Cellular uptake of self-assembled phytantriol-based hexosomes is independent of major endocytic machineries.
Despite increasing interests in non-lamellar liquid crystalline dispersions, such as hexosomes, for drug delivery, little is known about their interactions with cells and mechanism of cell entry. Here we examine the cellular uptake of hexosomes based on phytantriol and mannide monooleate by HeLa cells using live cell microscopy in comparison to conventional liposomes. To investigate the importance of specific endocytosis pathways upon particle internalization, we silenced regulatory proteins of major endocytosis pathways using short interfering RNA. While endocytosis plays a significant role in liposome internalization, hexosomes are not taken up via endocytosis but through a mechanism that is dependent on cell membrane tension. Biophysical studies using biomembrane models highlighted that hexosomes have a high affinity for membranes and an ability to disrupt lipid layers. Our data suggest that direct biomechanical interactions of hexosomes with membrane lipids play a crucial role and that the unique morphology of hexosomes is vital for their membrane activity. Based on these results, we propose a mechanism, where hexosomes destabilize the bilayer, allowing them to "phase through" the membrane. Understanding parameters that influence the uptake of hexosomes is critical to establish them as carrier systems that can potentially deliver therapeutics efficiently to intracellular sites of action.


Treatment options for permanent teeth with deep caries.
The goal of this narrative review was to summarize and compare treatment options for permanent teeth carious lesions that are radiographically close to the pulp chamber. Thanks to adhesive restorative materials, minimally invasive approaches are possible. In this context, the old question arises as to whether caries must be excavated completely, i.e., down to hard dentin, or whether it could be advantageous to leave some soft dentin, or even merely seal the whole lesion. To answer this question, the microbiological aspects of the lesion must be considered, along with the immunological response in the dental pulp, with the concurrent possible negative outcomes for the patient. Both aspects are considered in this review, and clinical studies comparing different treatment modalities are discussed. Situations in which calcium silicate cements could be advantageous over the gold standard calcium hydroxide preparations for covering the dentin/pulp wound are also discussed.


The use of computed tomographic three-dimensional reconstructions to develop instructional models for equine pelvic ultrasonography.
Ultrasonography has gained increased utility to diagnose pelvic fractures in horses; however, internal pelvic contours can be difficult to appreciate from external palpable landmarks. We developed three-dimensional (3D) simulations of the pelvic ultrasonographic examination to assist with translation of pelvic contours into two-dimensional (2D) images. Contiguous 1mm transverse computed tomography (CT) images were acquired through an equine femur and hemipelvis using a single slice helical scanner. 3D surface models were created using a DICOM reader and imported into a 3D modeling and animation program. The bone models were combined with a purchased 3D horse model and the skin made translucent to visualize pelvic surface contours. 3D models of ultrasound transducers were made from reference photos, and a thin sector shape was created to depict the ultrasound beam. Ultrasonographic examinations were simulated by moving transducers on the skin surface and rectally to produce images of pelvic structures. Camera angles were manipulated to best illustrate the transducer-beam-bone interface. Fractures were created in multiple configurations. Animations were exported as QuickTime movie files for use in presentations coupled with corresponding ultrasound videoclips. 3D models provide a link between ultrasonographic technique and image generation by depicting the interaction of the transducer, ultrasound beam, and structure of interest. The horse model was important to facilitate understanding of the location of pelvic structures relative to the skin surface. While CT acquisition time was brief, manipulation within the 3D software program was time intensive. Results were worthwhile from an instructional standpoint based on user feedback.


Reactivity of Cys4 zinc finger domains with gold(III) complexes: insights into the formation of "gold fingers".
Gold(I) complexes such as auranofin or aurothiomalate have been used as therapeutic agents for the treatment of rheumatoid arthritis for several decades. Several gold(I) and gold(III) complexes have also shown in vitro anticancer properties against human cancer cell lines, including cell lines resistant to cisplatin. Because of the thiophilicity of gold, cysteine-containing proteins appear as likely targets for gold complexes. Among them, zinc finger proteins have attracted attention and, recently, gold(I) and gold(III) complexes have been shown to inhibit poly(adenosine diphosphate ribose)polymerase-1 (PARP-1), which is an essential protein involved in DNA repair and in cancer resistance to chemotherapies. In this Article, we characterize the reactivity of the gold(III) complex [Au(III)(terpy)Cl]Cl2 (Auterpy) with a model of Zn(Cys)4 "zinc ribbon" zinc finger by a combination of absorption spectroscopy, circular dichroism, mass spectrometry, high-performance liquid chromatography analysis, and X-ray absorption spectroscopy. We show that the Zn(Cys)4 site of Zn·LZR is rapidly oxidized by Auterpy to form a disulfide bond. The Zn(2+) ion is released, and the two remaining cysteines coordinate the Au(+) ion that is produced during the redox reaction. Subsequent oxidation of these cysteines can take place in conditions of excess gold(III) complex. In the presence of excess free thiols mimicking the presence of glutathione in cells, mixing of the zinc finger model and gold(III) complex yields a different product: complex (Au(I))2·LZR with two Au(+) ions bound to cysteines is formed. Thus, on the basis of detailed speciation and kinetic measurements, we demonstrate herein that the destruction of Zn(Cys)4 zinc fingers by gold(III) complexes to achieve the formation of "gold fingers" is worth consideration, either directly or mediated by reducing agents.


Are self-adhesive resin cements a valid alternative to conventional resin cements? A laboratory study of the long-term bond strength.
The aim of the study was to test whether or not the shear bond strengths of six self-adhesive resin cements to dentin and to glass-ceramic, 24h and long-term-aged, are similar to the one of a conventional resin cement. Human molars (N=168, n=12 per group) and silicabased glass-ceramic specimens (N=168, n=12 per group) were embedded in acrylic resin and randomly divided into 28 groups. The following resin cements were luted according to the manufacturers' instructions: Clearfil SA (CSA), G-Cem (GCM), SmartCem2 (SMC), SpeedCEM (SPC), RelyX Unicem (RXU), RelyX Unicem2 (RXU2) and Panavia21 (control group, PAN). Shear bond strength was measured initially (24h of water storage 37°C) and after aging (24,000 thermal cycles, 5/55°C). The failure types (adhesive, and cohesive) were evaluated after debonding. The shear bond strength values were analyzed using three-way and one-way ANOVA, followed by a post hoc Scheffé and two-sample Student's t-tests. RXU, RXU2 and GCM showed similar after 24h and aged shear bond strength to dentin as the control group. CSA, SMC and SPC exhibited significantly lower values. Before aging, none of the bond strength values to glass-ceramic differed significantly from the other. After thermocycling, GCM showed higher results to glass-ceramic than CSA, SMC, RXU2 and the control group. Analyzing failure types after spontaneous debonding and shear bond test at dentin, solely adhesive failures were found, while at glass-ceramic only cohesive failures occurred. Not all self-adhesive resin cements can be a valid alternative to conventional resin cements in order to bond silica-based glass-ceramics to human dentin.


Histamine and the striatum.
The neuromodulator histamine is released throughout the brain during periods of wakefulness. Combined with an abundant expression of histamine receptors, this suggests potential widespread histaminergic control of neural circuit activity. However, the effect of histamine on many of these circuits is unknown. In this review we will discuss recent evidence for histaminergic modulation of the basal ganglia circuitry, and specifically its main input nucleus; the striatum. Furthermore, we will discuss recent findings of histaminergic dysfunction in several basal ganglia disorders, including in Parkinson's disease and most prominently, in Tourette's syndrome, which has led to a resurgence of interest in this neuromodulator. Combined, these recent observations not only suggest a central role for histamine in modulating basal ganglia activity and behaviour, but also as a possible target in treating basal ganglia disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.


Rapid Degradation of Caenorhabditis elegans Proteins at Single-Cell Resolution with a Synthetic Auxin.
As developmental biologists in the age of genome editing, we now have access to an ever-increasing array of tools to manipulate endogenous gene expression. The auxin-inducible degradation system allows for spatial and temporal control of protein degradation via a hormone-inducible Arabidopsis F-box protein, transport inhibitor response 1 (TIR1). In the presence of auxin, TIR1 serves as a substrate-recognition component of the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), ubiquitinating auxin-inducible degron (AID)-tagged proteins for proteasomal degradation. Here, we optimize the Caenorhabditis elegans AID system by utilizing 1-naphthaleneacetic acid (NAA), an indole-free synthetic analog of the natural auxin indole-3-acetic acid (IAA). We take advantage of the photostability of NAA to demonstrate via quantitative high-resolution microscopy that rapid degradation of target proteins can be detected in single cells within 30 min of exposure. Additionally, we show that NAA works robustly in both standard growth media and physiological buffer. We also demonstrate that K-NAA, the water-soluble, potassium salt of NAA, can be combined with microfluidics for targeted protein degradation in C. elegans larvae. We provide insight into how the AID system functions in C. elegans by determining that TIR1 depends on C. elegans SKR-1/2, CUL-1, and RBX-1 to degrade target proteins. Finally, we present highly penetrant defects from NAA-mediated degradation of the FTZ-F1 nuclear hormone receptor, NHR-25, during C. elegans uterine-vulval development. Together, this work improves our use and understanding of the AID system for dissecting gene function at the single-cell level during C. elegans development.


