Waiting to inhale: factors associated with healthcare workers' fears of occupationally-acquired tuberculosis (TB).
Fear of TB infection is rooted in historical and social memories of the disease, marked by stigma, segregation and exclusion. Healthcare workers (HCWs) face these same fears today, and even seek to hide their TB status when infected. This study sought to investigate factors associated with HCWs fears of acquiring TB while at work, including selected biographic characteristics, TB knowledge, infection control and perceptions that their colleagues stigmatise co-workers with TB/ presumed to have TB. In the Free State Province, South Africa, a representative sample of 882 HCWs from eight hospitals completed self-administered questionnaires on issues related to fear of occupationally acquired TB, infection control, TB knowledge and workplace TB stigma. The data were analysed using descriptive statistics as well as binomial logistic regression. Most of the HCWs (67.2%) were concerned about contracting TB at work. Support staff were less likely to worry about acquiring TB than clinical staff (OR = 0.657, P = 0.041). Respondents who indicated that there were inadequate numbers of disposable respirators at work, were 1.6 times more likely to be afraid of contracting TB at work (P = 0.040). With every unit increase on the TB stigma scale, respondents were 1.1 times more likely to fear acquiring TB at work (P = 0.000). Being a professional clinical HCW, not having adequate disposable respirators available and seeing/perceiving co-workers stigmatise colleagues with (presumptive) TB were all significantly associated with the fear of occupationally-acquired TB. It is recommended that campaigns to destigmatise TB, as well as appropriate TB infection control education and measures, are necessary to alleviate HCWs fears of acquiring the disease in the workplace. Ultimately this should create a health-enabling working environment, where HCWs are not afraid to function and are free to seek treatment and support when necessary.


Guanylate-Binding Protein 1, an Interferon-Induced GTPase, Exerts an Antiviral Activity against Classical Swine Fever Virus Depending on Its GTPase Activity.
Many viruses trigger the type I interferon (IFN) pathway upon infection, resulting in the transcription of hundreds of interferon-stimulated genes (ISGs), which define the antiviral state of the host. Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a highly contagious viral disease endangering the pig industry in many countries. However, anti-CSFV ISGs are poorly documented. Here we screened 20 ISGs that are commonly induced by type I IFNs against CSFV in lentivirus-delivered cell lines, resulting in the identification of guanylate-binding protein 1 (GBP1) as a potent anti-CSFV ISG. We observed that overexpression of GBP1, an IFN-induced GTPase, remarkably suppressed CSFV replication, whereas knockdown of endogenous GBP1 expression by small interfering RNAs significantly promoted CSFV growth. Furthermore, we demonstrated that GBP1 acted mainly on the early phase of CSFV replication and inhibited the translation efficiency of the internal ribosome entry site of CSFV. In addition, we found that GBP1 was upregulated at the transcriptional level in CSFV-infected PK-15 cells and in various organs of CSFV-infected pigs. Coimmunoprecipitation and glutathione S-transferase (GST) pulldown assays revealed that GBP1 interacted with the NS5A protein of CSFV, and this interaction was mapped in the N-terminal globular GTPase domain of GBP1. Interestingly, the K51 of GBP1, which is crucial for its GTPase activity, was essential for the inhibition of CSFV replication. We showed further that the NS5A-GBP1 interaction inhibited GTPase activity, which was critical for its antiviral effect. Taking our findings together, GBP1 is an anti-CSFV ISG whose action depends on its GTPase activity. Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), an economically important viral disease affecting the pig industry in many countries. To date, only a few host restriction factors against CSFV, including interferon-stimulated genes (ISGs), have been characterized. Using a minilibrary of porcine ISGs, we identify porcine guanylate-binding protein 1 (GBP1) as a potent antiviral ISG against CSFV. We further show that the anti-CSFV action of GBP1 depends on its GTPase activity. The K51 of GBP1, critical for its GTPase activity, is essential for the antiviral action of GBP1 against CSFV replication, and the binding of the NS5A protein to GBP1 antagonizes the GTPase activity and thus the antiviral effect. This study will facilitate the development of anti-CSFV therapeutic agents by targeting host factors and may provide a new strategy for the control of CSF.


Decay times of the spin-forbidden and spin-enabled transitions of Yb2+ doped in CsCaX3 and CsSrX3 (X = Cl, Br, I).
In this paper, a systematic study of the decay times of the spin-enabled and spin-forbidden transitions of Yb2+ doped into the halidoperovskites CsMX3 (M = Ca, Sr; X = Cl, Br, I) is presented. The spin-forbidden transitions are characterized by ms decay times, which are typical for Yb2+. On the contrary, the spin-enabled transitions show much shorter decay times in the range of μs and have so far only been rarely observed. These results allow detailed conclusions about systematics of the decay times of Yb2+ doped in similar compounds and their correlation to the local structure of the coordination sphere of Yb2+ as well as the role of vibrational interaction between the excited high spin (HS) and low spin (LS) states. The halidoperovskites are ideally suited as host lattices in this context and may work as text book examples due to their comparable structures, which allows a detailed interpretation of the decay times in relation to the local structure. An understanding of the impact of the composition and structure of the host material on the decay times of Yb2+ will be of relevance for future applications of this activator in scintillators or lighting materials.


Drug-like Fragments Inhibit agr-Mediated Virulence Expression in Staphylococcus aureus.
In response to the increasingly problematic emergence of antibiotic resistance, novel strategies for combating pathogenic bacteria are being investigated. Targeting the agr quorum sensing system, which regulates expression of virulence in Staphylococcus aureus, is one potentially useful approach for combating drug-resistant pathogens that has not yet been fully explored. A previously published study of a fragment screen resulted in the identification of five compound fragments that interact with the DNA-binding domain of the response regulator AgrA from S. aureus. We have analyzed the ability of these compounds to affect agr-mediated virulence gene expression in cultured S. aureus cells. Three of the compounds demonstrated the ability to reduce agr-driven transcription at the P2 and P3 promoters of the agr operon and increase biofilm formation, and two of these compounds also showed the ability to reduce levels of secreted toxins. The finding that the compounds tested were able to reduce agr activity suggests that they could be useful tools for probing the effects of agr inhibition. Furthermore, the characteristics of compound fragments make them good starting materials for the development of compound libraries to iteratively improve the inhibitors.


Application of Kogelnik's two-wave theory to deep, slanted, highly efficient, relief transmission gratings.
Deep photoresist gratings, slanted as well as unslanted, were produced holographically in clear Shipley 1400 photoresist. The diffraction efficiencies of these gratings were measured as a function of incident angle for three wavelengths with polarization perpendicular to the plane of incidence. It is shown that the results agree fairly well with those predicted by Kogelnik's two-wave theory, indicating that these relief gratings behave like volume holograms. An explanation in terms of thin and thick gratings is given, and practical conclusions are drawn from these observations.


Money makes you reveal more: consequences of monetary cues on preferential disclosure of personal information.
With continuous growth in information aggregation and dissemination, studies on privacy preferences are important to understand what makes people reveal information about them. Previous studies have demonstrated that short-term gains and possible monetary rewards make people risk disclosing information. Given the malleability of privacy preferences and the ubiquitous monetary cues in daily lives, we measured the contextual effect of reminding people about money on their privacy disclosure preferences. In experiment 1, we found that priming money increased willingness to disclose their personal information that could be shared with an online shopping website. Beyond stated willingness, experiment 2 tested whether priming money increases propensity for actually giving out personal information. Across both experiments, we found that priming money increases both the reported willingness and the actual disclosure of personal information. Our results imply that not only do short-term rewards make people trade-off personal security and privacy, but also mere exposure to money increases self-disclosure.


Genes or culture: are mitochondrial genes associated with tool use in bottlenose dolphins (Tursiops sp.)?
Some bottlenose dolphins use marine sponges as foraging tools ('sponging'), which appears to be socially transmitted from mothers mainly to their female offspring. Yet, explanations alternative to social transmission have been proposed. Firstly, the propensity to engage in sponging might be due to differences in diving ability caused by variation of mitochondrial genes coding for proteins of the respiratory chain. Secondly, the cultural technique of sponging may have selected for changes in these same genes (or other autosomal ones) among its possessors. We tested whether sponging can be predicted by mitochondrial coding genes and whether these genes are under selection. In 29 spongers and 54 non-spongers from two study sites, the non-coding haplotype at the HVRI locus was a significant predictor of sponging, whereas the coding mitochondrial genes were not. There was no evidence of selection in the investigated genes. Our study shows that mitochondrial gene variation is unlikely to be a viable alternative to cultural transmission as a primary driver of tool use in dolphins.


