not affect the knee and functional scores (p = 0.90 and 0.89, respectively). However, symptoms such as difficulty rising from a chair or reluctance to use the involved lower limb while climbing stairs were noted. Preoperative patellar maltracking was identified as the only risk factor leading to postoperative patellar abnormalities (relative risk, 2.7; 95% confidence interval, 2.21 to 3.30; p = 0.003). At the time of follow-up, at an average of 8.5 years, patellar tracking and the patellofemoral joint remained normal after approximately 60% of the total knee arthroplasties performed without resurfacing of the patella. Progressive degenerative changes of the nonresurfaced patella (mainly on the lateral facet) and patellar maltracking were the most common abnormal radiographic changes. Patients with preoperative patellar maltracking were at risk for the development of these changes and clinical symptoms. Resurfacing of the patella during total knee arthroplasty may benefit such patients.


Estimating Health-State Utility Values in Kidney Transplant Recipients and Waiting-List Patients Using the EQ-5D-5L.
To report health-state utility values measured using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) in a large sample of patients with end-stage renal disease and to explore how these values vary in relation to patient characteristics and treatment factors. As part of the prospective observational study entitled "Access to Transplantation and Transplant Outcome Measures," we captured information on patient characteristics and treatment factors in a cohort of incident kidney transplant recipients and a cohort of prevalent patients on the transplant waiting list in the United Kingdom. We assessed patients' health status using the EQ-5D-5L and conducted multivariable regression analyses of index scores. EQ-5D-5L responses were available for 512 transplant recipients and 1704 waiting-list patients. Mean index scores were higher in transplant recipients at 6 months after transplant surgery (0.83) compared with patients on the waiting list (0.77). In combined regression analyses, a primary renal diagnosis of diabetes was associated with the largest decrement in utility scores. When separate regression models were fitted to each cohort, female gender and Asian ethnicity were associated with lower utility scores among waiting-list patients but not among transplant recipients. Among waiting-list patients, longer time spent on dialysis was also associated with poorer utility scores. When comorbidities were included, the presence of mental illness resulted in a utility decrement of 0.12 in both cohorts. This study provides new insights into variations in health-state utility values from a single source that can be used to inform cost-effectiveness evaluations in patients with end-stage renal disease.


Frankixalus, a New Rhacophorid Genus of Tree Hole Breeding Frogs with Oophagous Tadpoles.
Despite renewed interest in the biogeography and evolutionary history of Old World tree frogs (Rhacophoridae), this family still includes enigmatic frogs with ambiguous phylogenetic placement. During fieldwork in four northeastern states of India, we discovered several populations of tree hole breeding frogs with oophagous tadpoles. We used molecular data, consisting of two nuclear and three mitochondrial gene fragments for all known rhacophorid genera, to investigate the phylogenetic position of these new frogs. Our analyses identify a previously overlooked, yet distinct evolutionary lineage of frogs that warrants recognition as a new genus and is here described as Frankixalus gen. nov. This genus, which contains the enigmatic 'Polypedates' jerdonii described by Günther in 1876, forms the sister group of a clade containing Kurixalus, Pseudophilautus, Raorchestes, Mercurana and Beddomixalus. The distinctiveness of this evolutionary lineage is also corroborated by the external morphology of adults and tadpoles, adult osteology, breeding ecology, and life history features.


Estimating incidence and prevalence of treated psychiatric disorders from routine statistics: the example of schizophrenia in Oxfordshire.
To use routine statistical records to estimate the incidence and prevalence of treated schizophrenia. Analysis of linked records in Oxfordshire (population 540,000) for all people in contact with specialist psychiatric services from 1975-86. Records of 685 people with a diagnosis of schizophrenia as an inpatient and a further 294 people who received specialist psychiatric care for schizophrenia outside hospital without any record of inpatient care. The measures most commonly recorded in psychiatric statistics, first admission rates for people in whom schizophrenia was recorded at their first psychiatric admission, were 8.7 per 100,000 males and 5.6 per 100,000 females. First contact rates for people in whom schizophrenia was recorded at any time in the study period and in any setting were 15.1 per 100,000 males and 11.4 per 100,000 females. Whichever patient population was analysed, the broad profile of schizophrenia by age, sex, and calendar time was similar. First admission rates for schizophrenia, as identifiable in current routine information systems, are useful indicators of the general pattern of disease but are inadequate absolute indicators of treated incidence. These data are limited to the first ever contact. Reliable information about the treated incidence of disease requires information systems which incorporate information about when and where each diagnosis was first made. Reliable information about treated prevalence requires systems which also incorporate data about death, recovery, and migration into and out of the study population.


PET neuroimaging and mutations in the DJ-1 gene.
Mutations in the DJ-1 gene lead to autosomal recessive early-onset parkinsonism. We performed F-DOPA and FDG PET neuroimaging in two parkinsonism patients homozygous for DJ-1 mutations, three relatives heterozygous for a DJ-1 mutation and one non-carrier, all from the originally described kindred from The Netherlands. Their characteristics were compared to those of typical Parkinson's disease patients and healthy controls. Both parkinsonism patients had reduced F-DOPA uptake concordant with typical Parkinson's disease. In the, clinically unaffected, heterozygous relatives, F-DOPA metabolism was unremarkable, thus not suggesting a dosage effect of the DJ-1 gene.