Transcriptional initiation and postinitiation effects of murine leukemia virus long terminal repeat R-region sequences.
Sequences within the R components of the long terminal repeats (LTRs) of several retroviruses are known to be involved at various steps in expression of the viral genomes. A series of experiments was performed to test whether sequences within the R regions of the murine leukemia viruses Akv and SL3-3 affect viral expression. By using plasmid clones of the viral LTRs linked to a reporter gene, deletion of the R region was found to decrease expression to variable extents in a series of mammalian cell lines, with the largest effects being detected in murine fibroblasts. R-region sequences from the human immunodeficiency virus type 1 LTR or a random sequence were unable to substitute for the murine leukemia virus sequences. Transcripts from the R-region-deleted templates were initiated at the proper site in the LTR, but their levels were decreased at least 10-fold. Nuclear run-on assays showed that the decrease caused by the R-region deletions was due, in part, to an effect on RNA polymerase loading, suggesting an effect on transcriptional initiation. The remainder of the activity was presumably due to a posttranscriptional effect. Analysis of the R-region sequences of murine leukemia viruses and related retroviruses led to the prediction of a conserved secondary structure in the transcribed RNA that might have a role in activity. We conclude that R-region sequences are of importance for the expression of a variety of retroviruses.


Restoration of error-diffused images using projection onto convex sets.
A novel inverse halftoning method is proposed to restore a continuous tone image from a given half-tone image. A set theoretic formulation is used where three sets are defined using the prior information about the problem. A new space-domain projection is introduced assuming the halftoning is performed using error diffusion, and the error diffusion filter kernel is known. The space-domain, frequency-domain, and space-scale domain projections are used alternately to obtain a feasible solution for the inverse halftoning problem which does not have a unique solution.


Common terms for rare epilepsies: Synonyms, associated terms, and links to structured vocabularies.
Identifying individuals with rare epilepsy syndromes in electronic data sources is difficult, in part because of missing codes in the International Classification of Diseases (ICD) system. Our objectives were the following: (1) to describe the representation of rare epilepsies in other medical vocabularies, to identify gaps; and (2) to compile synonyms and associated terms for rare epilepsies, to facilitate text and natural language processing tools for cohort identification and population-based surveillance. We describe the representation of 33 epilepsies in 3 vocabularies: Orphanet, SNOMED-CT, and UMLS-Metathesaurus. We compiled terms via 2 surveys, correspondence with parent advocates, and review of web resources and standard vocabularies. UMLS-Metathesaurus had entries for all 33 epilepsies, Orphanet 32, and SNOMED-CT 25. The vocabularies had redundancies and missing phenotypes. Emerging epilepsies (SCN2A-, SCN8A-, KCNQ2-, SLC13A5-, and SYNGAP-related epilepsies) were underrepresented. Survey and correspondence respondents included 160 providers, 375 caregivers, and 11 advocacy group leaders. Each epilepsy syndrome had a median of 15 (range 6-28) synonyms. Nineteen had associated terms, with a median of 4 (range 1-41). We conclude that medical vocabularies should fill gaps in representation of rare epilepsies to improve their value for epilepsy research. We encourage epilepsy researchers to use this resource to develop tools to identify individuals with rare epilepsies in electronic data sources.


In-depth proteomic characterization of Schistosoma haematobium: Towards the development of new tools for elimination.
Schistosomiasis is a neglected disease affecting hundreds of millions worldwide. Of the three main species affecting humans, Schistosoma haematobium is the most common, and is the leading cause of urogenital schistosomiasis. S. haematobium infection can cause different urogenital clinical complications, particularly in the bladder, and furthermore, this parasite has been strongly linked with squamous cell carcinoma. A comprehensive analysis of the molecular composition of its different proteomes will contribute to developing new tools against this devastating disease. By combining a comprehensive protein fractionation approach consisting of OFFGEL electrophoresis with high-throughput mass spectrometry, we have performed the first in-depth characterisation of the different discrete proteomes of S. haematobium that are predicted to interact with human host tissues, including the secreted and tegumental proteomes of adult flukes and secreted and soluble egg proteomes. A total of 662, 239, 210 and 138 proteins were found in the adult tegument, adult secreted, soluble egg and secreted egg proteomes, respectively. In addition, we probed these distinct proteomes with urine to assess urinary antibody responses from naturally infected human subjects with different infection intensities, and identified adult fluke secreted and tegument extracts as being the best predictors of infection. We provide a comprehensive dataset of proteins from the adult and egg stages of S. haematobium and highlight their utility as diagnostic markers of infection intensity. Protein composition was markedly different between the different extracts, highlighting the distinct subsets of proteins that different development stages present in their different niches. Furthermore, we have identified adult fluke ES and tegument extracts as best predictors of infection using urine antibodies of naturally infected people. This study provides the first steps towards the development of novel tools to control this important neglected tropical disease.


Habitat stability and occurrences of malaria vector larvae in western Kenya highlands.
Although the occurrence of malaria vector larvae in the valleys of western Kenya highlands is well documented, knowledge of larval habitats in the uphill sites is lacking. Given that most inhabitants of the highlands actually dwell in the uphill regions, it is important to develop understanding of mosquito breeding habitat stability in these sites in order to determine their potential for larval control. A total of 128 potential larval habitats were identified in hilltops and along the seasonal streams in the Sigalagala area of Kakamega district, western Kenya. Water availability in the habitats was followed up daily from August 3, 2006 to February 23, 2007. A habitat is defined as stable when it remains aquatic continuously for at least 12 d. Mosquito larvae were observed weekly. Frequencies of aquatic, stable and larvae positive habitats were compared between the hilltop and seasonal stream area using chi2-test. Factors affecting the presence/absence of Anopheles gambiae larvae in the highlands were determined using multiple logistic regression analysis. Topography significantly affected habitat availability and stability. The occurrence of aquatic habitats in the hilltop was more sporadic than in the stream area. The percentage of habitat occurrences that were classified as stable during the rainy season is 48.76% and 80.79% respectively for the hilltop and stream area. Corresponding frequencies of larvae positive habitats were 0% in the hilltop and 5.91% in the stream area. After the rainy season, only 23.42% of habitat occurrences were stable and 0.01% larvae positive habitats were found in the hilltops, whereas 89.75% of occurrences remained stable in the stream area resulting in a frequency of 12.21% larvae positive habitats. The logistic regression analysis confirmed the association between habitat stability and larval occurrence and indicated that habitat surface area was negatively affecting the occurrence of An. gambiae larvae. While An. gambiae and An. funestus larvae occurred throughout the study period along the streams, a total of only 15 An. gambiae larvae were counted in the hilltops, and no An. funestus were found. Moreover, no larvae managed to develop into adults in the hilltops, and the density of adult An. gambiae was consistently low, averaging at 0.06 females per house per survey. The occurrence of malaria vector larvae in the hilltop area was uncommon as a result of the low availability and high instability of habitats. To optimize the cost-effectiveness of malaria interventions in the western Kenya highlands, larval control should be focused primarily along the streams, as these are likely the only productive habitats at high altitude.


Thermosensitive drug-loading system based on copper sulfide nanoparticles for combined photothermal therapy and chemotherapy in vivo.
A phase-change material (PCM) is an efficient energy storage material, but its poor thermal conductivity has limited its application in nanomedicine research. In this study, we used the photothermal material copper sulfide (CuS) to tackle this challenge. The designed CuS-DOX-MBA@PCM nanoparticles (NPs) were prepared by a nanoprecipitation method, and were composed of CuS, the anticancer drug (DOX), and near-infrared (NIR) dyes (MBA) encapsulated with stearic acid and lauric acid, which are characterized by a low eutectic point close to human physiological temperature. Because the CuS-DOX-MBA@PCM NPs could release the drug quickly in physiological conditions, it implied that they could have potential as a promising drug-loading system. CuS-DOX-MBA@PCM NPs were utilized as an imaging-guided photothermal agent for photothermal therapy (PTT) combined with chemotherapy in cells and in a mice model. In vitro fluorescence imaging indicated the high uptake of CuS-DOX-MBA@PCM NPs in tumor cells due to enhanced permeability and retention effects, while in vivo experiments showed that the tumor growth in tumor-bearing mice models could be inhibited by the CuS-DOX-MBA@PCM NPs. Such an evident enhanced tumor inhibition could be attributed to the synergistic effect of the DOX chemotherapy and the photothermal therapy with a safe laser irradiation at 808 nm with a power density of 1.0 W cm-2. Furthermore, this combined therapy offers the possibility to lower the dosage of DOX in anticancer therapy, which would thus decrease the toxic effects on cancer patients. The results from this study confirmed the effect of CuS-DOX-MBA@PCM NPs for use as a chemo-photothermal therapy and the clinical value of the designed thermosensitive drug-loading system in the field of combined cancer therapy.