Microwave thermal ablation using CT-scanner for predicting the variation of ablated region over time: advantages and limitations.
This study aims at investigating in real-time the structural and dynamical changes occurring in an ex vivo tissue during a microwave thermal ablation (MTA) procedure. The experimental set-up was based on ex vivo liver tissue inserted in a dedicated box, in which 3 fibre-optic (FO) temperature probes were introduced to measure the temperature increase over time. Computed tomography (CT) imaging technique was exploited to experimentally study in real-time the Hounsfield Units (HU) modification occurring during MTA. The collected image data were processed with a dedicated MATLAB tool, developed to analyse the FO positions and HU modifications from the CT images acquired over time before and during the ablation procedures. The radial position of a FO temperature probe (rFO) and the value of HU in the region of interest (ROI) containing the probe (HUo), along with the corresponding value of HU in the contralateral ROI with respect to the MTA antenna applicator (HUc), were determined and registered over time during and after the MTA procedure. Six experiments were conducted to confirm results. The correlation between temperature and the above listed predictors was investigated using univariate and multivariate analysis. At the multivariate analysis, the time, rFO and HUc resulted significant predictive factors of the logarithm of measured temperature. The correlation between predicted and measured temperatures was 0.934 (p < 0.001). The developed tool allows identifying and registering the image-based parameters useful for predicting the temperature variation over time in each investigated voxel by taking into consideration the HU variation.


Tracking contributions to human body burden of environmental chemicals by correlating environmental measurements with biomarkers.
The work addresses current knowledge gaps regarding causes for correlations between environmental and biomarker measurements and explores the underappreciated role of variability in disaggregating exposure attributes that contribute to biomarker levels. Our simulation-based study considers variability in environmental and food measurements, the relative contribution of various exposure sources (indoors and food), and the biological half-life of a compound, on the resulting correlations between biomarker and environmental measurements. For two hypothetical compounds whose half-lives are on the order of days for one and years for the other, we generate synthetic daily environmental concentrations and food exposures with different day-to-day and population variability as well as different amounts of home- and food-based exposure. Assuming that the total intake results only from home-based exposure and food ingestion, we estimate time-dependent biomarker concentrations using a one-compartment pharmacokinetic model. Box plots of modeled R2 values indicate that although the R2 correlation between wipe and biological (e.g., serum) measurements is within the same range for the two compounds, the relative contribution of the home exposure to the total exposure could differ by up to 20%, thus providing the relative indication of their contribution to body burden. The novel method introduced in this paper provides insights for evaluating scenarios or experiments where sample, exposure, and compound variability must be weighed in order to interpret associations between exposure data.


Molecular imaging biomarkers for immune checkpoint inhibitor therapy.
Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients' immune system, resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with 18F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy.


Tamoxifen-Induced Apoptosis of MCF-7 Cells via GPR30/PI3K/MAPKs Interactions: Verification by ODE Modeling and RNA Sequencing.
Tamoxifen (Nolvadex) is one of the most widely used and effective therapeutic agent for breast cancer. It benefits nearly 75% of patients with estrogen receptor (ER)-positive breast cancer that receive this drug. Its effectiveness is mainly attributed to its capacity to function as an ER antagonist, blocking estrogen binding sites on the receptor, and inhibiting the proliferative action of the receptor-hormone complex. Although, tamoxifen can induce apoptosis in breast cancer cells via upregulation of pro-apoptotic factors, it can also promote uterine hyperplasia in some women. Thus, tamoxifen as a multi-functional drug could have different effects on cells based on the utilization of effective concentrations or availability of specific co-factors. Evidence that tamoxifen functions as a GPR30 (G-Protein Coupled Receptor 30) agonist activating adenylyl cyclase and EGFR (Epidermal Growth Factor Receptor) intracellular signaling networks, provides yet another means of explaining the multi-functionality of tamoxifen. Here ordinary differential equation (ODE) modeling, RNA sequencing and real time qPCR analysis were utilized to establish the necessary data for gene network mapping of tamoxifen-stimulated MCF-7 cells, which express the endogenous ER and GPR30. The gene set enrichment analysis and pathway analysis approaches were used to categorize transcriptionally upregulated genes in biological processes. Of the 2,713 genes that were significantly upregulated following a 48 h incubation with 250 μM tamoxifen, most were categorized as either growth-related or pro-apoptotic intermediates that fit into the Tp53 and/or MAPK signaling pathways. Collectively, our results display that the effects of tamoxifen on the breast cancer MCF-7 cell line are mediated by the activation of important signaling pathways including Tp53 and MAPKs to induce apoptosis.


Quantitative Studies of Muscleblind Proteins and Their Interaction With TCF4 RNA Foci Support Involvement in the Mechanism of Fuchs' Dystrophy.
Fuchs' endothelial corneal dystrophy (FECD) is a major cause of vision loss and the most common nucleotide repeat disorder, affecting 4% of United States population greater than 40 years of age. Seventy percent of FECD cases are due to an intronic CTG expansion within the TCF4 gene, resulting in accumulation of CUG repeat RNA nuclear foci in corneal endothelium. Each endothelial cell has approximately two sense foci, and each focus is a single RNA molecule. This study aimed to obtain a better understanding of how rare repeat RNA species lead to disease. We quantitatively examined muscleblind-like (MBNL) proteins and their interaction with foci in both patient-derived corneal endothelial cell lines and human corneal endothelial tissue. Using fluorescent in situ hybridization and immunofluorescence, we found that depletion of both MBNL1 and MBNL2 reduces nuclear RNA foci formed by the repeat, suggesting that both are necessary for foci. Quantitative studies of RNA and protein copy number revealed MBNLs to be abundant in the total cellular pool in endothelial cell lines but are much lower in human corneal endothelial tissue. Studies using human tissue nuclear and cytoplasmic fractions indicate that most MBNL proteins are localized to the cytoplasm. The low levels of MBNL1/2 in corneal tissue, in combination with the small fraction of protein in the nucleus, may make corneal endothelial cells especially susceptible to sequestration of MBNL1/2 by CUG repeat RNA. These observations may explain how a limited number of RNA molecules can cause widespread alteration of splicing and late-onset degenerative FECD.


Beta-thalassemia, HB S-beta-thalassemia and sickle cell anemia among Tunisians.
We analyzed the mutations present in 19 patients with beta-thalassemia major, in 11 patients with Hb S-beta-thalassemia, and the beta S haplotypes of 34 patients with sickle cell anemia. The study included 84 relatives. Dot-blot analysis of amplified DNA with various specific oligonucleotide probes identified 11 different known beta-thalassemia mutations and frameshifts; a new frameshift at codons 25/26 (+T) was detected through sequencing of amplified DNA. The common beta-thalassemia mutations at codon 39 (C----T) and at IVS-I-110 (G----A) were also most prevalent among the Tunisian patients, while the milder T----C mutation at IVS-I-6 was not found. All mutations cause a beta 0-thalassemia or a severe beta + -thalassemia [T----A at -30; IVS-I-5 (G----A); IVS-I-110 (G----A)] which explains the need for regular blood transfusions in the thalassemia major and S-beta-thalassemia patients. Nearly all sickle cell anemia patients carried the beta S mutation on a chromosome with haplotype 19 (or Benin) and all had severe anemia with sickling complications. Identification of the beta S haplotype was through dot-blot analysis with oligonucleotide probes that detect mutations in the G gamma and A gamma promoter sequences, specific for this haplotype.


Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.
The vesicle-associated membrane protein-associated proteins (VAPs) VAPA and VAPB interact with lipid-binding proteins carrying a short motif containing two phenylalanines in an acidic tract (FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum (ER). A genetic mutation (P56S) in the conserved major sperm protein homology domain of VAPB has been linked to motor-neuron degeneration in affected amyotrophic lateral sclerosis (ALS) patients. We report that in the CNS, VAPB is abundant in motor neurons and that the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAP in mutant aggregates. Expression of mutant VAPB or reduction of VAP by short hairpin RNA in primary neurons causes Golgi dispersion and cell death. VAPA and VAPB are reduced in human ALS patients and superoxide dismutase 1 (SOD1)-ALS-transgenic mice, suggesting that VAP family proteins may be involved in the pathogenesis of sporadic and SOD1-linked ALS. Our data support a model in which reduced levels of VAP family proteins result in decreased ER anchoring of lipid-binding proteins and cause motor neuron degeneration.


The experiences of inpatient nursing staff caring for young people with early psychosis.
Early intervention services aim to improve outcomes for people with first episode psychosis and, where possible, to prevent psychiatric hospital admission. When hospitalisation does occur, inpatient staff are required to support patients and families who may be less familiar with services, uncertain about possible outcomes, and may be experiencing a psychiatric hospital for the first time. Our study aimed to understand the process of hospitalisation in early psychosis, from the perspective of inpatient nursing staff. We were particularly interested in their experiences of working with younger people in the context of adult psychiatric wards. Nine inpatient nursing staff took part in semi-structured interviews, which were transcribed and then analysed using interpretative phenomenological analysis. Five themes are outlined: 'it's all new and it's all learning'; the threatening, unpredictable environment; care and conflict within the intergenerational relationship; motivation and hope; and coping and self-preservation. The phenomenological focus of our approach throws the relational component of psychiatric nursing into sharp relief. We reflect on the implications for organisations, staff, families and young people. We suggest that the conventional mode of delivering acute psychiatric inpatient care is not likely to support the best relational and therapeutic outcomes.