A Monte Carlo dosimetry-based evaluation of the 7Li(p,n)7Be reaction near threshold for accelerator boron neutron capture therapy.
Advanced methods of boron neutron capture therapy (BNCT) use an epithermal neutron beam in conjunction with tumor-targeting boron compounds for irradiation of glioblastomas and metastatic melanomas. A common neutron-producing reaction considered for accelerator-based BNCT is 7Li(p,n)7Be, whose cross section increases very rapidly within several tens of keV of the reaction threshold at 1.88 MeV. Operation in the proton energy region near threshold will have an appreciable thick target neutron yield, but the neutrons produced will have relatively low energies that require little moderation to reach the epithermal range desirable for BNCT. Because of its relatively low projected accelerator cost and the portability of the neutron source/target assembly, BNCT based on the near-threshold technique is considered an attractive candidate for widespread hospital use. A systematic Monte Carlo N-Particle (MCNP) investigation of the dosimetric properties of near-threshold neutron beams has been performed. Results of these studies indicate that accelerator proton energies between 1.93 and 1.99 MeV, using 5 cm of H2O moderator followed by thin 6Li and Pb shields, can provide therapeutically useful beams with treatment times less than one hour and accelerator currents less than 5 mA.


Malaria prophylaxis for aircrew: safety of atovaquone/proguanil in healthy volunteers under aircraft cabin pressure conditions.
Because malaria in endemic areas presents a serious threat to the health of aircrew, optimal prevention is important. An effective and safe prophylactic antimalarial drug is needed. The combination of 250 mg atovaquone with 100 mg proguanil HCl (atovaquone/proguanil, or A/P) has shown good prophylactic efficacy and tolerance for prevention of falciparum malaria. However, medication for use by aircrew on duty is subject to approval by national and international aviation authorities, who require convincing evidence that the treatment has no negative effects on the flight performance of crews. The purpose of the present study was to evaluate the risk of detrimental effects of atovaquone/proguanil on flight-related performance and alertness in healthy subjects under conditions of aircraft cabin pressure. A randomized, double-blind crossover study was conducted in which 24 subjects were enrolled to use A/P and placebo, each in a 14-day prophylactic dosing regimen with a 21-day washout phase. Vigilance, alertness, complex information processing, and sleepiness were assessed in a hypobaric chamber at 75.2 kPa, which equals the lower limit of commercial aircraft cabin pressure. Furthermore, duration and quality of sleep at home were recorded during the 14 days of drug administration. Twenty-two subjects completed the study. No significant differences were found between the effects of placebo and A/P on vigilance, alertness, complex information processing, sleep duration and quality, and the occurrence of adverse effects. In-flight performance and alertness of aircrew will not be affected by the prophylactic use of A/P during a period of 14 days.


Environmentally relevant exposure to an antidepressant alters courtship behaviours in a songbird.
Pharmaceuticals in the environment are a recently identified global threat to wildlife, including birds. Like other human pharmaceuticals, the antidepressant fluoxetine (Prozac) enters the environment via sewage and has been detected at wastewater treatment plants. Birds foraging on invertebrates at these sites can be exposed to pharmaceuticals, although the implications of exposure are poorly understood. We conducted experiments to test whether chronic exposure to a maximally environmentally relevant concentration of fluoxetine (2.7 μg day-1) altered courtship behaviour and female reproductive physiology in wild-caught starlings (Sturnus vulgaris), a species commonly found foraging on invertebrates at wastewater treatment plants. When paired with a female over two days, males sang less and were more aggressive towards fluoxetine-treated females than controls. Fluoxetine-treated females were initially aggressive towards males, becoming significantly less aggressive by the second day. In contrast, control females expressed intermediate levels of aggression throughout. We found no effect of female treatment on female courtship behaviour. Female body condition, circulating testosterone and circulating oestradiol were unaffected by treatment and did not account for male preference. Our findings suggest that exposure to an antidepressant reduced female attractiveness, adding to growing evidence that environmental concentrations of pharmaceuticals can alter important traits related to individual fitness and population dynamics.


Cadmium intake and systemic exposure in postmenopausal women and age-matched men who smoke cigarettes.
Mean blood cadmium (B-Cd) concentrations are two- to threefold higher in smokers than in nonsmokers. The basis for this phenomenon is not well understood. We conducted a detailed, multifaceted study of cadmium exposure in smokers. Groups were older smokers (62±4 years, n = 25, 20% male) and nonsmokers (62±3 years, n = 16, 31% male). Each subject's cigarettes were machine smoked, generating individually paired measures of inhaled cadmium (I-Cd) versus B-Cd; I-Cd and B-Cd were each evaluated three times, at monthly intervals. Urine cadmium (U-Cd) was analyzed for comparison. In four smokers, a duplicate-diet study was conducted, along with a kinetic study of plasma cadmium versus B-Cd. Female smokers had a mean B-Cd of 1.21ng Cd/ml, with a nearly 10-fold range (0.29-2.74ng Cd/ml); nonsmokers had a lower mean B-Cd, 0.35ng Cd/ml (p < 0.05), and narrower range (0.20-0.61ng Cd/ml). Means and ranges for males were similar. Estimates of cadmium amounts inhaled daily for our subjects smoking ≥ 20 cigarettes/day were far less than the 15 µg Cd reported to be ingested daily via diet. This I-Cd amount was too low to alone explain the 3.5-fold elevation of B-Cd in our smokers, even assuming greater cadmium absorption via lungs than gastrointestinal tract; cadmium accumulated in smokers' lungs may provide the added cadmium. Finally, B-Cd appeared to be linearly related to I-Cd values in 75% of smokers, whereas 25% had far higher B-Cd, implying a possible heterogeneity among smokers regarding circulating cadmium concentrations and potentially cadmium toxicity.