The development of a simple scaffold of axon tracts in the brain of the embryonic zebrafish, Brachydanio rerio.
We have examined neuronal differentiation and the formation of axon tracts in the embryonic forebrain and midbrain of the zebrafish, between 1 and 2 days postfertilisation. Axons were visualised with three techniques; immunocytochemistry (using HNK-1 and antiacetylated tubulin antibodies) and horseradish peroxidase (HRP) labelling in whole-mounted brains, and transmission electron microscopy. Differentiation was monitored by histochemical staining for acetylcholinesterase (AChE). These independent methods demonstrated that a simple grid of tracts and commissures forms the initial axon scaffold of the brain. At 1 day, the olfactory nerve, four commissures, their associated tracts and three other non-commissural tracts are present. By 2 days, these tracts and commissures have all greatly enlarged and, in addition, the optic nerve and tract, and three new commissures and their associated tracts have been added. Small applications of HRP at various sites revealed the origins and projections of some of these earliest axons. Retrogradely labelled cell bodies originated from regions that were also positive for AChE activity. At 1 day, HRP-labelled axons were traced: (1) from the olfactory placode through the olfactory nerve to the dorsal telencephalon; (2) from the telencephalon into the tract of the anterior commissure and also to the postoptic region of the diencephalon; (3) from the hindbrain through the ventral midbrain and diencephalon to the postoptic commissure; (4) from the dorsal diencephalon (in or near the epiphysis) to the tract of the postoptic commissure; (5) from ventral and rostral midbrain through the posterior commissure. Three new projections were demonstrated at 2 days: (1) from the retina through the tract of the postoptic commissure to the tectum; (2) from the telencephalon to the contralateral diencephalon; and (3) from the telencephalon to the ventral flexure. These results show that at 1 day, the zebrafish brain is impressively simple, with a few small, well-separated tracts but by 2 days the brain is already considerably more complex. Most of the additional axons added onto pre-existent tracts rather than pioneered new ones supporting the notion that other axons play a crucial role in the guidance of early central nervous system (CNS) axons.


Structure and function of a mycobacterial NHEJ DNA repair polymerase.
Non homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks in prokaryotes requires Ku and a specific multidomain DNA ligase (LigD). We present crystal structures of the primase/polymerisation domain (PolDom) of Mycobacterium tuberculosis LigD, alone and complexed with nucleotides. The PolDom structure combines the general fold of the archaeo-eukaryotic primase (AEP) superfamily with additional loops and domains that together form a deep cleft on the surface, likely used for DNA binding. Enzymatic analysis indicates that the PolDom of LigD, even in the absence of accessory domains and Ku proteins, has the potential to recognise DNA end-joining intermediates. Strikingly, one of the main signals for the specific and efficient binding of PolDom to DNA is the presence of a 5'-phosphate group, located at the single/double-stranded junction at both gapped and 3'-protruding DNA molecules. Although structurally unrelated, Pol lambda and Pol mu, the two eukaryotic DNA polymerases involved in NHEJ, are endowed with a similar capacity to bind a 5'-phosphate group. Other properties that are beneficial for NHEJ, such as the ability to generate template distortions and realignments of the primer, displayed by Pol lambda and Pol mu, are shared by the PolDom of bacterial LigD. In addition, PolDom can perform non-mutagenic translesion synthesis on termini containing modified bases. Significantly, ribonucleotide insertion appears to be a recurrent theme associated with NHEJ, maximised in this case by the deployment of a dedicated primase, although its in vivo relevance is unknown.


Love or fear: can punishment promote cooperation?
Cooperation is a paradox: Why should one perform a costly behavior only to increase the fitness of another? Human societies, in which individuals cooperate with genetically unrelated individuals on a considerably larger scale than most mammals do, are especially puzzling in this regard. Recently, the threat of punishment has been given substantial attention as one of the mechanisms that could help sustain human cooperation in such situations. Nevertheless, using punishment to explain cooperation only leads to further questions: Why spend precious resources to penalize free-riders, especially if others can avoid this investment and cheaters can punish you back? Here, it is argued that current evidence supports punishment as an efficient means for the maintenance of cooperation, and that the gravity of proposed limitations of punishment for maintaining cooperation may have been overestimated in previous studies due to the features of experimental design. Most notably, the importance of factors as characteristic of human societies as reputation and language has been greatly neglected. Ironically, it was largely the combination of the two that enabled humans to shape costly punishment into numerous low-cost and less detrimental strategies that clearly can promote human cooperation.


Fear of pain and movement in a patient with musculoskeletal chronic pain.
Pain-related fear may pose a serious barrier in the management of patients with chronic musculoskeletal pain, resulting in severe functional impairment in many cases. The paper describes the cognitive-behavioural therapy of a patient with a specific phobia (fear of pain and movement). The principal objective of the therapy was to educate the patient in strategies and skills to manage his fear and to verify the effect of the therapy. Both group and individual therapy was used. Group multimodal therapy of pain was provided by an interdisciplinary team of health care providers, specialising in pain management (psychotherapist, doctors and physiotherapists). The programme was based on operant therapy principles and included pacing and graded exercising and walking, relaxation, group education about ergonomics, and fear and pain relapse prevention. Reduction in the fear of pain and movement was achieved, and social bonds and physical and social activities improved after the psychotherapy, while the results were stable for two years.


Refinement.
The ultimate goal of the Three Rs is the full replacement of animals used in biomedical research and testing. However, replacement is unlikely to occur in the near future; therefore the scientific community as a whole must continue to devote considerable effort to ensure optimal animal welfare for the benefit of the science and the animals, i.e., the R of refinement. Laws governing the care and use of laboratory animals have recently been revised in Europe and the US and these place greater emphasis on promoting the well-being of the animals in addition to minimizing pain and distress. Social housing for social species is now the default condition, which can present a challenge in certain experimental settings and for certain species. The practice of positive reinforcement training of laboratory animals, particularly non-human primates, is gathering momentum but is not yet universally employed. Enhanced consideration of refinement extends to rodents, particularly mice, whose use is still increasing as more genetically modified models are generated. The wastage of extraneous mice and the method of their euthanasia are refinement issues that still need to be addressed. An international, concerted effort into defining the needs of laboratory animals is still necessary to improve the quality of the animal models used as well as their welfare.


Risks of cancer among a cohort of 23,935 men and women with osteoporosis.
Low hormone levels among persons with osteoporosis may decrease risk of some cancers. Other osteoporosis risk factors, such as smoking and alcohol consumption, however, may increase risk. As these deleterious factors are more often associated with osteoporosis diagnosed prior to age 70 years, cancer risk may be higher in these younger persons than in the general population. To examine this hypothesis, a cohort study of 23,935 persons with osteoporosis was conducted in Denmark. Patients hospitalized with osteoporosis between 1978 and 1993 were identified in the Danish Inpatient Register. Linkage to the Danish Cancer Registry identified all cancer outcomes through 2003. Standardized incidence ratios (SIR) and 95% confidence intervals (95%CI) were calculated to compare cancer incidence in the cohort with that in the general population. Persons diagnosed prior to age 70 years were at increased cancer risk (women: SIR = 1.11, 95%CI = 1.04-1.19; men: SIR = 1.31, 95%CI = 1.13-1.50) due, in part, to increased risks of cancers of the buccal cavity, esophagus, liver, pancreas and lung. Persons diagnosed at ages 70 and older were at decreased risk (women: SIR = 0.91, 95%CI = 0.87-0.96; men: SIR = 0.89, 0.77-1.01) due, in part, to decreased risks of breast, endometrial, colon, rectal and brain cancers in women and prostate cancer in men. These results suggest that risk factors associated with earlier onset osteoporosis may be associated with increased risk of cancer. Conversely, factors associated with later onset osteoporosis may be related to a decreased risk of cancer.


Pluripotent stem cells as new drugs? The example of Parkinson's disease.
Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowledge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinson's disease is of particular interest. It is one of the most prevalent neurodegenerative diseases caused by the loss of dopaminergic neurons in the Substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from the progressive decline of efficacy as the disease progresses. Cell therapy application has emerged about two decades ago as a valid therapeutic alternative and recent advances in stem cell research suggest that pluripotent stem cell transplantation may be a promising approach to replace degenerated neurons in Parkinson's disease. Various sources of pluripotent stem cells (PSC) currently tested in animal models of Parkinson's disease have proven their efficacy in relieving symptoms and restoring damaged brain function. This review summarizes and discusses the important challenges that actually must be solved before the first studies of PSC transplantation can be undertaken into humans.


Nonlinear elasticity of disordered fiber networks.
Disordered biopolymer gels have striking mechanical properties including strong nonlinearities. In the case of athermal gels (such as collagen-I) the nonlinearity has long been associated with a crossover from a bending dominated to a stretching dominated regime of elasticity. The physics of this crossover is related to the existence of a central-force isostatic point and to the fact that for most gels the bending modulus is small. This crossover induces scaling behavior for the elastic moduli. In particular, for linear elasticity such a scaling law has been demonstrated [Broedersz et al. Nat. Phys., 2011 7, 983]. In this work we generalize the scaling to the nonlinear regime with a two-parameter scaling law involving three critical exponents. We test the scaling law numerically for two disordered lattice models, and find a good scaling collapse for the shear modulus in both the linear and nonlinear regimes. We compute all the critical exponents for the two lattice models and discuss the applicability of our results to real systems.


Pediatricians as Child Health Advocates: The Role of Advocacy Education.
In this article, we discuss the role of formal advocacy education with high-effort advocacy activities among pediatricians. We discuss the historical role of advocacy in the field of pediatrics and the changing role of advocacy education in pediatric training programs. We describe our survey of pediatricians in New York, in which we asked about a history of formal child health advocacy education, current high- and low-effort advocacy activities, perceived barriers to advocacy work, and child health advocacy issues of interest. Our findings demonstrate an association between a history of formal child health advocacy education and recent participation in high-effort advocacy activities on behalf of children's health. We also found that practicing pediatricians were more likely to participate in high-effort advocacy work than individuals still in pediatric residency training. Our findings imply that education in child health advocacy should be considered an important part of pediatric training. Advocacy education should not only be included in residency and fellowship training programs but also made available as part of continuing medical education for pediatricians. Time for professional advocacy work should be allotted and encouraged.