What you see is what you get--reloaded: can jackdaws (Corvus monedula) find hidden food through exclusion?
Choice by exclusion, that is, the ability to base the choice of a target on the rejection of potential alternatives, is becoming increasingly interesting for comparative cognition research. Recently, ravens have been shown to solve an exclusion task and it had been suggested that this ability might benefit ravens in a food-caching context. To investigate this possibility, the raven study was replicated with a closely related, but noncaching, species, the jackdaw (Corvus monedula). In the first test, the birds had to find food hidden in one of two differently shaped tubes. The results suggest that the jackdaws found the food through intensive search behavior, with little evidence for exclusion abilities. In a follow-up experiment, the tubes were replaced by cups, and before the birds made a choice, one of the cups was lifted to inform them about its content. In a final task, this procedure was modified to control for the influence of local enhancement. In both experiments, the jackdaws were successful only if they had seen the food before. These findings are in contrast to the previous results on ravens and support the idea that exclusion abilities may have evolved as specific adaptations to food caching.


A simple approach to improve recording of concerns about child maltreatment in primary care records: developing a quality improvement intervention.
Information is lacking on how concerns about child maltreatment are recorded in primary care records. To determine how the recording of child maltreatment concerns can be improved. Development of a quality improvement intervention involving: clinical audit, a descriptive survey, telephone interviews, a workshop, database analyses, and consensus development in UK general practice. Descriptive analyses and incidence estimates were carried out based on 11 study practices and 442 practices in The Health Improvement Network (THIN). Telephone interviews, a workshop, and a consensus development meeting were conducted with lead GPs from 11 study practices. The rate of children with at least one maltreatment-related code was 8.4/1000 child years (11 study practices, 2009-2010), and 8.0/1000 child years (THIN, 2009-2010). Of 25 patients with known maltreatment, six had no maltreatment-related codes recorded, but all had relevant free text, scanned documents, or codes. When stating their reasons for undercoding maltreatment concerns, GPs cited damage to the patient relationship, uncertainty about which codes to use, and having concerns about recording information on other family members in the child's records. Consensus recommendations are to record the code 'child is cause for concern' as a red flag whenever maltreatment is considered, and to use a list of codes arranged around four clinical concepts, with an option for a templated short data entry form. GPs under-record maltreatment-related concerns in children's electronic medical records. As failure to use codes makes it impossible to search or audit these cases, an approach designed to be simple and feasible to implement in UK general practice was recommended.


Academic practice-policy partnerships for health promotion research: experiences from three research programs.
The development of knowledge for health promotion requires an effective mechanism for collaboration between academics, practitioners, and policymakers. The challenge is better to understand the dynamic and ever-changing context of the researcher-practitioner-policymaker-community relationship. The aims were to explore the factors that foster Academic Practice Policy (APP) partnerships, and to systematically and transparently to review three cases. Three partnerships were included: Power and Commitment-Alcohol and Drug Prevention by Non-Governmental Organizations in Sweden; Healthy City-Social Inclusion, Urban Governance, and Sustainable Welfare Development; and Empowering Families with Teenagers-Ideals and Reality in Karlskoga and Degerfors. The analysis includes searching for evidence for three hypotheses concerning contextual factors in multi-stakeholder collaboration, and the cumulative effects of partnership synergy. APP partnerships emerge during different phases of research and development. Contextual factors are important; researchers need to be trusted by practitioners and politicians. During planning, it is important to involve the relevant partners. During the implementation phase, time is important. During data collection and capacity building, it is important to have shared objectives for and dialogues about research. Finally, dissemination needs to be integrated into any partnership. The links between process and outcomes in participatory research (PR) can be described by the theory of partnership synergy, which includes consideration of how PR can ensure culturally and logistically appropriate research, enhance recruitment capacity, and generate professional capacity and competence in stakeholder groups. Moreover, there are PR synergies over time. The fundamentals of a genuine partnership are communication, collaboration, shared visions, and willingness of all stakeholders to learn from one another.


Lymphotoxin beta receptor signaling induces the chemokine CCL20 in intestinal epithelium.
The follicle-associated epithelium (FAE) that overlies Peyer's patches (PPs) exhibits distinct features compared with the adjacent villus epithelium. Besides the presence of antigen-sampling membranous M cells and the down-regulation of digestive functions, it constitutively expresses the chemokine CCL20. The mechanisms that induce FAE differentiation and CCL20 expression are poorly understood. The aim of this work was to test whether lymphotoxin beta receptor signaling (LTbetaR), which plays a central role in PPs' organogenesis, mediates CCL20 gene expression in intestinal epithelial cells. CCL20, lymphotoxin beta (LTbeta) and LTbetaR expression were monitored during embryonic development by in situ hybridization of mouse intestine. The human intestinal epithelial cell line T84 was used to study CCL20 expression following LTalpha(1)/beta(2) stimulation. In vivo CCL20 expression following agonistic anti-LTbetaR antibody treatment was studied by laser microdissection and quantitative RT-PCR. CCL20 was expressed in the FAE before birth at the time when the first hematopoietic CD4(+)CD3(-) appeared in the PP anlage. LTbetaR was expressed in the epithelium during PP organogenesis, making it a putative target for LTalpha(1)beta(2)signals. In vitro, CCL20 was induced in T84 cells upon LTbetaR signaling, either using an agonistic ligand or anti-LTbeta receptor agonistic antibody. LTalpha(1)beta(2)-induced CCL20 expression was found to be NF-kappaB dependent. LTbetaR signaling up-regulated CCL20 expression in the small intestinal epithelium in vivo. Our results show that LTbetaR signaling induces CCL20 expression in intestinal epithelial cells, suggesting that this pathway triggers constitutive production of CCL20 in the FAE.


Percutaneous imaging-guided core breast biopsy: 5 years' experience in a community hospital.
This study reports the results of a percutaneous imaging-guided core breast biopsy program in a community hospital. We reviewed the prospectively collected results of our imaging-guided core biopsy program during its first 5 years (1994-1998). A total of 1333 lesions (94% of which were Breast Imaging Reporting and Data System (BI-RADS) assessment category 4) were sampled in 1183 patients. Patients with BI-RADS assessment category 5 lesions were referred to surgeons. Stereotactic guidance was used for the core biopsy of 506 lesions, and sonography was used to guide the predominantly 16-gauge needle core biopsy of 827 solid masses. One hundred forty-seven cancers were diagnosed in 1333 biopsies, resulting in a positive yield of 11%. Of 1020 patients with benign, concordant core biopsy results, 981 (96%) had at least one follow-up imaging examination within 36 months of the biopsy. Nineteen (2%) of these 1020 patients had a suspicious change at follow-up; 18 of these patients underwent surgical excision with benign findings. No cancers were found at imaging follow-up or by tumor registry linkage. All malignant core biopsy results were confirmed as malignant at surgical excision (positive predictive value 100%). Twenty-two patients with atypical ductal hyperplasia at core biopsy had subsequent surgery, and 12 (55%) of them were found to have cancer at surgery. An imaging-guided core biopsy program, developed and implemented by a small group of radiologists in a community hospital, can achieve successful results and provide an important service to patients and a cost-effective alternative to surgical biopsy. Our program emphasized sonographic guidance and achieved high follow-up compliance.


Seropositivity for pathogens associated with chronic infections is a risk factor for all-cause mortality in the elderly: findings from the Memory and Morbidity in Augsburg Elderly (MEMO) Study.
Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.


Wogonin mitigates intervertebral disc degeneration through the Nrf2/ARE and MAPK signaling pathways.
Intervertebral disc degeneration (IVDD) is a prevalent disease characterized by the progressive loss of the extracellular matrix in the local nucleus pulposus region. Metalloproteinases and pro-inflammatory cytokines play an important role in this process. Thus, anti-inflammatory strategies are an important component of IVDD treatment. Wogonin, a naturally existing monoflavonoid, has been reported to have potential anti-inflammatory effects in some inflammatory diseases. Hence, in our present study we investigated the protective effects and potential mechanisms of wogonin in rat nucleus pulposus cells that had been treated with interleukin-1beta (IL-1β) to induce severe IVDD. An in vivo rat caudal vertebrae needle-stab model was also designed and its validity was evaluated as an IVDD model. The results demonstrated that wogonin suppressed IL-1β-induced inflammatory mediators (iNOS, IL-6 and COX2) and matrix-degrading proteinases (MMP1, MMP3, MMP13 and ADAMTS4). Wogonin also upregulated some of the key components of the extracellular matrix, such as collagen II. Furthermore, we discovered that wogonin exerted anti-inflammatory effects by activating the Nrf2/HO-1-SOD2-NQO1-GCLC signaling axis. Moreover, the IL-1β-induced stimulation of the MAPK signaling pathway was reversed by wogonin treatment. The in vivo MRI and histological results also revealed that wogonin protected the nucleus pulposus from the progression of IVDD. Therefore, wogonin may be a potential agent for the treatment of IVDD.