Time resolved measurements by the pulse height analysis soft x-ray diagnostic on TCV.
A single chord, single processing chain, hybrid (analog/digital) pulse height analysis diagnostic has been developed for the TCV tokamak, aiming to provide the evolution of the plasma electron temperature with a software selectable minimum temporal resolution of 100 ms. The high count rate (approximately 65 kHz) together with an energy resolution of 190 eV (at 5.9 keV) were achieved by encoding the data stream with an on-site developed interface amplifier and time generator. The diagnostic was also used to investigate the non-Maxwellian behavior of the electron energy distribution function with strong electron cyclotron resonance heating and to monitor the presence of intrinsic and injected impurities in the 700 eV-20 keV energy range. The conversion of this diagnostic into a real-time control tool is under development.


Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward.
Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule-associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer's, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model.


Review of Participatory Epidemiology Practices in Animal Health (1980-2015) and Future Practice Directions.
In this study we combined an inventory of the major applications, geographic regions and diseases covered by participatory epidemiology (PE) activities in the field of animal health since 1980, together with an email discussion forum with PE practitioners from different regions of the world. The inventory included the search of peer-reviewed papers, master and technical reports, conference proceedings, manuals, training materials and projects. The search resulted in a low number of PE activity results until the year 2000, followed by a considerable increase (especially from 2012). Most of the identified activities were implemented in Africa and Asia, and focused on surveillance, disease survey and prioritization, and disease control. Seventy-nine PE practitioners working predominantly in Africa, Asia and Europe (29, 22 and 18 respectively) contributed to the email discussion forum. They proposed various modifications to the existing PE definition and discussed different issues related to the applicatoin of PE, its institutionalization for use in policy development, as well as the priorities for future development. The need to increase the number of PE trained people together with some methodological developments and the application of this methodology in developed countries, were some of the points highlighted during the forum. These factors stress the importance of further developing PE as a useful approach for engaging communities in addressing animal and related public health risks.


First Report of Lasiodiplodia theobromae Associated with Stem Canker of Almond in California.
California is a major almond (Prunus dulcis) producer in the world. In September 2012, 2-year-old almond trees from an orchard in Fresno Co. with stem cankers were submitted for disease diagnosis. In a survey of the orchard, 12 ha (1,500 Nonpareil and 1,800 Monterey almond trees) of 48 ha trees had been killed apparently due to a stem canker. The cankers developed above the graft union, were covered with amber sap, and often girdled the trunk. Isolations made from tissues at the canker margins onto acidified potato dextrose agar (PDA) yielded two fungi, Macrophomina phaseolina (Tassi) Goid and Lasiodiplodia theobromae (Pat.) Griffon & Maubl (1). M. phaseolina and L. theobromae were isolated from eight and two of 10 cankered trees, respectively. No mixed infections were found. M. phaseolina isolates were characterized by gray hyphae that turned black with developing microsclerotia. L. theobromae isolates were characterized by white, aerial mycelium that turned mouse gray after 5 days. Young conidia were ellipsoidal, thick walled, initially hyaline, granular, and nonseptate; aged conidia were brown, 1-septate with longitudinal striations in the wall. Identity was confirmed by analyses of the internal transcribed spacer (ITS), β-tubulin 2 (BT2), and the translation elongation factor 1-alpha (TEF-1α) gene regions. BLAST searches at GenBank showed a high identity with reference sequences of type specimens both for M. phaseolina (isolates 7E64 to 7E69: ITS, 100%; BT2, 99%; TEF-1α, 99%) and L. theobromae (isolates 7E86 to 7E88: ITS, 99%; BT2, 99%; TEF-1α, 100%). Sequences of three gene regions were deposited as GenBank accessions KC357271 to KC357279 (ITS); KC357280 to KC357288 (BT2); and KC357289 to KC357297 (TEF-1α). The pathogenicity of M. phaseolina and L. theobromae to P. dulcis cultivars Butte, Carmel, Nonpareil, and Padre was investigated in an orchard at KARE using four isolates of M. phaseolina (7E64, 7E65, 7E66, and 7E69) and two isolates of L. theobromae (7E86 and 7E88). Ten 2-year-old branches per isolate from 7-year-old trees were inoculated with each isolate in late September 2012, after removing the bark with a 7-mm cork borer and placing a 7-day-old 7-mm-diameter agar plug bearing mycelium of each isolate directly into the fresh wound, mycelium side down. Ten additional branches of each of the four cultivars were inoculated with sterile PDA plugs and served as negative controls. Three weeks after inoculation, the average lesion produced by M. phaseolina on Butte, Carmel, Nonpareil, and Padre was 53, 52, 41, and 37 mm in length, respectively. Lesions produced by L. theobromae were 191, 206, 194, and 103 mm in length on the four cultivars, respectively. No disease lesion, only wounds, were produced on negative controls. Lesions produced by both pathogens were longer (P < 0.05) than wounds on the controls (average length 10 mm on all cultivars). Both L. theobromae isolates killed branches of cultivars Butte, Carmel, and Nonpareil in 2 weeks. M. phaseolina and L. theobromae were reisolated from the inoculated branches, and no fungus was reisolated from controls. Based on pathogenicity results, L. theobromae is more virulent to almond branches than M. phaseolina. To our knowledge, this is the second report of M. phaseolina (2) and the first report of L. theobromae as pathogens of P. dulcis trees in California. References: (1) A. Alves et al. Fungal Diversity 28:1, 2008. (2) P. Inderbitzin et al. Mycologia 102:1350, 2010.