Suppression of the frequency drift of modulational instability sidebands by means of a fiber system associated with a photon reservoir.
We analyze fiber systems where the linear losses act as a strong perturbation, causing a frequency drift of the modulational instability sidebands. We achieve the total suppression of this frequency drift by means of a technique based on the concept of a photon reservoir, which feeds in situ the process of modulational instability by continually supplying it the amount of photons absorbed by the fiber.


Synthesis, structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents.
Three novel series of 2,5-disubstituted indole derivatives were synthesized and evaluated in vitro for their antiproliferative activity against human cancer cells and HIV-1 inhibition activity used as a readout of cellular activity. Most compounds were found to have potent anticancer activity. In particular, 2c and 3b which showed effectively to repress HIV-1 transcription had a pan antiproliferative activity in cervical cancer cells (HeLa), breast cancer cells (MCF-7), liver cancer cells (HepG2), and lung cancer cells (H460 and A549). While 3b exhibited high sensitivity to A549 cells with the IC50 value 0.48 ± 0.15 μm, 2c showed high selectivity toward HepG2 cells with the IC50 value 13.21 ± 0.30 μm. With respect to the cellular mechanism of action, HepG2 cells treated with 2c and A549 cells treated with 3b for 24 h were studied by annexin V/PI staining and Western blot analysis, and results revealed that 2c and 3b may induce cancer cells apoptosis through inhibiting the phosphorylation at Ser2 of RNAPII CTD which can be phosphorylated by cyclin-dependent kinase 9. These studies indicated that 2c and 3b may develop as potent lead compounds in the therapy of cancer. However, determining their roles in preventing HIV-1 still requires further intensive study.


LPS-induced delayed myocardial adaptation enhances acute preconditioning to optimize postischemic cardiac function.
Myocardial tolerance to ischemia and reperfusion (I/R) injury can be achieved by either acute or delayed cardioprotective mechanisms. Ischemic preconditioning has been demonstrated to be a powerful acute cardioprotective stimulus. We have reported that lipopolysaccharide (LPS) pretreatment induces delayed myocardial adaptation to I/R injury. To optimize myocardial protection, we examined the ability of delayed myocardial adaptation to enhance acute ischemic preconditioning in the isolated working rat heart. Male Sprague-Dawley rats were divided into control, acute [transient ischemia (TI); 5-min global ischemia, 37 degrees C], delayed (LPS; 500 micrograms/kg i.p.), or combined (LPS + TI) cardioprotective groups. Delayed cardioprotection involved LPS injection 72 h before heart isolation. All hearts were subjected to 20-min global ischemia (37 degrees C) and 30-min reperfusion. Coronary effluent collected during reperfusion was assayed for creatine kinase (CK) activity. Both TI and LPS treatment improved postischemic aortic flow recovery (29 +/- 4.5 and 44 +/- 4.0%, respectively; P < 0.05, LPS vs. TI) compared with control hearts (11 +/- 2.2%; P < 0.05, TI or LPS vs. control). When TI was applied to LPS-treated hearts (LPS + TI), aortic flow recovery was further enhanced (57 +/- 3.8%; P < 0.05 vs. TI or LPS alone). CK release during 20 and 30 min of reperfusion was decreased in all treated hearts compared with control hearts (P < 0.05). These results indicate that delayed myocardial adaptation and acute ischemic preconditioning independently activate protective mechanisms against ischemia. Enhanced protection occurs when induced delayed mechanisms are combined with acute cardioprotective stimuli, which optimize postischemic myocardial function and reduce myocellular necrosis.


Correction.
In the 24 April "Inside AAAS" article "AAAS organizes more meetings of the mind" (p. 548), it is stated incorrectly that Paul Berg of Stanford University will be giving the keynote address and that Helen Donis-Keller of Washington University will be presenting a paper at the Science Innovation '92 meeting in San Francisco (21 to 25 July 1992). The Science Innovation '92 program was tentative at the time the article was written. Joseph Martin of the University of California, San Francisco, will deliver the keynote address on one of the major themes of the meeting, "Mapping the Human Brain." Helen Donis-Keller and Paul Berg were invited to speak but will not be on the program this year.


Irreversible electroporation (Nanoknife® treatment) in the field of hepatobiliary surgery: Current status and future perspectives.
We aimed to provide an overview of current understanding on the potential use of irreversible electroporation (IRE) in the field of hepatobiliary surgery with a focus on current results in hepatic and pancreatic cancers, its limitations, and its current directions. Through a review of the literature we have gathered the key articles and trials that are shaping our understanding of the current status of IRE and its prospective uses, and organized them in an easily understandable format showcasing the most up to date results. IRE appears to be comparable in effectiveness and postoperative pain to the more established thermal ablation methods, while having the benefit of avoiding their detrimental thermal effects. In liver cancer, IRE was shown to be efficacious with low levels of local recurrences and only minimal complications. In pancreatic cancer it proved to have significant survival benefits but more significant (although rare) complications compared to the ones seen when IRE is used in liver cancer. Current evidence suggests a promising future for IRE, but clinical randomized control trials, and further developments of treatment protocols are required to come to more stable conclusions on the effectiveness and safety of IRE. IRE is proving to be an adequate method for the treatment of tumors of the pancreas and liver in cases where traditional methods are unavailable. It has been proven particularly efficacious in patients with masses in close proximity to vital structures such as vessels, as well as major biliary and hepatic structures where thermal methods of ablation would cause significant complications.


Vestibular heading discrimination and sensitivity to linear acceleration in head and world coordinates.
Effective navigation and locomotion depend critically on an observer's ability to judge direction of linear self-motion, i.e., heading. The vestibular cue to heading is the direction of inertial acceleration that accompanies transient linear movements. This cue is transduced by the otolith organs. The otoliths also respond to gravitational acceleration, so vestibular heading discrimination could depend on (1) the direction of movement in head coordinates (i.e., relative to the otoliths), (2) the direction of movement in world coordinates (i.e., relative to gravity), or (3) body orientation (i.e., the direction of gravity relative to the otoliths). To quantify these effects, we measured vestibular and visual discrimination of heading along azimuth and elevation dimensions with observers oriented both upright and side-down relative to gravity. We compared vestibular heading thresholds with corresponding measurements of sensitivity to linear motion along lateral and vertical axes of the head (coarse direction discrimination and amplitude discrimination). Neither heading nor coarse direction thresholds depended on movement direction in world coordinates, demonstrating that the nervous system compensates for gravity. Instead, they depended similarly on movement direction in head coordinates (better performance in the horizontal plane) and on body orientation (better performance in the upright orientation). Heading thresholds were correlated with, but significantly larger than, predictions based on sensitivity in the coarse discrimination task. Simulations of a neuron/anti-neuron pair with idealized cosine-tuning properties show that heading thresholds larger than those predicted from coarse direction discrimination could be accounted for by an amplitude-response nonlinearity in the neural representation of inertial motion.


Epidemiology of rubella infection in Cameroon: a 7-year experience of measles and rubella case-based surveillance, 2008-2014.
The aim of this study was to estimate the proportion of rubella disease in a measles case-based surveillance in Cameroon prior to rubella vaccine introduction into the national immunisation programme. This was a cross-sectional study for rubella infection in Cameroon for the period 2008 to 2014. Patients suspected with measles from the 10 regions of Cameroon were recruited according to the WHO measles case definition and were tested for rubella IgM antibodies accompanied with the case report/investigation forms. All persons with rash and fever within 14 days of onset of rash according to the standard WHO African Regional Office (WHO/AFRO) case definition for a suspected measles case. Descriptive analyses and simple logistic regressions were performed. OR were estimated. A total of 9907 serum samples from people with fever and rash were received in the laboratory from 2008 to 2014. A total of 7489 (75.59%) measles-negative samples were tested for rubella; 699 (9.3%) were positive for rubella IgM antibodies. Logistic regression analysis was done using IgM antibodies detection as the outcome variable. Age, sex and setting were explanatory variables. Logistic regression analysis revealed that, comparing the proportion of rubella IgM seropositivity status by age, the association to a positive rubella IgM increased with age from 1 to 4 years (OR 7.11; 95% CI 4.35 to 12.41; p<0.0001), through 5 to 9 years (OR 13.07; 95% CI 7.93 to 22.93; p<0.001), to 10 to 14 years of age (OR 13.86; 95% CI 8.06 to 25.12; p<0.001). Persons aged ≥15 years were also more likely to have rubella infection than children under one (OR 3.69; 95% CI 1.85 to 7.48; p=0.0001). There were also significant associations with sex, with males being less associated to a positive rubella serology than females (OR 1.33; 95% CI 1.14 to 1.56; p=0.0001). No statistically significant difference in proportion of rubella cases was observed between urban and rural populations (OR 1.11; 95% CI 0.94 to 1.31; p=0.208). This study reveals that rubella virus circulates in Cameroon, with important number of cases in children under 15 years. This finding supports the planned introduction of rubella-containing vaccines into the Expanded Program on Immunization.


Genetic structure and mating system of wild cowpea populations in West Africa.
Cowpea is a highly inbred crop. It is part of a crop-weed complex, whose origin and dynamics is unknown, which is distributed across the African continent. This study examined outcrossing rates and genetic structures in 35 wild cowpea (Vigna unguiculata ssp. unguiculata var. spontanea) populations from West Africa, using 21 isozyme loci, 9 of them showing polymorphism. Outcrossing rates ranged from 1% to 9.5% (mean 3.4%), which classifies the wild cowpea breeding system as primarily selfing, though rare outcrossing events were detected in each population studied. Furthermore, the analyses of both the genetic structure of populations and the relationships between the wild and domesticated groups suggest possibilities of gene flow that are corroborated by field observations. As expected in a predominantly inbred breeding system, wild cowpea shows high levels of genetic differentiation and low levels of genetic diversity within populations. Gene flow from domesticated to wild cowpea does occur, although the lack of strong genetic swamping and modified seed morphology in the wild populations suggest that these introgressions should be rare.