Paradoxical accumulation of the cyclin-dependent kinase inhibitor p27kip1 during the cAMP-dependent mitogenic stimulation of thyroid epithelial cells.
In different systems, cAMP either blocks or promotes cell cycle progression in mid to late G1 phase. Dog thyroid epithelial cells in primary culture constitute a model of positive control of DNA synthesis initiation and G0-S pre-replicative phase progression by cyclic AMP (cAMP) as a second messenger for thyrotropin (TSH). We report here that TSH markedly increases the expression of p27kip1, the inhibitor of the cell cycle and cyclin-dependent kinases. This effect was prevented by the concomitant administration of the cAMP-independent mitogens, epidermal growth factor (EGF)+serum. EGF+serum also slightly inhibited the weak basal accumulation of p27kip1. Nevertheless, in the case of stimulation by TSH alone, the cAMP-dependent cell cycle progression was fully compatible with the enhanced expression of p27kip1. This observation is paradoxical since a decrease of p27kip1 is generally associated with growth stimulation in other systems, and since a similar cAMP-dependent increase of p27kip1 in macrophages has been found responsible for mid-G1 cell cycle arrest. The opposite regulation of p27kip1 in response to TSH or EGF+serum in dog thyroid epithelial cells suggests a major difference at mid to late G1 stages between cAMP-dependent and cAMP-independent mitogenic pathways.


Topical treatments for diabetic neuropathic pain.
Diabetic neuropathic pain (DNP) has a huge impact on quality of life and can be difficult to treat. Oral treatment is the most frequently used method for DNP, but its use is often limited by systemic side effects. Topical use of drugs as an alternative option for DNP treatment is currently gaining interest. In the present review, a summary is provided of the available agents for topical use in patients with DNP, including lidocaine plasters or patches, capsaicin cream, gel or patches, amitriptyline cream, clonidine gel, ketamine cream, extracts from medicinal plants including nutmeg extracts and Citrullus colocynthis extract oil, and certain compounded topical analgesics. Furthermore, the potential efficacy of these treatments is addressed according to the available clinical research literature. It has been indicated that these topical drugs have the potential to be valuable additional options for the management of DNP, with adequate safety and continuous long-term treatment efficacy. Compounded topical agents are also effective and safe for patients with DNP and could be another area worthy of further investigation based on the strategy of using low-dose, complementary therapies for DNP. The findings indicate that developing topical drugs acting on different targets in the process of DNP is a valuable area of future research.


Primary cardiac hydatid disease. A case report.
A young Coloured man whose only symptom was that of minimal dyspnoea on exertion, on examination had signs of infundibular stenosis which were confirmed by cardiac catheterization. Additional features were left anterior hemiblock and cardiomegaly as delineated radiologically. Cross-sectional echocardiography revealed a very large cystic mass located within the interventricular septum which encroached upon the right ventricular outflow tract. This cystic mass was further delineated by cardiac cine angiography. It is postulated that this mass was a primary cardiac echinococcal cyst and was directly responsible for the complications of left anterior hemiblock and the infundibular obstruction. The patient declined surgery and a definitive pathological diagnosis could therefore not be made. If this is a hydatid cyst then it is the second case reported in the literature diagnosed by two-dimensional echocardiography and in which left anterior hemiblock has been recorded. The clinical features, complications and surgical correction are briefly outlined.


Nurse Practitioners' Use of Communication Techniques: Results of a Maryland Oral Health Literacy Survey.
We examined nurse practitioners' use and opinions of recommended communication techniques for the promotion of oral health as part of a Maryland state-wide oral health literacy assessment. Use of recommended health-literate and patient-centered communication techniques have demonstrated improved health outcomes. A 27-item self-report survey, containing 17 communication technique items, across 5 domains, was mailed to 1,410 licensed nurse practitioners (NPs) in Maryland in 2010. Use of communication techniques and opinions about their effectiveness were analyzed using descriptive statistics. General linear models explored provider and practice characteristics to predict differences in the total number and the mean number of communication techniques routinely used in a week. More than 80% of NPs (N = 194) routinely used 3 of the 7 basic communication techniques: simple language, limiting teaching to 2-3 concepts, and speaking slowly. More than 75% of respondents believed that 6 of the 7 basic communication techniques are effective. Sociodemographic provider characteristics and practice characteristics were not significant predictors of the mean number or the total number of communication techniques routinely used by NPs in a week. Potential predictors for using more of the 7 basic communication techniques, demonstrating significance in one general linear model each, were: assessing the office for user-friendliness and ever taking a communication course in addition to nursing school. NPs in Maryland self-reported routinely using some recommended health-literate communication techniques, with belief in their effectiveness. Our findings suggest that NPs who had assessed the office for patient-friendliness or who had taken a communication course beyond their initial education may be predictors for using more of the 7 basic communication techniques. These self-reported findings should be validated with observational studies. Graduate and continuing education for NPs should increase emphasis on health-literate and patient-centered communication techniques to increase patient understanding of dental caries prevention. Non-dental healthcare providers, such as NPs, are uniquely positioned to contribute to preventing early childhood dental caries through health-literate and patient-centered communication.


Minor traumatic brain injury: a primer for the orthopaedic surgeon.
Minor traumatic brain injury (mTBI) is a major public health problem. The Centers for Disease Control and Prevention and the National Center for Injury Prevention and Control label it a "silent epidemic." Subtle signs and symptoms of mTBI, including headache, fatigue, and memory loss, are often seen in conjunction with musculoskeletal trauma. Although sometimes evident immediately, mTBI may not manifest until patients return to work and their personal lives. In the patient with acute concurrent mTBI, skeletal management must be based on either a period of observation to rule out evolving neurologic symptoms or, when warranted, the recommendations of a neurosurgeon. Such input is particularly important when mTBI is associated with a prolonged loss of consciousness or posttraumatic amnesia. In the outpatient setting, when concern for mTBI exists weeks after an injury, familiarity with and referral to locally available mTBI specialists and programs can facilitate proper care. Armed with this knowledge, the orthopaedic surgeon has an opportunity to positively influence outcomes and help provide crucial care that extends beyond the management of musculoskeletal injuries.


A Distalless-responsive enhancer of the Hox gene Sex combs reduced is required for segment- and sex-specific sensory organ development in Drosophila.
Hox genes are involved in the patterning of animal body parts at multiple levels of regulatory hierarchies. Early expression of Hox genes in different domains along the embryonic anterior-posterior (A/P) axis in insects, vertebrates, and other animals establishes segmental or regional identity. However, Hox gene function is also required later in development for the patterning and morphogenesis of limbs and other organs. In Drosophila, spatiotemporal modulation of Sex combs reduced (Scr) expression within the first thoracic (T1) leg underlies the generation of segment- and sex-specific sense organ patterns. High Scr expression in defined domains of the T1 leg is required for the development of T1-specific transverse bristle rows in both sexes and sex combs in males, implying that the patterning of segment-specific sense organs involves incorporation of Scr into the leg development and sex determination gene networks. We sought to gain insight into this process by identifying the cis-and trans-regulatory factors that direct Scr expression during leg development. We have identified two cis-regulatory elements that control spatially modulated Scr expression within T1 legs. One of these enhancers directs sexually dimorphic expression and is required for the formation of T1-specific bristle patterns. We show that the Distalless and Engrailed homeodomain transcription factors act through sequences in this enhancer to establish elevated Scr expression in spatially defined domains. This enhancer functions to integrate Scr into the intrasegmental gene regulatory network, such that Scr serves as a link between leg patterning, sex determination, and sensory organ development.


Impact of hospice disenrollment on health care use and medicare expenditures for patients with cancer.
Patients with cancer represent the largest diagnostic group of hospice users, with 560,000 referred for hospice in 2008. Oncologists rely on hospice teams to provide care for patients who have completed disease-directed treatment and desire to remain at home. However, 11% to 15% of hospice users disenroll from hospice, and little is known about their health care use and Medicare expenditures. We used Surveillance, Epidemiology and End Results-Medicare data for hospice users who died as a result of cancer between 1998 and 2002 (N = 90,826) to compare rates of hospitalization, emergency department, and intensive care unit admission and hospital death for hospice disenrollees and those who remained with hospice until death. We also compared per-day and total Medicare expenditures across the two groups. Patients with cancer who disenrolled from hospice were more likely to be hospitalized (39.8% v 1.6%; P < .001), more likely to be admitted to the emergency department (33.9% v 3.1%; P < .001) or intensive care unit (5.7% v 0.1%; P < .001), and more likely to die in the hospital (9.6% v 0.2%; P < .001). Patients who disenrolled from hospice died a median of 24 days following disenrollment, suggesting that the reason for hospice disenrollment was not improved health. In multivariable analyses, hospice disenrollees incurred higher per-day Medicare expenditures than patients who remained with hospice until death (higher per-day expenditures of $124; P < .001). Hospice disenrollment is a marker for higher health care use and expenditures for care. Strategies to manage a patient's care and support family caregivers following hospice disenrollment may be beneficial and should be explored.