Progression in Behavioral Variant Frontotemporal Dementia: A Longitudinal Study.
A gap in the literature exists regarding progression in behavioral variant frontotemporal dementia (BVFTD). Guidance is needed concerning markers that will enable clinicians to discriminate FTD more effectively from phenocopies and to identify factors that determine progression and thereby prognosis. To observe longitudinal outcomes and progression in probable and possible BVFTD in accordance with international diagnostic criteria and to identify features that may aid clinicians to prognosticate better in cases of possible BVFTD. Longitudinal cohort study performed in a specialist tertiary FTD research clinic. Fifty-eight consecutive patients were followed up longitudinally from January 1, 2008, through December 31, 2013, and classified as having possible, probable, or definite BVFTD at presentation and latest review. Final follow-up was completed on December 31, 2013, and data were analyzed from January 1 to August 1, 2014. Clinical, pathological, genetic, neuropsychological, and neuroimaging data were analyzed to categorize patients, to compare differences between groups with changed and unchanged diagnoses, to determine rates of progression in BVFTD, and to identify prognostic features in possible BVFTD. At presentation, 38 of the 58 patients fulfilled criteria for probable BVFTD; of these, 36 continued to satisfy probable criteria or underwent conversion to definite criteria over time. The remaining 20 patients satisfied possible criteria only, and 11 of these patients changed categories over time to probable or definite BVFTD and showed progression on cognitive and functional measures (termed changed status). Of these 11 patients, 8 (73%) carried the C9orf72 expansion. A positive family history, memory impairment, and clinical abnormalities at presentation were key features of progression (P < .05). A continuum of neuropsychological scores, progression rates, and atrophy severity emerged across patients in probable, possible, changed status, and nonchanged status groups; patients with probable BVFTD exhibited the most severe abnormalities. Behavioral variant FTD shows variable progression over time. Clinicians can use a detailed neurologic and cognitive assessment to identify key predictive features of progression when faced with possible BVFTD, whereas a diagnosis of probable BVFTD is accurate in a clinical setting.


Deviation from symmetrically self-similar branching in trees predicts altered hydraulics, mechanics, light interception and metabolic scaling.
The West, Brown, Enquist (WBE) model derives symmetrically self-similar branching to predict metabolic scaling from hydraulic conductance, K, (a metabolism proxy) and tree mass (or volume, V). The original prediction was Kα V(0.75). We ask whether trees differ from WBE symmetry and if it matters for plant function and scaling. We measure tree branching and model how architecture influences K, V, mechanical stability, light interception and metabolic scaling. We quantified branching architecture by measuring the path fraction, Pf : mean/maximum trunk-to-twig pathlength. WBE symmetry produces the maximum, Pf = 1.0. We explored tree morphospace using a probability-based numerical model constrained only by biomechanical principles. Real tree Pf ranged from 0.930 (nearly symmetric) to 0.357 (very asymmetric). At each modeled tree size, a reduction in Pf led to: increased K; decreased V; increased mechanical stability; and decreased light absorption. When Pf was ontogenetically constant, strong asymmetry only slightly steepened metabolic scaling. The Pf ontogeny of real trees, however, was 'U' shaped, resulting in size-dependent metabolic scaling that exceeded 0.75 in small trees before falling below 0.65. Architectural diversity appears to matter considerably for whole-tree hydraulics, mechanics, photosynthesis and potentially metabolic scaling. Optimal architectures likely exist that maximize carbon gain per structural investment.


Organic solar cells using CVD-grown graphene electrodes.
We report on the development of flexible organic solar cells (OSCs) incorporating graphene sheets synthesized by chemical vapor deposition (CVD) as transparent conducting electrodes on polyethylene terephthalate (PET) substrates. A key barrier that must be overcome for the successful fabrication of OSCs with graphene electrodes is the poor-film properties of water-based poly(3,4-ethylenedioxythiphene):poly(styrenesulfonate) (PEDOT:PSS) when coated onto hydrophobic graphene surfaces. To form a uniform PEDOT:PSS film on a graphene surface, we added perfluorinated ionomers (PFI) to pristine PEDOT:PSS to create 'GraHEL', which we then successfully spin coated onto the graphene surface. We systematically investigated the effect of number of layers in layer-by-layer stacked graphene anode of an OSC on the performance parameters including the open-circuit voltage (Voc), short-circuit current (Jsc), and fill factor (FF). As the number of graphene layers increased, the FF tended to increase owing to lower sheet resistance, while Jsc tended to decrease owing to the lower light absorption. In light of this trade-off between sheet resistance and transmittance, we determined that three-layer graphene (3LG) represents the best configuration for obtaining the optimal power conversion efficiency (PCE) in OSC anodes, even at suboptimal sheet resistances. We finally developed efficient, flexible OSCs with a PCE of 4.33%, which is the highest efficiency attained so far by an OSC with CVD-grown graphene electrodes to the best of our knowledge.