A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures.
G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small "druglike" optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure-activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.


Probing the dynamics of plasmon-excited hexanethiol-capped gold nanoparticles by picosecond X-ray absorption spectroscopy.
Picosecond X-ray absorption spectroscopy (XAS) is used to investigate the electronic and structural dynamics initiated by plasmon excitation of 1.8 nm diameter Au nanoparticles (NPs) functionalised with 1-hexanethiol. We show that 100 ps after photoexcitation the transient XAS spectrum is consistent with an 8% expansion of the Au-Au bond length and a large increase in disorder associated with melting of the NPs. Recovery of the ground state occurs with a time constant of ∼1.8 ns, arising from thermalisation with the environment. Simulations reveal that the transient spectrum exhibits no signature of charge separation at 100 ps and allows us to estimate an upper limit for the quantum yield (QY) of this process to be <0.1.


Four-wave-mixing experiments with seeded free electron lasers.
The development of free electron laser (FEL) sources has provided an unprecedented bridge between the scientific communities working with ultrafast lasers and extreme ultraviolet (XUV) and X-ray radiation. Indeed, in recent years an increasing number of FEL-based applications have exploited methods and concepts typical of advanced optical approaches. In this context, we recently used a seeded FEL to demonstrate a four-wave-mixing (FWM) process stimulated by coherent XUV radiation, namely the XUV transient grating (X-TG). We hereby report on X-TG measurements carried out on a sample of silicon nitride (Si3N4). The recorded data bears evidence for two distinct signal decay mechanisms: one occurring on a sub-ps timescale and one following slower dynamics extending throughout and beyond the probed timescale range (100 ps). The latter is compatible with a slower relaxation (time decay > ns), that may be interpreted as the signature of thermal diffusion modes. From the peak intensity of the X-TG signal we could estimate a value of the effective third-order susceptibility which is substantially larger than that found in SiO2, so far the only sample with available X-TG data. Furthermore, the intensity of the time-coincidence peak shows a linear dependence on the intensity of the three input beams, indicating that the measurements were performed in the weak field regime. However, the timescale of the ultrafast relaxation exhibits a dependence on the intensity of the XUV radiation. We interpreted the observed behaviour as the generation of a population grating of free-electrons and holes that, on the sub-ps timescale, relaxes to generate lattice excitations. The background free detection inherent to the X-TG approach allowed the determination of FEL-induced electron dynamics with a sensitivity largely exceeding that of transient reflectivity and transmissivity measurements, usually employed for this purpose.


Gasless trans-axillary robotic thyroidectomy: the technique and evidence.
Robot assisted thyroid surgery has the advantage of a superior field vision and technical advancements of robotic technology that have permitted novel remote access thyroid surgical approaches. Gasless trans-axillary robot-assisted thyroidectomy has been proved to be among the most current feasible approaches. This approach offers an excellent cosmetic outcome, with comparable outcomes to conventional surgical approaches. This review aims to provide details of this specific remote access technique for thyroid resection with most recent evidences in the literature.


Intermittent hypoxia: cause of or therapy for systemic hypertension?
During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.


Phthalocyanine derivatives possessing 2-(morpholin-4-yl)ethoxy groups as potential agents for photodynamic therapy.
Three 2-(morpholin-4-yl)ethoxy substituted phthalocyanines were synthesized and characterized. Phthalocyanine derivatives revealed moderate to high quantum yields of singlet oxygen production depending on the solvent applied (e.g., in DMF ranging from 0.25 to 0.53). Their photosensitizing potential for photodynamic therapy was investigated in an in vitro model using cancer cell lines. Biological test results were found particularly encouraging for the zinc(II) phthalocyanine derivative possessing two 2-(morpholin-4-yl)ethoxy substituents in nonperipheral positions. Cells irradiated for 20 min at 2 mW/cm(2) revealed the lowest IC50 value at 0.25 μM for prostate cell line (PC3), whereas 1.47 μM was observed for human malignant melanoma (A375) cells. The cytotoxic activity in nonirradiated cells of novel phthalocyanine was found to be very low. Moreover, the cellular uptake, localization, cell cycle, apoptosis through an ELISA assay, and immunochemistry method were investigated in LNCaP cells. Our results showed that the tested photosensitizer possesses very interesting biological activity, depending on experimental conditions.


The predicted structure of immunoglobulin D1.3 and its comparison with the crystal structure.
Predictions of the structures of the antigen-binding domains of an antibody, recorded before its experimental structure determination and tested subsequently, were based on comparative analysis of known antibody structures or on conformational energy calculations. The framework, the relative positions of the hypervariable regions, and the folds of four of the hypervariable loops were predicted correctly. This portion includes all residues in contact with the antigen, in this case hen egg white lysozyme, implying that the main chain conformation of the antibody combining site does not change upon ligation. The conformations of three residues in each of the other two hypervariable loops are different in the predicted models and the experimental structure.


Initial refugee health assessments. New recommendations for Minnesota.
Historically, the purpose of medical screening of new refugees has been to identify acute conditions such as infections that can be effectively addressed with short-term therapy. More recently, screening of refugees who are new to Minnesota has included identifying conditions that require ongoing care. But regular screening for chronic conditions only makes sense when follow-up care can be provided. To address this issue, the Minnesota Department of Health's Refugee Health Program, in conjunction with outside experts, reviewed its guidelines for medical screening of new refugees and revised its recommendations. In addition to recommending screening for infections and other acute conditions, the new guidelines call for screening for chronic conditions and repeat testing for diseases or conditions of long latency. The guidelines take into account the ability of the screening clinic to provide ongoing care or assure the patient's transition to primary care.


Molecular basis of substrate-induced permeation by an amino acid antiporter.
Transporters of the amino acid, polyamine and organocation (APC) superfamily play essential roles in cell redox balance, cancer, and aminoacidurias. The bacterial L-arginine/agmatine antiporter, AdiC, is the main APC structural paradigm and shares the "5 + 5 inverted repeat" fold found in other families like the Na(+)-coupled neurotransmitter transporters. The available AdiC crystal structures capture two states of its transport cycle: the open-to-out apo and the outward-facing Arg(+)-bound occluded. However, the role of Arg(+) during the transition between these two states remains unknown. Here, we report the crystal structure at 3.0 Å resolution of an Arg(+)-bound AdiC mutant (N101A) in the open-to-out conformation, completing the picture of the major conformational states during the transport cycle of the 5 + 5 inverted repeat fold-transporters. The N101A structure is an intermediate state between the previous known AdiC conformations. The Arg(+)-guanidinium group in the current structure presents high mobility and delocalization, hampering substrate occlusion and resulting in a low translocation rate. Further analysis supports that proper coordination of this group with residues Asn101 and Trp293 is required to transit to the occluded state, providing the first clues on the molecular mechanism of substrate-induced fit in a 5 + 5 inverted repeat fold-transporter. The pseudosymmetry found between repeats in AdiC, and in all fold-related transporters, restraints the conformational changes, in particular the transmembrane helices rearrangements, which occur during the transport cycle. In AdiC these movements take place away from the dimer interface, explaining the independent functioning of each subunit.


A 'busy day' effect on perinatal complications of delivery on weekends: a retrospective cohort study.
To evaluate whether busy days on a labour and delivery unit are associated with maternal and neonatal complications of childbirth in California hospitals, accounting for weekday/weekend births. This is a population-based retrospective cohort study. Linked vital statistics/patient discharge data for California births between 2009 and 2010 from the Office of Statewide Health Planning and Development. All singleton, cephalic, non-anomalous California births between 2009 and 2010 (N=724 967). The key exposure was high daily obstetric volume, defined as giving birth on a day when the number of births exceeded the hospital-specific 75th percentile of daily delivery volume. Outcomes were a range of maternal and neonatal complications. Several maternal and neonatal complications were increased on high-volume days and weekends following adjustment for maternal demographics, annual hospital birth volume and teaching hospital status. For example, compared with low-volume weekdays, the odds of Apgar <7 on low-volume weekend days and high-volume weekend days were 11% (adjusted OR (aOR) 1.11, CI 1.03 to 1.21) and 29% higher (aOR 1.29, CI 1.10 to 1.52), respectively. High volume was associated with increased odds of neonatal seizures on weekdays (aOR 1.33, CI 1.01 to 1.71) and haemorrhage on weekends (aOR 1.11, CI 1.01 to 1.22). After accounting for between-hospital variation, weekend delivery remained significantly associated with increased odds of Apgar score <7, neonatal intensive care unit admission, prolonged maternal length of stay and the odds of neonatal seizures remained increased on high-volume weekdays. Our findings suggest that weekend delivery is a consistent risk factor for a range of perinatal complications and there may be variability in how well hospitals handle surges in volume.