Social ecology of asthma: engaging stakeholders in integrating health behavior theories and practice-based evidence through systems mapping.
This article describes a process for integrating health behavior and social science theories with practice-based insights using participatory systems thinking and diagramming methods largely inspired by system dynamics methods. This integration can help close the gap between research and practice in health education and health behavior by offering a systematic approach to bring together stakeholders across multiple domains. In this process we create a diagram using constructs from multiple health behavior theories at all levels of the social ecological framework as variables in causal loop diagrams. The goal of this process is to elucidate the reciprocal relationships between explanatory factors at various levels of the social ecological framework that render so many public health problems intractable. To illustrate, we detail a theory-based, replicable process for creating a qualitative diagram to enrich understanding of caregiver and provider behavior around adherence to pediatric asthma action plans. We describe how such diagramming can serve as the foundation for translating evidence into practice to address real-world challenges. Key insights gained include recognition of the complex, multilevel factors affecting whether, and how effectively, parents/caregivers and medical providers co-create an asthma action plan, and important "feedback" dynamics at play that can support or derail ongoing collaboration. Although this article applies this method to asthma action plan adherence in children, the method and resulting diagrams are applicable and adaptable to other health behaviors requiring continuous, daily action.


Opioids in the systemic hemodynamic and renal responses to stress in spontaneously hypertensive rats.
Endogenous opioid peptides have been implicated in the regulation of cardiovascular and renal function. We tested this hypothesis by examining whether the opioid antagonist naloxone alters the cardiovascular or renal responses produced by environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR). Before naloxone administration, air stress produced significant increases in heart rate, mean arterial pressure, and renal sympathetic nerve activity, and it caused a decrease in urinary sodium excretion. After intravenous and intracerebroventricular administration of naloxone, the air stress-induced pressor and antinatriuretic responses were inhibited. Subsequent studies with a different opioid antagonist, the quaternary compound naltrexone methylbromide, also showed inhibition of the air stress-induced pressor and antinatriuretic responses and demonstrated opioid receptor specificity of this inhibition. Furthermore, since only intracerebroventricular and not intravenous administration of naltrexone methylbromide inhibited the pressor and antinatriuretic responses to air stress, a central nervous system site of action was established. The opioid antagonists caused inhibition of the pressor and antinatriuretic responses to air stress without affecting the air stress-induced increase in renal sympathetic nerve activity. Our investigations indicate that central endogenous opioid peptides contribute to the pressor and antinatriuretic responses that occur in conscious SHR during acute environmental stress.


Effect of Sodium Hypochlorite on Push-out Bond Strength of Four Calcium Silicate-based Endodontic Materials when used for repairing Perforations on Human Dentin: An in vitro Evaluation.
This study aimed to evaluate the push-out bond strength of NeoMTA Plus (NMTA), EndoSequence root repair material fast set putty (ERRMF), biodentine (BD), and ProRoot white mineral trioxide aggregate (PMTA) when used as perforation repair materials after exposure to 2.5% sodium hypochlorite (NaOCl) during the early setting phase. Horizontal midroot sections were prepared from single-rooted human teeth. Sections (n = 144) were randomly divided into four groups: PMTA, BD, NMTA, and ERRMF. Materials were condensed and allowed to set for 10 minutes. The groups were further divided into two subgroups. The NaOCl group included specimens that were immersed in 2.5% NaOCl for 30 minutes, and the control group included specimens on which a wet cotton pellet was placed over the test material. After 48 hours, the highest force applied to the materials at the time of dislodgement was recorded. Slices were then examined under a digital microscope to evaluate the nature of the bond failure. The surfaces of two specimens from each subgroup were observed by scanning electron microscopy. Data were statistically analyzed with two-way and one-way analysis of variances, independent t-tests, and chi-square tests. The statistical significance was set at 0.05. In NaOCl-treated groups, PMTA showed a significantly higher push-out bond strength than the other three materials (p = 0.00). In the control groups, the bond strength of BD was significantly higher than that of PMTA, ERRMF, and NMTA (p < 0.05). Compared with the control group, NaOCl treatment significantly increased the push-out bond strength of PMTA (p = 0.00) and ERRMF (p = 0.00) and significantly reduced the bond strength of BD (p = 0.00) and NMTA (p = 0.03). None of the specimens showed an adhesive type of failure. The majority of the samples exhibited a cohesive failure type. Morphological observations revealed that the surfaces exhibited cubic crystals. In ERRMF, the crystals were few in number. Sodium hypochlorite enhanced the crystallization of NMTA. The push-out bond strengths of PMTA and ERRMF were significantly increased after exposure to 2.5% NaOCl in the early setting phase, and those of BD and NMTA were significantly decreased. The results of the present study suggest that early exposure of NaOCl increase the push-out bond strength of PMTA and ERRMF. PMTA had the highest push-out values. Therefore, it would be a potentially useful perforation repair material for single visit endodontic treatment.


Antibacterial efficacy of an endodontic sonic-powered irrigation system: An in vitro study.
To evaluate the efficacy of EDDY, a new sonic-powered irrigation system, in reducing intracanal bacteria load. Thirty-eight instrumented, autoclaved single-rooted human premolars were inoculated with Enterococcus faecalis (ATCC-29212) for 21 days. Two teeth were used as negative control without bacterial contamination. For the bacteria-inoculated teeth, 6 were used as positive control without irrigation. The remaining 30 teeth were randomly divided into 2 groups (N = 15), using 3% NaOCl as irrigant: (A) 30-gauge syringe needle irrigation (SNI), (B) EDDY (VDW, Munich, Germany). Twelve teeth per group and 4 teeth in the positive control were evaluated for bacterial reduction using MTT assay. The remaining teeth were split for BacLight LIVE/DEAD staining to examine the percentages of live/dead bacteria present in the dentinal tubules from different canal locations (coronal, mid-root and apical portions of the canal space) using confocal laser scanning microscopy (CLSM). MTT assay indicated that both SNI and EDDY significantly reduced overall intracanal bacterial load compared with the positive control, with no significant difference between the two techniques. CLSM indicated that EDDY had better intratubular bacterial killing efficacy than SNI in the coronal and mid-root portions of the canal space only but not in the apical portion. In all canal locations (coronal, mid-root apical), both systems failed to eliminate bacteria that proliferated deep within the dentinal tubules. With the use of 3% NaOCl, sonic-powered irrigant activation with EDDY tips did not provide additional advantage over SNI in killing Enterococcus faecalis from deep intraradicular dentin. Both the sonic-powered root canal irrigant activation system and syringe needle irrigation can reduce intracanal bacteria load but are incapable of completely killing all bacteria that resided deep within the dentinal tubules of root canals infected with Enterococcus faecalis.


Selection of haploid maize kernels from hybrid kernels for plant breeding using near-infrared spectroscopy and SIMCA analysis.
Samples of haploid and hybrid seed from three different maize donor genotypes after maternal haploid induction were used to test the capability of automated near-infrared transmission spectroscopy to individually differentiate haploid from hybrid seeds. Using a two-step chemometric analysis in which the seeds were first classified according to genotype and then the haploid or hybrid status was determined proved to be the most successful approach. This approach allowed 11 of 13 haploid and 25 of 25 hybrid kernels to be correctly identified from a mixture that included seeds of all the genotypes.


Effects of Acute Endurance Exercise Performed in the Morning and Evening on Inflammatory Cytokine and Metabolic Hormone Responses.
To compare the effects of endurance exercise performed in the morning and evening on inflammatory cytokine responses in young men. Fourteen healthy male participants aged 24.3 ± 0.8 years (mean ± standard error) performed endurance exercise in the morning (0900-1000 h) on one day and then in the evening (1700-1800 h) on another day with an interval of at least 1 week between each trial. In both the morning and evening trials, the participants walked for 60 minutes at approximately 60% of the maximal oxygen uptake (VO2max) on a treadmill. Blood samples were collected to determine hormones and inflammatory cytokines at pre-exercise, immediately post exercise, and 2 h post exercise. Plasma interleukin (IL)-6 and adrenaline concentrations were significantly higher immediately after exercise in the evening trial than in the morning trial (P < 0.01, both). Serum free fatty acids concentrations were significantly higher in the evening trial than in the morning trial at 2 h after exercise (P < 0.05). Furthermore, a significant correlation was observed between the levels of IL-6 immediately post-exercise and free fatty acids 2 h post-exercise in the evening (r = 0.68, P < 0.01). These findings suggest that the effect of acute endurance exercise in the evening enhances the plasma IL-6 and adrenaline concentrations compared to that in the morning. In addition, IL-6 was involved in increasing free fatty acids, suggesting that the evening is more effective for exercise-induced lipolysis compared with the morning.