Live but not heat-killed mycobacteria cause rapid chemotaxis of large numbers of eosinophils in vivo and are ingested by the attracted granulocytes.
We studied leukocyte chemotaxis triggered by a local injection of mycobacteria (Mycobacterium avium and M. smegmatis) in BALB/c and C57BL/6 mice. Our experimental model consisted of the induction of a subcutaneous air pouch in the dorsal area of mice and inoculation 6 days later of 10(8) CFU of myocobacteria. Inflammatory exudates were harvested from the air pouch cavities 15, 30, and 45 min after the injection of the inocula. Injection of the microorganisms resulted in the migration of an elevated number of eosinophilic granulocytes into the inflammatory cavities. At 30 min after the inoculation of the mycobacteria, the air pouches contained between (3.9 +/- 0.3) x 10(5) (M. avium) and (3.3 +/- 0.3) x 10(5) (M. smegmatis) eosinophils, corresponding to more than one-third (41.4 to 38.3%) of the leukocytes present in the inflammatory cavities. Less than one-half of the eosinophils were attracted to the air pouches when the same number of heat-killed mycobacteria were inoculated [(1.3 +/- 0.2) x 10(5) cells for M. avium and (1.5 +/- 0.2) x 10(5) cells for M. smegmatis]. Injection of gram-negative bacteria (Escherichia coli), of latex beads, or of casein resulted in the attraction of inflammatory eosinophils in numbers that were comparable to those attracted by the heat-killed mycobacteria. Our data document the fact that live mycobacteria exert a rapid chemotactic effect on eosinophils. We therefore postulate that mycobacteria either contain or induce the production of an eosinophilotactic factor. Because this chemotactic effect occurs during the acute inflammatory response to mycobacteria, it cannot be due to the formation of immune complexes (a major infection-associated chemotactic factor for eosinophils). The attracted eosinophils had an important role in the local phagocytosis of mycobacteria, as indicated by our finding, derived from thin-section electron microscopy quantifications, that at 30 min after M. avium inoculation the inflammatory exudates contained (2.2 +/- 0.5) x 10(5) mycobacterium-bearing eosinophils (corresponding to 57% of the total eosinophils), as compared with (2.1 +/- 0.1) x 10(5) neutrophils and (1.5 +/- 0.2) x 10(5) macrophages with ingested bacilli. We conclude that mycobacteria induce the attraction of eosinophils to inflammatory sites and that these granulocytes have the capacity to phagocytize these bacilli in situ.


Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis.
Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] α1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of α1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E-null (ApoE(-/-)) atherosclerotic mice. Responses were α1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE(-/-) mice, anti-col(V) immunity was tempered by an interleukin (IL)-10-dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE(-/-) mice on a regular chow diet overcame IL-10-mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17-producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.


Bayesian Multilevel MIMIC Modeling for Studying Measurement Invariance in Cross-group Comparisons.
Recent methodological advancements should catalyze the evaluation of measurement invariance across groups, which is required for conducting meaningful cross-group comparisons. The aim of this study was to apply a state-of-the-art statistical method for comparing latent mean scores and evaluating measurement invariance across managers' and frontline workers' ratings of the organization of hospital care. On the 87 nursing units in a single institution, French-speaking and Dutch-speaking nursing unit managers' and staff nurses' ratings of their work environment were measured using the multidimensional 32-item practice environment scale of the nursing work index (PES-NWI). Measurement invariance and latent mean scores were evaluated in the form of a Bayesian 2-level multiple indicators multiple causes model with covariates at the individual nurse and nursing unit level. Role (manager, staff nurse) and language (French, Dutch) are of primary interest. Language group membership accounted for 7 of 11 PES-NWI items showing measurement noninvariance. Cross-group comparisons also showed that covariates at both within-level and between-level had significant effects on PES-NWI latent mean scores. Most notably, nursing unit managers, when compared with staff nurses, hold more positive views of several PES-NWI dimensions. Using a widely used instrument for measuring nurses' work environment, this study shows that precautions for the potential threat of measurement noninvariance are necessary in all stages of a study that relies on survey data to compare groups, particularly in multilingual settings. A Bayesian multilevel multiple indicators multiple causes approach can accommodate for detecting all possible instances of noninvariance for multiple covariates of interest at the within-level and between-level jointly.


Activities of tigecycline (GAR-936) against Legionella pneumophila in vitro and in guinea pigs with L. pneumophila pneumonia.
The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp. strains was 4 micro g/ml versus 0.125 and 0.25 micro g/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 micro g/ml) against the F889 strain of L. pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 micro g/ml) was more active than (F889) or as active as (F2111) tigecycline (1 micro g/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L. pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 micro g/ml (1.2 and 1.5 micro g/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 micro g. h/ml, respectively. Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 x 10(6) CFU/g (range, 2.5 x 10(4) to 3.2 x 10(6) CFU/g) versus <1 x 10(2) CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear L. pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log(10) 4.2 to log(10) 5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular L. pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.