Contraceptive use--United States and territories, Behavioral Risk Factor Surveillance System, 2002.
Contraceptive use is an important determinant of unintended pregnancy. In the United States, approximately half of all pregnancies are unintended. Population-based information about contraceptive use patterns is limited at the state level. Information about contraceptive use for states can be used to guide the development of state programs and policies to decrease unintended pregnancy and the spread of sexually transmitted infections. Information about contraceptive use for specific subpopulations can be used to further refine state efforts to improve contraceptive use and subsequently decrease the occurrence of unintended pregnancy. Data were collected in 2002 for men and women. The Behavioral Risk Factor Surveillance System (BRFSS) is a random-digit--dialed, telephone survey of the noninstitutionalized U.S. population aged > or =18 years. All 50 states, the District of Columbia, Guam, the Commonwealth of Puerto Rico, and the U.S. Virgin Islands participated in BRFSS in 2002. These data can be used to track state progress towards the national health objectives for 2010 for responsible sexual behavior. The 2002 BRFSS data represent the first time state data on contraceptive use in all 50 states will be presented and examined by selected sociodemographic characteristics. The 2002 BRFSS also, for the first time, provided an opportunity to examine state-level contraceptive use patterns among men. Variation across states and territories was observed for the majority of contraceptive methods among the different demographics analyzed and among men and women. The percentage of men and women at risk for pregnancy who said they or their partner was using birth control was high overall and ranged from 67% (Guam) to 88% (Idaho). Oral contraceptives (i.e., the pill), vasectomy, tubal ligation, and condoms were the methods most frequently reported by both male and female respondents who said they or their partner was using birth control. Among female respondents using birth control, the pill was the most common method reported. Among men, vasectomy was the most commonly reported method. The prevalence of use for the four most commonly reported methods (pills, vasectomy, tubal ligation, condoms) varied as much as six-fold among states for vasectomy and three- to four-fold for condoms, pills, and tubal ligation. The findings in this report document substantial differences among states and sociodemographic groups within states in contraceptive method use. These data can help states identify populations with an unmet need for birth control, barriers to birth control use, and gaps in the range of birth control methods offered by health-care providers. An analysis of the prevalence of birth control use by state and selected population characteristics can help states target contraceptive programs to best meet the needs of their population.


Impacts of continuous quality improvement in Aboriginal and Torres Strait islander primary health care in Australia.
Purpose Continuous quality improvement (CQI) programmes have been taken up widely by indigenous primary health care services in Australia, but as yet there has not been a systematic assessment of their focus and achievements. A scoping review of the literature from studies of CQI in indigenous primary health care services was undertaken to explore impacts on service systems, care and client outcomes with the aim of providing guidance on future evaluation efforts. The paper aims to discuss these issues, Design/methodology/approach Searches were conducted in MEDLINE, CINAHL and the Cochrane Database of Systematic Reviews to December 2016 and handsearching of key websites and publications. Studies of CQI programs or activities in Indigenous primary health care services which demonstrated some combination of CQI characteristics, as described by Rubenstein (2013) were included. A two-stage approach to analysis was undertaken. Stage 1 identified the range and scope of literature, and Stage 2 investigated impacts to service systems, care and client outcomes. The Framework for Performance Assessment in Primary Health Care was used to frame the Stage 2 analysis. Findings The majority of Aboriginal community controlled health services have been involved in CQI but there are gaps in knowledge about uptake in general practice and government clinics. There are as many baseline studies as studies on impacts over time. Of the 14 studies included for further analysis, 6 reported on impacts on service systems; all 14 reported on impacts on care and 6 on client outcomes. Changes to services systems are variable and studies of impacts on care and client outcomes show promising though uneven improvements. There are no economic studies or studies addressing community engagement in CQI activities. Research limitations/implications To supplement existing limited knowledge about which service system change strategies are effective and sustainable for which problems in which settings, there needs to be investment in research and development. Research needs to be grounded in the realities of service delivery and contribute to the development of CQI capacity at the service level. Knowledge translation needs to be built into implementation to ensure maximum benefit to those endeavouring on a daily basis to constantly reflect on and improve the quality of the care they deliver to clients, and to the stewardship structures supporting services at regional, state/territory and national levels. Practical implications Improved approaches, methods, data capture and reporting arrangements are needed to enhance existing activity and to ensure maximum benefit to services endeavouring to reflect on and improve quality of care and to the stewardship structure supporting services at regional, state/territory and national levels. Originality/value Although there is a growing body of research evidence about CQI both nationally and internationally, and considerable investment by the federal government in Australia to support CQI as part of routine practice, there has not been a systematic assessment of the achievements of CQI in Indigenous primary health care services. Many unanswered questions remain about the extent of uptake, implementation and impacts. This is a barrier to future investment and regional and local programme design, monitoring and evaluation. The authors conducted a scoping review to address these questions. From this, the authors draw conclusions about the state of knowledge in Australia with a view to informing how future CQI research and evaluation might be intensified.


Looking for frailty in community-dwelling older persons: the Gérontopôle Frailty Screening Tool (GFST).
The frailty syndrome is a pre-disability condition suitable to be targeted by preventive interventions against disability. In order to identify frail older persons at risk of negative outcomes, general practitioners must be provided with an easy and quick screening tool for detecting frailty without special effort. In the present paper, we present the screening tool for frailty that the Gérontopôle of Toulouse (France) has developed and implemented in primary care in the region with the collaboration of the Department of Family Medicine of the University of Toulouse. The Gérontopôle Frailty Screening Tool (GFST) is designed to be administered to persons aged ≥65 years with no physical disability and acute clinical disease. It is composed by an initial questionnaire aimed at attracting the general practitioner's attention to very general signs and/or symptoms suggesting the presence of an underlying frailty status. Then, in a second section, the general practitioner expresses his/her own view about the frailty status of the individual. The clinical judgment of the general practitioner is finally retained for determining the eventual presence of frailty. Preliminary data document that almost everyone (95.2%) of the 442 patients referred to the Gérontopôle frailty clinic by general practitioners using the GFST indeed presents a condition of (pre-)frailty according to the criteria proposed by Fried and colleagues in the Cardiovascular Health Study. The use of the GFST may help at raising awareness about the importance of identifying frailty, training healthcare professionals at the detection of the syndrome, and developing preventive interventions against disabling conditions.


Antonovsky's sense of coherence and resistance resources reduce perception of burden in family carers of people with Alzheimer's disease.
Objectives: Taking care of people with dementia (PWD) has been associated with some degree of burden. The variability of the carer's burden can be partially explained by their personal characteristics. Antonovsky's model of health defined the resistance resources (RRs) as essential mechanisms to cope with stressors, and to shape the personal sense of coherence (SOC). This study identifies the RRs related with carer's SOC, and their implications in the perception of burden in family dementia carers.Methods: A sample of 308 participants from the 'SOC & DEM study' (154 carers and 154 PWD) was recruited from two memory clinics. Carer's personal characteristics of burden, SOC, self-efficacy, coping strategies, perceived social support, and depression were evaluated using standardized instruments. PWD's degree of dependence and behaviour and psychological symptoms of dementia (BPSD) were assessed too. A path analysis was used to test the relationship between caregiver burden and SOC including the personal RRs of the carers and clinical data of PWD.Results: The path model identified SOC as a major factor related to carer's burden perception (r = -.327). Self-efficacy (r = .285), two coping strategies, 'use instrumental support' (r = -.235) and 'behavioural disengagement' (r = -.219), and social support perceived (r = .304) were the main carer's personal characteristics directly related with SOC. Caring experience (r = -.281) was the main carer factor related with burden while dependence (r = .156) and BPSD (r = .157) were the dementia factors.Conclusion: The SOC has previously related with carer's burden. The results contributed to identify relevant and modifiable personal characteristics as RRs that could reduce this burden.


PNMT-containing neurons of the C1 cell group express c-fos in response to changes in baroreceptor input.
The immunocytochemical detection of Fos, the protein product of the immediate-early gene c-fos, was used as a marker for activated neurons to examine whether the C1 neurons in the rat rostral ventrolateral medulla (RVLM) respond to changes in baroreceptor afferent activity. After hydralazine-induced hypotension or sinoaortic denervation, two treatments that reduce baroreceptor afferent activity, numerous Fos-positive neurons were observed in the RVLM. The number of Fos-positive neurons in the RVLM was counted in brain stem sections from hydralazine-treated rats that had been previously injected with Fluorogold into the upper thoracic spinal cord to label spinally projecting RVLM neurons as well as stained for phenylethanolamine-N-methyltransferase (PNMT) as a marker of C1 neurons. The results indicate that approximately 80% of the C1 neurons expressed Fos in response to hydralazine injection; this was true of spinally projecting C1 neurons as well as those C1 neurons that were not labeled with Fluorogold. Furthermore, in hydralazine-treated rats, the majority of Fluorogold-labeled Fos-positive neurons contained PNMT. These results suggest that C1 neurons are sensitive to baroreceptor afferent input and support a role of these neurons in cardiovascular regulation.


Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors.
The tolerance effects of continuous intrathecal infusions of opioids at mu and delta receptors were studied in rats. These effects were compared to those of chronic systemic morphine. A chronic intrathecal infusion of the relatively selective delta agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), produced a larger degree of tolerance to DADLE than to the highly specific mu-activating morphiceptin analog [N-methyl-Phe3, D-Pro4]morphiceptin (PL017). The slope of the analgesic dose-response curve for the highly specific delta agonist, cyclic [D-Penicillamine2, D-Penicillamine5]enkephalin (DPDPE), was significantly different (flatter) from those of mu agonists or DADLE. High-dose infusion of PL017 induced a 61-fold parallel shift of the dose-response curve for PL017. This same treatment also induced a corresponding flattened, nonparallel change of the dose-response curve for DADLE. This altered curve for DADLE was very similar in slope to that of DPDPE. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine, caused a parallel rightward shift of the dose-response curve for PL017 but did not affect DPDPE activity. beta-Funaltrexamine treatment induced a nonparallel rightward shift of the dose-response curve for DADLE with a change of slope similar to that of DPDPE. These findings demonstrate a mixed mu-delta analgesic activity for the compound DADLE, which is often referred to as a prototypic delta agonist. These interactions differ from prior reports of none or minimal mu-ligand interactions with DADLE. Despite the cross-reactivity of DADLE to mu receptors, DADLE remains a more effective analgesic than do mu agonists in states of mu receptor tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)


Electron reconstruction and identification efficiency measurements with the ATLAS detector using the 2011 LHC proton-proton collision data.
Many of the interesting physics processes to be measured at the LHC have a signature involving one or more isolated electrons. The electron reconstruction and identification efficiencies of the ATLAS detector at the LHC have been evaluated using proton-proton collision data collected in 2011 at [Formula: see text] TeV and corresponding to an integrated luminosity of 4.7 fb[Formula: see text]. Tag-and-probe methods using events with leptonic decays of [Formula: see text] and [Formula: see text] bosons and [Formula: see text] mesons are employed to benchmark these performance parameters. The combination of all measurements results in identification efficiencies determined with an accuracy at the few per mil level for electron transverse energy greater than 30 GeV.


TMS to the lateral occipital cortex disrupts object processing but facilitates scene processing.
The study of brain-damaged patients and advancements in neuroimaging have lead to the discovery of discrete brain regions that process visual image categories, such as objects and scenes. However, how these visual image categories interact remains unclear. For example, is scene perception simply an extension of object perception, or can global scene "gist" be processed independently of its component objects? Specifically, when recognizing a scene such as an "office," does one need to first recognize its individual objects, such as the desk, chair, lamp, pens, and paper to build up the representation of an "office" scene? Here, we show that temporary interruption of object processing through repetitive TMS to the left lateral occipital cortex (LO), an area known to selectively process objects, impairs object categorization but surprisingly facilitates scene categorization. This result was replicated in a second experiment, which assessed the temporal dynamics of this disruption and facilitation. We further showed that repetitive TMS to left LO significantly disrupted object processing but facilitated scene processing when stimulation was administered during the first 180 msec of the task. This demonstrates that the visual system retains the ability to process scenes during disruption to object processing. Moreover, the facilitation of scene processing indicates disinhibition of areas involved in global scene processing, likely caused by disrupting inhibitory contributions from the LO. These findings indicate separate but interactive pathways for object and scene processing and further reveal a network of inhibitory connections between these visual brain regions.


Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers.
Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole-genome and matched RNA-sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense-mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein-Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1 Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers.


Radiologist experience effects on contrast detection.
Current literature shows that radiologist experience does not affect detection tasks when the object does not require medical training to detect. However, the research was never sufficiently detailed to examine if the contrast detection threshold is also the same for radiologists versus nonradiologists. Previously, contrast threshold research was performed predominantly on nonradiologists. Therefore, any differences could lead to over- or under-estimation of the performance capabilities of radiologists. Fourteen readers, evenly divided between radiologists and nonradiologists, read a set of 150 mammogram-like images. The study was performed with the location of the objects known and unknown, requiring two separate readings. No difference in the contrast detection threshold between reader groups for either the location-unknown (4.9 just noticeable differences) or location-known (3.3 just noticeable differences) images was seen. The standard deviation for the location-unknown condition had no difference (p 0.91). But for the location-known condition, a significant difference (p 0.0009) was seen between radiologists and nonradiologists. No difference in contrast detection based on reader experience was observed, but decreased variance was seen with radiologists in the location-known condition.


Selective extraction of uranyl ions using ion-imprinted chelating microspheres.
In this work, uranyl complex with Schiff base derived from condensation of p-aminostyrene and salicyaldehyde (HASS) was synthesized. Both ligand and uranyl complex were characterized using elemental analysis, FTIR, (1)H and (13)C NMR spectra. The complex was then copolymerized with styrene and divinylbenzene cross-linker using potassium persulfate free radical initiator through emulsion polymerization technique. The uranyl ions were then leached out from the cross-linked network to finally produce uranyl ion-imprinted microspheres (U-PASS), which were investigated using SEM and FTIR. The effect of various significant parameters such as pH, temperature, contact times and initial uranyl concentration on the removal of uranyl from aqueous solution was examined and the results indicated that the adsorption was exothermic in nature and the kinetics of adsorption fit with the second-order kinetic model. Also, Langmuir adsorption isotherm exhibited the best fit with the experimental results with maximum adsorption capacity 147.8 mg/g. Moreover, the selectivity studies revealed that the ion-imprinted microspheres resin exhibited an obvious affinity toward the uranyl ions in presence of other interfering metal ions compared to the non-imprinted resin.


Effects of quercetin on apoptosis, NF-κB and NOS gene expression in renal ischemia/reperfusion injury.
The aim of this study was to investigate the effects of quercetin on nitric oxide synthase (NOS), nuclear factor-κB (NF-κB) and apoptosis in renal ischemia/reperfusion (I/R) injury in rats. A total of 42 Sprague-Dawley rats were divided into three groups. The control, I/R and I/R+quercetin (I/R+Q) groups were treated with quercetin (50 mg/kg intraperitoneal) 1 h prior to the induction of ischemia. Tissue malondialdehyde (MDA) and glutathione (GSH) levels were determined by high-performance liquid chromatography (HPLC). p53, endothelial NOS (eNOS) and NF-κB expression were assessed immunohistochemically, and apoptosis assesment was performed using terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay. The mRNA levels of inducible NOS (iNOS) in renal tissue were determined by real-time polymerase chain reaction (RT-PCR). MDA levels were significantly decreased in the quercetin group compared to the I/R group. However, GSH levels were significantly increased with quercetin treatment in the I/R group. Histological results, the number of apoptotic and p53-positive cells, NF-κB and eNOS expression levels were significantly decreased in the quercetin treatment group compared to the I/R group. iNOS gene expression increased in the I/R group, but no significant difference was found between the I/R and quercetin treatment groups. Therefore, quercetin not only has antioxidant and anti-apoptotic activities, but also has an inhibitory effect on eNOS and NF-κB for renal tissue protection during I/R injury in rats. Therefore, quercetin may be a promising renoprotective therapeutic agent.


Near-infrared incoherent broadband cavity enhanced absorption spectroscopy (NIR-IBBCEAS) for detection and quantification of natural gas components.
The principle of near-infrared incoherent broadband cavity enhanced absorption spectroscopy was employed to develop a novel instrument for detecting natural gas leaks as well as for testing the quality of natural gas mixtures. The instrument utilizes the absorption features of methane, butane, ethane, and propane in the wavelength region of 1100 nm to 1250 nm. The absorption cross-section spectrum in this region for methane was adopted from the HITRAN database, and those for the other three gases were measured in the laboratory. A singular-value decomposition (SVD) based analysis scheme was employed for quantifying methane, butane, ethane, and propane by performing a linear least-square fit. The developed instrument achieved a detection limit of 460 ppm, 141 ppm, 175 ppm and 173 ppm for methane, butane, ethane, and propane, respectively, with a measurement time of 1 second and a cavity length of 0.59 m. These detection limits are less than 1% of the Lower Explosive Limit (LEL) for each gas. The sensitivity can be further enhanced by changing the experimental parameters (such as cavity length, lamp power etc.) and using longer averaging intervals. The detection system is a low-cost and portable instrument suitable for performing field monitorings. The results obtained on the gas mixture emphasize the instrument's potential for deployment at industrial facilities dealing with natural gas, where potential leaks pose a threat to public safety.


The effects of empagliflozin vs metformin on endothelial microparticles in overweight/obese women with polycystic ovary syndrome.
Endothelial microparticles (EMPs) are novel, surrogate biomarkers of endothelial function and have been shown to be elevated in women with polycystic ovary syndrome (PCOS). It remains poorly understood how pharmacological options for managing PCOS affect EMP levels. To characterise and compare the effects of empagliflozin vs metformin on the circulating levels of EMPs in overweight/obese women with PCOS. This was a randomised, comparative, 12-week single-centre trial conducted at the Academic Diabetes, Endocrinology and Metabolism Research Centre, Hull, UK. This analysis includes data from 39 overweight/obese women with PCOS who completed the study and were randomised to empagliflozin (15 mg/day) (n = 19) or metformin (1500 mg/day) (n = 20). Blood samples were collected at baseline and 12 weeks after treatment and analysed for specific surface proteins (ICAM-1, VCAM-1, PECAM-1, E-selectin and endoglin) expressed by circulating EMPs using flow cytometry. In the empagliflozin group, ICAM-1 (P = 0.006), E-selectin (P = 0.016) and VCAM-1 (P = 0.001) EMPs increased significantly following 12 weeks of treatment, but no changes were seen in PECAM-1 (P = 0.93) or endoglin (P = 0.13) EMPs. In the metformin group, VCAM-1 EMPs (P < 0.001) increased significantly after 12 weeks of treatment, whereas all other EMPs remained unchanged. When data were expressed as percentage change from baseline in each group, no significant differences were seen between groups for any biomarker (P-values from 0.22 to 0.80). Short-term administration of empagliflozin and metformin in overweight/obese women with PCOS appear to increase EMPs expressed by endothelial cells during their activation.