Projected lung areas using dynamic X-ray (DXR).
Dynamic X-ray (DXR) provides images of multiple phases of breath with less radiation exposure than CT. The exact images at end-inspiratory or end-expiratory phases can be chosen accurately. To investigate the correlation of the projected lung area (PLA) by dynamic chest X-ray with pulmonary functions. One hundred sixty-two healthy volunteers who received medical check-ups for health screening were included in this study. All subjects underwent DXR in both posteroanterior (PA) and lateral views and pulmonary function tests on the same day. All the volunteers took several tidal breaths before one forced breath as instructed. The outlines of lungs were contoured manually on the workstation with reference to the motion of diaphragm and the graph of pixel values. The PLAs were calculated automatically, and correlations with pulmonary functions and demographic data were analyzed statistically. The PLAs have correlation with physical characteristics, including height, weight and BMI, and pulmonary functions such as vital capacity (VC) and forced expiratory volume in one second (FEV1). VC and FEV1 revealed moderate correlation with the PLAs of PA view in forced inspiratory phase (VC: right, r = 0.65; left, r = 0.69. FEV1: right, r = 0.54; left, r = 0.59). Multivariate analysis showed that body mass index (BMI), sex and VC were considered independent correlation factors, respectively. PLA showed statistically significant correlation with pulmonary functions. Our results indicate DXR has a possibility to serve as an alternate method for pulmonary function tests in subjects requiring contact inhibition including patients with suspected or confirmed covid-19.


Non-enzymatic in vitro production of circular hammerhead ribozyme targeting the template region of human telomerase RNA.
Circular RNA is more stable than linear RNA both in vitro and in vivo because of its inaccessibility to exoribonucleases. Therefore, circularization of functional RNAs is a potentially useful methodology for designing therapeutic RNA reagents. We designed a circular hammerhead ribozyme that can cleave the template region of human telomerase RNA. This circular hammerhead ribozyme was generated by in vitro transcription followed by spontaneous self-circularization activity using the permuted intron-exon (PIE) method. Two-dimensional gel electrophoresis and alkaline digestion of the in vitro transcription products revealed that the circular hammerhead ribozyme could be produced by the PIE method. The purified circular hammerhead ribozyme cleaved the template region of human telomerase RNA in a magnesium-dependent manner. These results indicated that the circular hammerhead ribozyme generated by the PIE method maintained the specific feature of canonical hammerhead catalytic activity.


Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish.
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone-a potent human PPARγ agonist-exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.


Holographic storage using shift multiplexing.
We demonstrate theoretically and experimentally a new multiplexing method for volume holographic storage using a single reference beam that is composed of multiple plane waves or is a spherical wave. We multiplex the holograms by shifting the recording material or the recording/readout head. The volume properties of the recording medium allow selective readout of holograms stored in successive overlapping locations. High storage densities can be achieved with a relatively simple implementation by use of the new method.


Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study.
Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.


Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.
Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.


An intensive, progressive exercise program reduces disability and improves functional performance in patients after single-level lumbar microdiskectomy.
Restoration of physical function following lumbar microdiskectomy may be influenced by the postoperative care provided. The purpose of this study was to examine the effectiveness of a new interventional protocol to improve functional performance in patients who have undergone a single-level lumbar microdiskectomy. The study was conducted in physical therapy outpatient clinics. Ninety-eight participants (53 male, 45 female) who had undergone a single-level lumbar microdiskectomy were randomly allocated to receive education only or exercise and education. The exercise intervention consisted of a 12-week periodized program of back extensor strength (force-generating capacity) and endurance training and mat and upright therapeutic exercises. The Oswestry Disability Index (ODI) and physical measures of functional performance were tested 4 to 6 weeks postsurgery and 12 weeks later, following completion of the intervention program. Because some participants sought physical therapy outside of the study, postintervention scores were analyzed for both an as-randomized (2-group) design and an as-treated (3-group) design. In the 2-group analyses, exercise and education resulted in a greater reduction in ODI scores and a greater improvement in distance walked. In the 3-group analyses, post hoc comparisons showed a significantly greater reduction in ODI scores following exercise and education compared with the education-only and usual physical therapy groups. The limitations of this study include a lack of adherence to group assignment, disproportionate therapist contact time among treatment groups, and multiple use of univariate analyses. An intensive, progressive exercise program combined with education reduces disability and improves function in patients who have undergone a single-level lumbar microdiskectomy.


Electrochemical Aptatoxisensor Responses on Nanocomposites Containing Electro-Deposited Silver Nanoparticles on Poly(Propyleneimine) Dendrimer for the Detection of Microcystin-LR in Freshwater.
A sensitive and reagentless electrochemical aptatoxisensor was developed on cobalt (II) salicylaldiimine metallodendrimer (SDD-Co(II)) doped with electro-synthesized silver nanoparticles (AgNPs) for microcystin-LR (L, l-leucine; R, l-arginine), or MC-LR, detection in the nanomolar range. The GCE|SDD-Co(II)|AgNPs aptatoxisensor was fabricated with 5' thiolated aptamer through self-assembly on the modified surface of the glassy carbon electrode (GCE) and the electronic response was measured using cyclic voltammetry (CV). Specific binding of MC-LR with the aptamer on GCE|SDD-Co(II)|AgNPs aptatoxisensor caused the formation of a complex that resulted in steric hindrance and electrostatic repulsion culminating in variation of the corresponding peak current of the electrochemical probe. The aptatoxisensor showed a linear response for MC-LR between 0.1 and 1.1 µg·L-1 and the calculated limit of detection (LOD) was 0.04 µg·L-1. In the detection of MC-LR in water samples, the aptatoxisensor proved to be highly sensitive and stable, performed well in the presence of interfering analog and was comparable to the conventional analytical techniques. The results demonstrate that the constructed MC-LR aptatoxisensor is a suitable device for routine quantification of MC-LR in freshwater and environmental samples.


Ensembler: Enabling High-Throughput Molecular Simulations at the Superfamily Scale.
The rapidly expanding body of available genomic and protein structural data provides a rich resource for understanding protein dynamics with biomolecular simulation. While computational infrastructure has grown rapidly, simulations on an omics scale are not yet widespread, primarily because software infrastructure to enable simulations at this scale has not kept pace. It should now be possible to study protein dynamics across entire (super)families, exploiting both available structural biology data and conformational similarities across homologous proteins. Here, we present a new tool for enabling high-throughput simulation in the genomics era. Ensembler takes any set of sequences-from a single sequence to an entire superfamily-and shepherds them through various stages of modeling and refinement to produce simulation-ready structures. This includes comparative modeling to all relevant PDB structures (which may span multiple conformational states of interest), reconstruction of missing loops, addition of missing atoms, culling of nearly identical structures, assignment of appropriate protonation states, solvation in explicit solvent, and refinement and filtering with molecular simulation to ensure stable simulation. The output of this pipeline is an ensemble of structures ready for subsequent molecular simulations using computer clusters, supercomputers, or distributed computing projects like Folding@home. Ensembler thus automates much of the time-consuming process of preparing protein models suitable for simulation, while allowing scalability up to entire superfamilies. A particular advantage of this approach can be found in the construction of kinetic models of conformational dynamics-such as Markov state models (MSMs)-which benefit from a diverse array of initial configurations that span the accessible conformational states to aid sampling. We demonstrate the power of this approach by constructing models for all catalytic domains in the human tyrosine kinase family, using all available kinase catalytic domain structures from any organism as structural templates. Ensembler is free and open source software licensed under the GNU General Public License (GPL) v2. It is compatible with Linux and OS X. The latest release can be installed via the conda package manager, and the latest source can be downloaded from https://github.com/choderalab/ensembler.


Acute aortic thrombosis in long-term after endovascular aneurysm repair: A case report.
Acute aortic thrombosis which develops in the longterm following an endovascular aneurysm repair is rare. A 78-year-old male patient presented with rest pain and sudden-onset coldness at lower limbs for four hours. His medical history revealed an endovascular aneurysm repair for an infrarenal abdominal aortic aneurysm two years ago. He was diagnosed with acute ischemia at lower limbs due to acute thrombosis of the infrarenal aorta. We first performed an axillobifemoral bypass surgery for limb salvage. Due to recurrent thromboses of the left limb of the graft during longterm follow-up, we applied aortobifemoral bypass procedure to provide adequate lower limb flow.


Extra skeletal Soft Tissue Ewing's Sarcoma with Variant Translocation of Chromosome t (4; 22) (q35; q12)-A Case Report.
Ewing's sarcomas is a rare primitive neuroectodermal tumour (PNET) which has an annual incidence of 2.9 /million population in USA 1Jeffery Toretsky et al (2008) They are very uncommon in African and Asian population. It is commonly associated with reciprocal translocation between chromosome 11 and 12 t (11:12) or less frequently the t(21;22)(q22;ql 2) translocation. It is highly aggressive tumor which is PAS- and CD99 (MIC2)-positive relatively few variant translocations have been reported in primary Ewing's sarcomas (ES). We are hereby presenting a case of extra skeletal soft tissue Ewing's sarcoma with unusual translocation of chromosome t (4, 22) (q35, q12). Patient presented to us in advanced stage with pulmonary metastasis and lower limb neurological deficit. Relatively few variant translocations have been reported in primary Ewing's sarcomas (ES). To date, 13 variants of the EWS fusion gene have been described in literature. They are extremely rare, representing altogether < 1% of the cases' 23we are reporting a case of a variant simple translocation of chromosome t (4; 22) (q35;1 2). In our exhaustive literature search we could find only one case of complex translocation which was identified in a dysmorphic 15-year-old girl, t (4:11; 22)(q21; q24; q12) reported by Squire Jet al (1993). This type of translocation is extremely rare and has not been reported in the literature so far. Clinical presentation was initial indolent but later at the time patient presented to our institute he had developed pulmonary metastases and paraplegia due to involvement of spine. Our case report will provide new insight about rare translocation types in Ewing's sarcoma and understand their clinical behavior of Ewing's sarcoma with such type of translocation.


Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.
Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ((1)H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥ 7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo (1)H-MRS spectra discriminated between IDH-mutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy.


Learning multiple lists at the same time in the Hebb repetition effect.
In short-term ordered recall, when 1 list of items is repeated over the course of the experiment, recall performance typically improves. This is known as the Hebb repetition effect (Hebb, 1961). In the present study, we contrasted the typical condition involving a single repeated sequence with concurrent learning of 2 repeated sequences. Participants performed a spatial recall task, in which sequences of 7 dots were presented in each trial. For a given participant, the location of the dots were the same for all trials. Presentation order of dots varied randomly, except for 1 or 2 particular series that were repeated every 4 trials. Results revealed a significant learning slope for both the single and dual list conditions and learning was as efficient in both conditions. The findings provide further evidence in support of models linking the Hebb repetition effect to word-form learning.


Comparison of Surgical Resection and Systemic Treatment for Hepatocellular Carcinoma with Vascular Invasion: National Cancer Database Analysis.
Small studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with receipt of surgical resection in a US population. HCC patients with AJCC clinical TNM stage 7th T3BN0M0 diagnosed between 2010 and 2017 from the National Cancer Database were analyzed. Cox and logistic regression analyses identified factors associated with overall survival and receipt of surgical resection. Of 11,259 patients with T3BN0M0 HCC, 325 (2.9%) and 4,268 (37.9%) received surgical resection and systemic therapy, respectively. In multivariable analysis, surgical resection was associated with improved survival compared to systemic therapy (adjusted hazard ratio: 0.496, 95% confidence interval: 0.426-0.578) with a median survival of 21.4 and 8.1 months, respectively. Superiority of surgical resection was observed in noncirrhotic and cirrhotic subgroups and propensity score matching and inverse probability of treatment weighting adjusted analysis. Asians were more likely to receive surgical resection, whereas Charlson comorbidity ≥3, elevated alpha-fetoprotein, smaller tumor size, care in a community cancer program, and the South or West region were associated with a lower likelihood of surgical resection. HCC patients with vascular invasion may benefit from surgical resection compared to systemic therapies. Demographic and clinical features of HCC patients and region and type of treating facility were associated with surgical resection versus systemic treatment.


Insights into the structure and activity of prototype foamy virus RNase H.
RNase H is an endonuclease that hydrolyzes the RNA strand in RNA/DNA hybrids. Retroviral reverse transcriptases harbor a C-terminal RNase H domain whose activity is essential for viral replication. The RNase H degrades the viral genomic RNA after the first DNA strand is synthesized. Here, we report the biophysical and enzymatic properties of the RNase H domain of prototype foamy virus (PFV) as an independently purified protein. Sequence comparisons with other retroviral RNases H indicated that PFV RNase H harbors a basic protrusion, including a basic loop and the so-called C-helix, which was suggested to be important for activity and substrate binding and is absent in the RNase H domain of human immunodeficiency virus. So far, no structure of a retroviral RNase H containing a C-helix is available. RNase H activity assays demonstrate that the PFV RNase H domain is active, although its activity is about 200-fold reduced as compared to the full length protease-reverse transcriptase enzyme. Fluorescence equilibrium titrations with an RNA/DNA substrate revealed a KD for the RNase H domain in the low micromolar range which is about 4000-fold higher than that of the full-length protease-reverse transcriptase enzyme. Analysis of the RNase H cleavage pattern using a [32P]-labeled substrate indicates that the independent RNase H domain cleaves the substrate non-specifically. The purified RNase H domain exhibits a well defined three-dimensional structure in solution which is stabilized in the presence of Mg2+ ions. Our data demonstrate that the independent PFV RNase H domain is structured and active. The presence of the C-helix in PFV RNase H could be confirmed by assigning the protein backbone and calculating the chemical shift index using NMR spectroscopy.


The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells.
Dendritic cells (DCs) link innate and adaptive immunity, initiating and regulating effector cell responses. They ubiquitously express members of the LILR (ILT, LIR, CD85) family of molecules, some of which recognize self-HLA molecules, but little is known of their possible functions in DC biology. We demonstrate that the inhibitory receptor LILRB1 (ILT2, LIR1, CD85j) is selectively up-regulated during DC differentiation from monocyte precursors in culture. Continuous ligation of LILRB1 modulated cellular differentiation, conferred a unique phenotype upon the resultant cells, induced a profound resistance to CD95-mediated cell death, and inhibited secretion of cytokines IL-10, IL-12p70, and TGF-beta. These features remained stable even after exposure of the cells to bacterial LPS. Ligated DCs exhibited poor stimulatory activity for primary and memory T-cell proliferative responses, but this was substantially reversed by blockade of CD80 or its preferred ligand CTLA-4, or by depleting CD4(+) CD25(+) CD127(lo) regulatory T cells. Our findings suggest that ligation of LILRB1 on DCs by self-HLA molecules may play a key role in controlling the balance between the induction and suppression of adaptive immune responses.


Two Obese Patients with Presumptive Diagnosis of Anaphylactoid Syndrome of Pregnancy Presenting at a Community Hospital.
Anaphylactoid syndrome of pregnancy (ASP) is a rare but extremely serious complication, with an estimated incidence in North America of 1 in 15 200 deliveries. Despite its rarity, ASP is responsible for approximately 10% of all childbirth-associated deaths in the United States. At present, there is no validated biomarker or specific set of risk factors sufficiently predictive of ASP risk to incorporate into clinical practice. Toward the goal of developing a methodology predictive of an impending ASP event for use by obstetricians, anesthesiologists, and other practitioners participating in infant deliveries, physicians encountering an ASP event have been encouraged to report the occurrence of a case and its biologically plausible risk factors. Herein, we report on 2 patients who presented with a presumptive diagnosis of ASP to the delivery unit of a community hospital. Patient One was a 21-year-old, obese (5'11" tall, 250 lbs., BMI 34.9) white female, 1 pregnancy, no live births (G1P0), estimated gestational age (EGA) 40.2 weeks. Patient Two was a 29-year-old, obese (5'7" tall, 307 lbs., BMI 48.1) Hispanic female, second pregnancy, with 1 previous live birth via C-section (G2P1-0-0-1). Her pregnancy was at gestational age 38 weeks plus 2 days. Patient One had 2 possible risk factors: administration of Pitocin to induce labor and post-coital spotting from recent intercourse. Patient Two suffered premature rupture of the placental membranes. Both Patient One and Patient Two had very high body mass indices (BMIs), at the 97th and 99th percentiles, respectively. In the relatively few cases of anaphylactoid syndrome of pregnancy described to date, this is the first report of a possible association with high BMI.


The Inducible Response of the Nematode Caenorhabditis elegans to Members of Its Natural Microbiota Across Development and Adult Life.
The biology of all organisms is influenced by the associated community of microorganisms. In spite of its importance, it is usually not well understood how exactly this microbiota affects host functions and what are the underlying molecular processes. To rectify this knowledge gap, we took advantage of the nematode Caenorhabditis elegans as a tractable, experimental model system and assessed the inducible transcriptome response after colonization with members of its native microbiota. For this study, we focused on two isolates of the genus Ochrobactrum. These bacteria are known to be abundant in the nematode's microbiota and are capable of colonizing and persisting in the nematode gut, even under stressful conditions. The transcriptome response was assessed across development and three time points of adult life, using general and C. elegans-specific enrichment analyses to identify affected functions. Our assessment revealed an influence of the microbiota members on the nematode's dietary response, development, fertility, immunity, and energy metabolism. This response is mainly regulated by a GATA transcription factor, most likely ELT-2, as indicated by the enrichment of (i) the GATA motif in the promoter regions of inducible genes and (ii) of ELT-2 targets among the differentially expressed genes. We compared our transcriptome results with a corresponding previously characterized proteome data set, highlighting a significant overlap in the differentially expressed genes, the affected functions, and ELT-2 target genes. Our analysis further identified a core set of 86 genes that consistently responded to the microbiota members across development and adult life, including several C-type lectin-like genes and genes known to be involved in energy metabolism or fertility. We additionally assessed the consequences of induced gene expression with the help of metabolic network model analysis, using a previously established metabolic network for C. elegans. This analysis complemented the enrichment analyses by revealing an influence of the Ochrobactrum isolates on C. elegans energy metabolism and furthermore metabolism of specific amino acids, fatty acids, and also folate biosynthesis. Our findings highlight the multifaceted impact of naturally colonizing microbiota isolates on C. elegans life history and thereby provide a framework for further analysis of microbiota-mediated host functions.