Space, the final frontier: A critical review of recent experiments performed in microgravity.
Space biology provides an opportunity to study plant physiology and development in a unique microgravity environment. Recent space studies with plants have provided interesting insights into plant biology, including discovering that plants can grow seed-to-seed in microgravity, as well as identifying novel responses to light. However, spaceflight experiments are not without their challenges, including limited space, limited access, and stressors such as lack of convection and cosmic radiation. Therefore, it is important to design experiments in a way to maximize the scientific return from research conducted on orbiting platforms such as the International Space Station. Here, we provide a critical review of recent spaceflight experiments and suggest ways in which future experiments can be designed to improve the value and applicability of the results generated. These potential improvements include: utilizing in-flight controls to delineate microgravity versus other spaceflight effects, increasing scientific return via next-generation sequencing technologies, and utilizing multiple genotypes to ensure results are not unique to one genetic background. Space experiments have given us new insights into plant biology. However, to move forward, special care should be given to maximize science return in understanding both microgravity itself as well as the combinatorial effects of living in space.


Clinical significance of micropapillary urothelial carcinoma of the upper urinary tract.
The aim of this study was to improve understanding of the characteristics of micropapillary urothelial carcinoma (MPUC) in the renal pelvis and ureter, and to compare oncological outcomes between MPUC and non-MPUC. From September 1994 to October 2010, 418 patients underwent nephroureterectomy with bladder excision due to presumed urothelial carcinoma. Pathological review of all specimens was done by one uropathologist. Perioperative data from these patients were reviewed retrospectively. Patients were divided into MPUC and non-MPUC groups. Oncological outcomes were compared between the two groups via progression-free survival (PFS) and cancer-specific survival (CSS) rates. A total of 386 patients were included in the study. Of these, seven patients (1.81%) had MPUC. The median follow-up duration was 39.0 months (IQR range 21.1-70.6). All MPUC patients were men and had lymphovascular invasion, and six patients (85.7%) had grade III and T3 disease. On univariable analysis, MPUC showed significantly worse prognosis with regard to disease progression (p<0.001). In the subgroup analysis confined to T3 or T4 disease, MPUC showed worse prognosis than non-MPUC in terms of PFS and CSS, respectively (p<0.05). In the multivariable model, MPUC still remained a statistically significant independent predictor for PFS (HR (95% CI)=3.85 (1.59-9.32), p=0.003). MPUC was associated with poorer CSS than non-MPUC (p<0.001). We have observed that upper tract MPUC is associated with poor oncological outcomes in terms of PFS and CSS. MPUC was an independent prognostic factor for PFS in multivariable analysis.


The evolutionary psychology of climate change behaviors: Insights and applications.
We examine climate-related activities through an evolutionary psychology lens, zooming in on factors that motivate or discourage people to behave sustainably to mitigate climate change. Complementing current knowledge, we discuss five core ancestral psychological motivations that shape people's environmental decisions in fundamental ways. We review recent studies that explore how evolved psychological mechanisms related to self-interest, status, sensing, discounting tendencies, and social imitation can be used to promote proenvironmental behavior. We discuss the potential strengths and limitations of evolutionary-based behavioral interventions and briefly reflect on outstanding research questions that can further the integration of evolutionary approaches into mainstream environmental psychology.


Differential presentation of tumor antigen-derived epitopes by MHC-class I and antigen-positive tumor cells.
SSX2 is a member of the family of cancer/testis antigens. The SSX2 derived peptide SSX2(103-111) has been shown to be presented to cytotoxic T-lymphocytes (CTL) by Major-Histocompatibility (MHC) Class-I complexes after endogenous processing, more precisely by the allele HLA-A*0201. The HLA-A*0201- and SSX2-positive melanoma cell line SK-Mel-37 but not Me275 had been shown to elicit reactivity in SSX2(103-111) specific cytotoxic T-lymphocytes. To analyze the correlation between SSX2(103-111) presentation and T-cell stimulation, we intended to visualize presentation of SSX2(103-111) in these melanoma cell lines. Fab-antibodies were established from a human phage library with specificity for SSX2(103-111)/HLA-A*0201 complexes (but non-reactive with HLA-A*0201 or SSX2(103-111) alone) and used to visualize the presentation of SSX2(103-111) in the context of HLA-A*0201 by fluorescence microscopy. Presentation of SSX2(103-111) the context of HLA-A*0201 was demonstrated for the majority of SK-Mel-37, but for only a small fraction (<1%) of Me275 as indicated by a clear membrane-staining pattern in fluorescence microscopy. The presentation of SSX2(103-111) on SK-Mel37 and Me275, but not the expression of the SSX2 protein correlated with the capability of these cells to stimulate cells of an SSX2(103-111)-specific T-cell clone. MHC-peptide specific antibodies are a valuable tool for the analysis of antigenic peptides in the context of MHC-I molecules and for the structural definition of immunodominant epitopes.


Remembering new words: integrating early memory development into word learning.
In order to successfully acquire a new word, young children must learn the correct associations between labels and their referents. For decades, word-learning researchers have explored how young children are able to form these associations. However, in addition to learning label-referent mappings, children must also remember them. Despite the importance of memory processes in forming a stable lexicon, there has been little integration of early memory research into the study of early word learning. After discussing what we know about how young children remember words over time, this paper reviews the infant memory development literature as it relates to early word learning, focusing on changes in retention duration, encoding, consolidation, and retrieval across the first 2 years of life. A third section applies this review to word learning and presents future directions, arguing that the integration of memory processes into the study of word learning will provide researchers with novel, useful insights into how young children acquire new words.


Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century.
Diphtheria toxin is one of the most extensively studied and well understood bacterial toxins. Ever since its discovery in the late 1800's this toxin has occupied a central focus in the field of toxinology. In this review, I present a chronology of major discoveries that led to our current understanding of the structure and activity of diphtheria toxin.