NTP Comparative Toxicity and Carcinogenicity Studies of o-Nitrotoluene and o-Toluidine Hydrochloride (CAS Nos. 88-72-2 and 636-21-5) Administered in Feed to Male F344/N Rats.
o-Nitrotoluene and o-toluidine hydrochloride are structurally related chemicals that are suspected and demonstrated animal carcinogens, respectively. The metabolic potential of the gastrointestinal flora is considered an important factor in o-nitrotoluene-induced toxicity and involves the reduction of the nitro group to the corresponding amine (forming o-toluidine). These studies were designed to 1) compare the target organ toxicities of o-nitrotoluene and o-toluidine hydrochloride administered in feed at approximately equimolar doses (5,000 ppm) to male F344/N rats for 13 or 26 weeks, 2) determine the potential progression or reversibility of toxic or proliferative lesions following chemical withdrawal (stop-exposure) for 13 weeks after 13 weeks of exposure, and 3) examine the effect of antibiotic-altered gastrointestinal flora on the toxicity and/or carcinogenicity of o-nitrotoluene. o-Nitrotoluene and o-toluidine hydrochloride caused mesothelial hyperplasia and mesothelioma in male rats after 13 or 26 weeks of dietary exposure. The incidence of mesothelioma was greater and the latency was less in rats administered o-nitrotoluene than in rats administered o-toluidine hydrochloride. Additionally, o-nitrotoluene caused testicular degeneration in rats. Effects of o-nitrotoluene administration in the liver included progressive, irreversible increases in liver weight and irreversible increases in the incidences of cytoplasmic vacuolization and oval-cell hyperplasia. Placental glutathione S-transferase (PGST)-positive foci of cellular alteration occurred in the liver after 13 weeks of o-nitrotoluene exposure, and the number and size (as reflected by the volume fraction) of foci were increased after 26 weeks of continuous exposure. During the recovery period, the number of PGST-positive foci in rats in the stop-exposure group decreased slightly, but the size of the foci continued to increase. After 26 weeks, cholangiocarcinoma occurred in 2 of 20 rats in the stop-exposure group and 1 of 20 rats in the continuous-exposure group administered o-nitrotoluene. In contrast, liver effects in rats administered o-toluidine hydrochloride consisted of minimal hemosiderin accumulation in Kupffer cells; the incidence of this lesion in the stop-exposure group decreased during the recovery period. o-Toluidine hydrochloride caused fewer and much smaller PGST-positive foci than those caused by o-nitrotoluene. o-Nitrotoluene caused an accumulation of hyaline droplets in the renal tubule epithelium; this accumulation did not increase in severity with continued exposure and completely regressed during the recovery period. Exposure to o-toluidine hydrochloride did not cause hyaline droplet accumulation but did cause an accumulation of hemosiderin pigment in renal tubule epithelium. This change progressed in severity during the 26-week continuous-exposure study but decreased in severity in the stop-exposure study during the recovery period. Exposure to o-nitrotoluene or o-toluidine hydrochloride caused increased incidences of hematopoiesis, hemosiderin accumulation, and capsular fibrosis in the spleen. In rats administered o-toluidine, spleen effects were much more prominent and were also reflected by congestion and markedly increased spleen weights. During the recovery period for the stop-exposure groups administered either compound, incidences of hemosiderin accumulation and hematopoiesis were decreased, but the capsular fibrosis did not resolve. Hyperplasia of the transitional epithelium in the urinary bladder was observed only in rats administered o-toluidine hydrochloride; this lesion did not increase in severity after 26 weeks of continuous exposure and completely regressed in the stop-exposure group during the recovery period. Alteration of the gastrointestinal flora by daily gavage administration of antibiotics did not affect the pattern or severity of toxicity at any site or the development of mesothelioma in rats exposed to o-nitrotoluene, although cholangiocarcinomas that occurred in three rats with the normal flora did not occur in groups with the altered intestinal flora. Subsequent studies determined that the antibiotic regimen used was effective only in reducing the gut population of aerobic microorganisms and had little effect on obligate anaerobes, which are thought to play a mayor role in nitro group reduction. In summary, these studies confirmed the target organs and compared the relative toxicity for o-nitrotoluene and o-toluidine hydrochloride administered to male F344/N rats at equimolar concentrations in feed. With the exception of the spleen toxicity observed with each chemical, but more prominently with o-toluidine hydrochloride, morphologic effects of exposure to each of these chemicals in the testis/epididymis, liver, kidney, and urinary bladder were different. The results of these studies demonstrate the somewhat greater relative carcinogenic potential of o-nitrotoluene compared to o-toluidine hydrochloride after 13 or 26 weeks of administration based on the occurrence of mesothelioma and cholangiocarcinoma. The apparently lower potency of o-toluidine hydrochloride relative to o-o-nitrotoluene in the induction of mesothelioma suggests that simple intestinal reduction of the nitro group may not be sufficient for carcinogenic activity in the mesothelium.


The Cancer Editome Atlas: A Resource for Exploratory Analysis of the Adenosine-to-Inosine RNA Editome in Cancer.
Increasing evidence has suggested a role for adenosine-to-inosine RNA editing in carcinogenesis. However, the clinical utility of RNA editing remains limited because functions of the vast majority of editing events remain largely unexplored. To help the cancer research community investigate functional consequences of individual editing events, we have developed a user-friendly bioinformatic resource, The Cancer Editome Atlas (TCEA; http://tcea.tmu.edu.tw). TCEA characterizes >192 million editing events at >4.6 million editing sites from approximately 11,000 samples across 33 cancer types in The Cancer Genome Atlas. Clinical information, miRNA expression, and alteration in miRNA targeting modulated through RNA editing are also integrated into TCEA. TCEA supports several modules to search, analyze, and visualize the cancer editome, providing a solid basis for investigating the oncogenic mechanisms of RNA editing and expediting the identification of therapeutic targets in cancer. SIGNIFICANCE: This user-friendly bioinformatic resource reduces the barrier to analyzing the huge and complex cancer RNA editome that cancer researchers face and facilitates the identification of novel therapeutic targets in cancer.


The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages.
Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.


Comparative genome analysis of Bacillus cereus group genomes with Bacillus subtilis.
Genome features of the Bacillus cereus group genomes (representative strains of Bacillus cereus, Bacillus anthracis and Bacillus thuringiensis sub spp. israelensis) were analyzed and compared with the Bacillus subtilis genome. A core set of 1381 protein families among the four Bacillus genomes, with an additional set of 933 families common to the B. cereus group, was identified. Differences in signal transduction pathways, membrane transporters, cell surface structures, cell wall, and S-layer proteins suggesting differences in their phenotype were identified. The B. cereus group has signal transduction systems including a tyrosine kinase related to two-component system histidine kinases from B. subtilis. A model for regulation of the stress responsive sigma factor sigmaB in the B. cereus group different from the well studied regulation in B. subtilis has been proposed. Despite a high degree of chromosomal synteny among these genomes, significant differences in cell wall and spore coat proteins that contribute to the survival and adaptation in specific hosts has been identified.


Training Load Capacity, Cumulative Risk, and Bone Stress Injuries: A Narrative Review of a Holistic Approach.
Bone stress injuries (BSIs) are a common orthopedic injury with short-term, and potentially long-term, effects. Training load capacity, influenced by risk factors, plays a critical role in the occurrence of BSIs. Many factors determine how one's body responds to repetitive loads that have the potential to increase the risk of a BSI. As a scientific community, we have identified numerous isolated BSI risk factors. However, we have not adequately analyzed the integrative, holistic, and cumulative nature of the risk factors, which is essential to determine an individual's specific capacity. In this narrative review, we advocate for a personalized approach to monitor training load so that individuals can optimize their health and performance. We define "cumulative risk profile" as a subjective clinical determination of the number of risk factors with thoughtful consideration of their interaction and propose that athletes have their own cumulative risk profile that influences their capacity to withstand specific training loads. In our narrative review, we outline BSI risk factors, discuss the relationship between BSIs and training load, highlight the importance of individualizing training load, and emphasize the use of a holistic assessment as a training load guide.


Five Years of Journal Clubs With Pediatric Nurses and Allied Health Professionals: A Retrospective Study and Satisfaction Survey.
Journal Clubs (JCs) for nurses and allied health professionals have been held in an Italian pediatric hospital since April 2008. This study aimed to: examine what type of articles have been used during JCs across 5years; investigate the potential implications for clinical and organizational practice; assess the participants' satisfaction about JCs and their contribution to professional development. Using a retrospective design, all articles proposed in the JCs were examined. Specific criteria were used to evaluate the implications for practice within the hospital, which were classified as direct or indirect. Using a cross-sectional design, 63 JCs participants were asked to express their opinion and satisfaction about the JC sessions attended. Overall, 132 articles were analyzed: most of them focused on pediatric care (64.4%) and nursing (96.2%). Almost half of the articles (n=60, 45.6%) were appraised as having brought implications for clinical practice, both direct (58.3%) and indirect (41.7%). Forty-one participants (12 attendees; 29 active participants) completed a questionnaire about their opinion about JCs. Most of participants (80.5%) reported that the topics selected for the JCs were interesting and relevant to their everyday practice. Multidisciplinary JCs were considered useful for clinical practice, improvement of the quality of care, and professional development. However, lack of pragmatism and the difficulty to bridge the gap between research and practice were reported as weaknesses. JCs can represent a quality improvement strategy for promoting research utilization among health professionals and thereby improving the quality of care.