Cervical spondylotic myelopathy with reversible fasciculations in the lower extremities.
Cervical spondylosis and motor system disease can appear in a similar manner with upper and lower motor neuron signs. Four patients with spasticity and fasciculations in the upper and lower extremities had surgical decompression for cervical spondylosis. Postoperative examinations at 24 to 48 months, including electromyographic studies, disclosed neurological improvement in all patients and loss of fasciculations in the lower extremities in three. Three mechanisms by which cervical spondylosis might cause fasciculations in the lower extremities are vascular insufficiency, cord traction, and denervation.


Microengineered neural probes for in vivo recording.
One of the great challenges facing medicine is the repair of the damaged nervous system. Due to the limited capacity of the central (and to a lesser extent the peripheral) nervous systems to regenerate, damage such as spinal cord injury can often result in permanent paralysis. Researchers are attempting to overcome nerve injury by devising methods of sensing neural activity either in the brain or in the spinal cord or peripheral nervous system. This information can act as a control mechanism for either muscle stimulators (e.g. for restoring limb function) or providing function in some other way (such as controlling a cursor on a computer screen). Ideally, sensing devices are implanted into the body, directly accessing the nervous system. Whilst great advancements have been made in implantable neural stimulators, sensing of neural activity has proven to be a more difficult task. This chapter describes how microengineered probes allow construction of neuron-sized neural interfaces for enhanced recording in vivo.


Prevalence and characteristics of indoor tanning use among men and women in the United States.
Objectives To describe the prevalence and characteristics related to indoor tanning use among adults in the United States in the past year. Cross-sectional study. Health Information National Trends Study, 2005. The study included 2869 participants who were white and aged 18 to 64 years; a random subset of 821 participants were also asked questions about skin cancer prevention knowledge and attitudes. The study assessed the prevalence of self-reported use of indoor tanning in the past 12 months and its associations with demographic and lifestyle factors, knowledge, and attitudes. Overall, 18.1% of women and 6.3% of men reported tanning indoors in the past 12 months. Women who were older, were less educated, had lower income, and used sunscreen regularly were less likely to report the behavior, while women residing in the Midwest and the South and who used spray tanning products were more likely to report the behavior. Men who were less likely to report the behavior were older and obese but more likely to report the behavior if they lived in metropolitan areas and used spray tanning products. In an open-response format, only 13.3% of women and 4.2% of men suggested that avoidance of tanning bed use could reduce their risks of skin cancer. Greater skin cancer knowledge and higher perceived risk of skin cancer were inversely associated with the behavior in women. Prevalence and some characteristics associated with indoor tanning use, such as sunscreen use, differed between women and men in the United States. Most adults did not volunteer avoidance of tanning bed use to prevent skin cancer. Clinician-patient communication on risks of indoor tanning may be helpful to reduce indoor tanning use.


Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR3.
Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes. DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants. 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed. In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.


Robust synthesis of NIR-emissive P-rhodamine fluorophores.
P-Rhodamines were accessed by implementing a robust three step sequence consisting of (i) addition of m-metallated anilines to dichlorophosphine oxides, (ii) selective dibromination, and (iii) cyclization of the diaryllithium reagents derived from the dibromides to form the dihydroacridophosphine core of P-rhodamines. A modified route was developed to produce non-symmetric P-rhodamines. A library of prepared P-rhodamines provides first insight into dependence of fluorophore properties on the structure of P-rhodamines. A P-rhodamine with highest batochromic shifts and quantum yields in the class was identified.


TRAIT2D: a Software for Quantitative Analysis of Single Particle Diffusion Data.
Single particle tracking (SPT) is one of the most widely used tools in optical microscopy to evaluate particle mobility in a variety of situations, including cellular and model membrane dynamics. Recent technological developments, such as Interferometric Scattering microscopy, have allowed recording of long, uninterrupted single particle trajectories at kilohertz framerates. The resulting data, where particles are continuously detected and do not displace much between observations, thereby do not require complex linking algorithms. Moreover, while these measurements offer more details into the short-term diffusion behaviour of the tracked particles, they are also subject to the influence of localisation uncertainties, which are often underestimated by conventional analysis pipelines. we thus developed a Python library, under the name of TRAIT2D (Tracking Analysis Toolbox - 2D version), in order to track particle diffusion at high sampling rates, and analyse the resulting trajectories with an innovative approach. The data analysis pipeline introduced is more localisation-uncertainty aware, and also selects the most appropriate diffusion model for the data provided on a statistical basis. A trajectory simulation platform also allows the user to handily generate trajectories and even synthetic time-lapses to test alternative tracking algorithms and data analysis approaches. A high degree of customisation for the analysis pipeline, for example with the introduction of different diffusion modes, is possible from the source code. Finally, the presence of graphical user interfaces lowers the access barrier for users with little to no programming experience.


[Prevalence and risk factors for smoking among adolescents].
Tobacco smoking is one of the main causes of preventable disease and premature disability. The study was aimed at measuring smoking prevalence and related risk factors among adolescents. A population-based cross-sectional study was carried out in a representative sample of 1,187 adolescents aged 10 to 19 years living in the urban area of Pelotas, southern Brazil. All adolescents were interviewed separately using a confidential coded questionnaire. Kaplan-Meier test was performed for survival curve analysis. The overall smoking prevalence rate in the sample was 12.1% (95% CI 10.3%-14%). Boys and girls had similar prevalence rates. The following were the risk factors for smoking found in the multivariate logistic regression analysis: older age (OR=28.7; 95% CI 11.5-71.4), older smoking siblings (OR=2.4; 95% CI 1.5-3.8), three or more smoking friends (OR=17.5; 95% CI 8.8-34.8) and low schooling (OR=3.5; 95% CI 1.5-8.0). The prevalence of smoking among adolescents in the city of Pelotas was high. Campaigns against tobacco use should be aimed at the community and families, targeting adolescents. The government must adopt legal actions in order to prevent adolescents to have access to to smoking.


Considering both health-promoting and illness-related factors in assessment of health-related quality of life after myocardial infarction.
The present study addresses factors that contributed to explaining the variance in health-related quality of life (HRQOL) one year after myocardial infarction, considering both illness-related and health-promoting factors. The aim was to elucidate the influence of depression, fatigue, optimism and sense of coherence on HRQOL. The sample consisted of 95 persons who had been treated for myocardial infarction. Correlation and multiple regression analyses were performed. The results showed that depression, fatigue, optimism and sense of coherence variables were all correlated with both the physical and the mental dimensions of HRQOL. In two multiple regression analyses where the physical component score (PCS) and the mental component score (MCS) were the criterion variables, fatigue contributed to the explained variance in the PCS (p< 0.001), and both depression (p< 0.01) and fatigue (p< 0.01) contributed to explained the variance in the MCS, after controlling for age and gender. To conclude, fatigue was the most significant variable associated with HRQOL, which was interpreted as having the following clinical implication: When a person suffers from post-myocardial infarction fatigue, this must be addressed first. Clearly, it is time to take the problems of patients who suffer from post-myocardial infarction fatigue seriously. It is of vital importance to develop and evaluate fatigue relief strategies in cardiovascular nursing and to test them in interventional studies. This does not exclude investing in health-promoting factors, e.g. sense of coherence, in coronary care interventions. Intervention strategies focusing on both illness-related and salutogentic factors may be optimal. This is a question for further research.


Cognitive control of distinct vocalizations in rhesus monkeys.
Whether nonhuman primates can decouple their innate vocalizations from accompanied levels of arousal or specific events in the environment to achieve cognitive control over their vocal utterances has been a matter of debate for decades. We show that rhesus monkeys can be trained to elicit different call types on command in response to arbitrary visual cues. Furthermore, we report that a monkey learned to switch between two distinct call types from trial to trial in response to different visual cues. A controlled behavioral protocol and data analysis based on signal detection theory showed that noncognitive factors as a cause for the monkeys' vocalizations could be excluded. Our findings also suggest that monkeys also have rudimentary control over acoustic call parameters. These findings indicate that monkeys are able to volitionally initiate their vocal production and, therefore, are able to instrumentalize their vocal behavior to perform a behavioral task successfully.


Rethinking theory and practice: pre-registration student nurses experiences of simulation teaching and learning in the acquisition of clinical skills in preparation for practice.
In the United Kingdom (UK) simulation learning has been recognised in the form of a regulatory agreement that may replace hours from clinical practice. This integration has become an embedded feature of the pre-registration nursing programme at a University in the North of England, along with strategic investment in staff and simulation suites developed to underpin this curriculum change albeit in the absence of sparse empirical evidence, hence the rationale for the study which was designed to explore the relationship between simulation, theory and practice. The study features a thematic analysis of evaluation questionnaires from pre-registration student nurses (n=>500) collected over a 2 year period which informed subsequent focus group interviews to explore the themes in more detail. Consistent data findings were the students' positive response to simulation as a learning approach facilitating the application of theory in a safe controlled environment. Students reported that they felt prepared for practice, recognising that simulated learning improved their humanistic and problem solving abilities as well as the development of psychomotor, technical skills, and overall confidence. The theory-practice gap is a recurring narrative in the nursing literature, the findings of this study recognises that simulation offers an opportunity to enact the integration of theory and practice illuminating this relationship in a controlled environment thus, reinforcing the theory-practice relationship for nursing students.


Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.


A non-human primate BAC resource to study interchromosomal segmental duplications.
Segmental duplications (SDs) are involved in the reshaping and evolutionary development of primate genome architecture. Their intrinsic property to promote genomic instability facilitates genome rearrangements, thereby contributing to karyotype diversity in primates. However, comparative analyses of SDs based on whole-genome shotgun assemblies of primate genomes may lead to a distorted view of their evolutionary dynamics as this method will incorrectly assemble or simply not represent these regions. Therefore high-quality sequences of chromosomally assigned SDs are indispensable for unraveling the amplification and dispersal pattern of SDs during primate evolution. Here, we use an updated version of the ancestral duplicon state of the non-palindromic SDs of all 4 human Y-chromosome euchromatin/heterochromatin transition regions to perform a survey of duplicons genome-wide across 7 primate species. By adjusting experimental conditions to the mean nucleotide sequence divergence to human we identified 11,075 BAC clones carrying primate orthologs or paralogs of human Y chromosome-derived duplicons. Preliminary results indicate lineage-specific amplification of duplicons in prosimians and gibbons. This BAC-based framework represents the first complete set of a defined number of duplicons over 60 million years of primate evolution. Comparative sequence analysis of this genetic resource can contribute to our deeper understanding of the impact of segmental duplications on primate genome evolution.