Empathy in paediatric intensive care nurses part 2: Neural correlates.
To determine if there are brain activity differences between paediatric intensive care nurses and allied health professionals during pain intensity rating tasks and test whether these differences are related to the population observed (infant or adult) and professional experience. The underestimation of patients' pain by healthcare professionals has generally been associated with patterns of change in neural response to vicarious pain, notably reduced activation in regions associated with affective sharing and increased activation in regions associated with regulation, compared with controls. Paediatric nurses, however, have recently been found to provide higher estimates of infants' pain in comparison to allied health controls, suggesting that changes in neural response of this population might be different than other health professionals. Cross-sectional study. Functional MRI data were acquired from September 2014-June 2015 and used to compare changes in brain activity in 27 female paediatric care nurses and 24 allied health professionals while rating the pain of infants and adults in a series of video clips. Paediatric nurses rated infant and adult pain higher than allied health professionals, but the two groups' neural response only differed during observation of infant pain; paediatric nurses mainly showed significantly less activation in the medial prefrontal cortex (linked to cognitive empathy) and in the left anterior insula and inferior frontal cortex (linked to affective sharing). Patterns of neural activity to vicarious pain may vary across healthcare professions and patient populations and the amount of professional experience might explain part of these differences.


Potential colon cancer biomarker search using more than two performance measures in a multiple criteria optimization approach.
A new method using Multiple Criteria Optimization (MCO) proposed by our research group has shown evidence of being able to identify gene-based biomarkers for the detection of cancer using microarray data. Herein, we explore this method, considering more than two conflicting criteria for the MCO problem. Using this method would result in stronger outcomes when using different results from microarray analyses. It would also demonstrate that the method is suitable for carrying out meta-analysis. Statistical comparisons between normal and cancer tissues were performed using a colon cancer microarray database. The different comparisons were carried out with a Mann-Whitney non-parametric test using partial permutations of the data. An MCO problem was built using the different p-values obtained. The associated solution was the set of genes reaching the best compromises between the p-values under consideration that were located in the so-called efficient frontier. Data Envelopment Analysis (DEA) was used to find the efficient frontier of the MCO problem. The capacity of DEA was explored using different numbers of p-values (criteria) in the model. The set of identified genes was consistent across the instances using different numbers of p-values in the DEA model, thereby providing evidence of the outcome stability of the proposed strategy. It was also observed that convergence to a larger number of potential biomarkers is faster with additional criteria, i.e., more p-values. The MCO problem proposed for the cancer biomarker search using microarray data can be solved efficiently with DEA using more than two conflicting criteria. This approach can result in robust results when using different analyses of microarray data and, indeed, in a faster convergence to highly potential biomarkers.


Oxidation Resistance 1 Modulates Glycolytic Pathways in the Cerebellum via an Interaction with Glucose-6-Phosphate Isomerase.
Glucose metabolism is essential for the brain: it not only provides the required energy for cellular function and communication but also participates in balancing the levels of oxidative stress in neurons. Defects in glucose metabolism have been described in neurodegenerative disease; however, it remains unclear how this fundamental process contributes to neuronal cell death in these disorders. Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). Initially, we present a dysregulation of metabolites of glucose metabolism at the pre-symptomatic stage in the Oxr1 knockout cerebellum. We then demonstrate that Oxr1 and Gpi1 physically and functionally interact and that the level of Gpi1 oligomerisation is disrupted when Oxr1 is deleted in vivo. Furthermore, we show that Oxr1 modulates the additional and less well-understood roles of Gpi1 as a cytokine and neuroprotective factor. Overall, our data identify a new molecular function for Oxr1, establishing this protein as important player in neuronal survival, regulating both oxidative stress and glucose metabolism in the brain.


Open-source syringe pump library.
This article explores a new open-source method for developing and manufacturing high-quality scientific equipment suitable for use in virtually any laboratory. A syringe pump was designed using freely available open-source computer aided design (CAD) software and manufactured using an open-source RepRap 3-D printer and readily available parts. The design, bill of materials and assembly instructions are globally available to anyone wishing to use them. Details are provided covering the use of the CAD software and the RepRap 3-D printer. The use of an open-source Rasberry Pi computer as a wireless control device is also illustrated. Performance of the syringe pump was assessed and the methods used for assessment are detailed. The cost of the entire system, including the controller and web-based control interface, is on the order of 5% or less than one would expect to pay for a commercial syringe pump having similar performance. The design should suit the needs of a given research activity requiring a syringe pump including carefully controlled dosing of reagents, pharmaceuticals, and delivery of viscous 3-D printer media among other applications.


Impacts of experimental alteration of water table regime and vascular plant community composition on peat mercury profiles and methylmercury production.
Climate change is expected to alter the hydrology and vascular plant communities in peatland ecosystems. These changes may have as yet unexplored impacts on peat mercury (Hg) concentrations and net methylmercury (MeHg) production. In this study, peat was collected from PEATcosm, an outdoor, controlled mesocosm experiment where peatland water table regimes and vascular plant functional groups were manipulated over several years to simulate potential climate change effects. Potential Hg(II) methylation and MeHg demethylation rate constants were assessed using enriched stable isotope incubations at the end of the study in 2015, and ambient peat total Hg (THg) and MeHg concentration depth profiles were tracked annually from 2011 to 2014. Peat THg and MeHg concentrations and the proportion of THg methylated (%MeHg) increased significantly within the zone of water table fluctuation when water tables were lowered, but potential Hg(II) methylation rate constants were similar regardless of water table treatment. When sedges dominate over ericaceous shrubs, MeHg concentrations and %MeHg became significantly elevated within the sedge rooting zone. Increased desorption of Hg(II) and MeHg from the solid phase peat into pore water occurred with a lowered water table and predominant sedge cover, likely due to greater aerobic peat decomposition. Deeper, more variable water tables and a transition to sedge-dominated communities coincided with increased MeHg accumulation within the zone of water table fluctuation. Sustained high water tables promoted the net downward migration of Hg(II) and MeHg. The simultaneous decrease in Hg(II) and MeHg concentrations in the near-surface peat and accumulation deeper in the peat profile, combined with the trends in Hg(II) and MeHg partitioning to mobile pore waters, suggest that changes to peatland hydrology and vascular plant functional groups redistribute peat Hg(II) and MeHg via vertical hydrochemical transport mechanisms.


Endometrial carcinoma: immunohistochemically detected proliferation index is a prognosticator of long-term outcome.
To test which immunohistochemically detected tumour parameters are predictive of outcome in endometrial carcinoma. A retrospective study of 300 patients diagnosed with endometrial carcinoma between 1980 and 1985, ensuring a follow up of at least 10 years. Paraffin wax embedded tissues from 236 patients with endometrial carcinoma were evaluated in terms of histological tumour type and grade, stage of disease, and certain immunohistochemical biological parameters. These parameters included the expression of oestrogen and progesterone receptors, the expression of p53 protein, the expression of the c-erbB-2 oncoprotein, and the expression of protease cathepsin D, together with the rate of cell proliferation. Using univariate analysis, the following parameters correlated significantly with adjusted survival: histological type (p = 0.025), grade (p = 0.00003), FIGO stage (p < 0.00001), proliferation rate (p = 0.00002), oestrogen receptor expression (p = 0.007), progesterone receptor expression (p = 0.0092), and p53 expression (p = 0.00028). These parameters also correlated significantly with both disease free and overall survival. There was a weak correlation of cathepsin D expression with survival, but no correlation of c-erb B-2 expression with survival. Using multivariate analysis, only FIGO stage (p = 0.0021), histological grade (p = 0.005), and proliferation rate (p = 0.0007) remained statistically significant prognosticators of adjusted survival as well as of disease free and overall survival. In addition to conventional histological parameters, the immunohistochemical determination of proliferative activity could contribute to the identification of a high risk subgroup of endometrial carcinomas. The other parameters tested were not of significant additional predictive value.


Sox10 regulates the development of neural crest-derived melanocytes in Xenopus.
The transcription factors of the Sox family play important roles in diverse developmental processes. A number of genetic studies have established that Sox10 is a major regulator of neural crest formation. Here, we report the cloning and functional analysis of the Xenopus Sox10 gene. Sox10 mRNA accumulates during gastrulation at the lateral edges of the neural plate, in the neural crest-forming region. In this tissue, Sox10 expression is regulated by Wnt signaling and colocalizes with two major regulators of neural crest formation, Slug and Sox9. While initially expressed in neural crest cells from all axial levels, at the tailbud stage, Sox10 is downregulated in the cranial neural crest and persists mostly in neural crest cells from the trunk region. Overexpression of Sox10 causes a dramatic expansion of the Slug expression domain. We show that the C-terminal portion of Sox10 is sufficient to mediate this activity. Later during embryogenesis, Sox10-injected embryos show a massive increase in pigment cells (Trp-2-expressing cells). The responsiveness of the embryo to Sox10 overexpression by expansion of the Slug expression domain and ectopic production of Trp-2-positive cells and differentiated melanocytes is lost during gastrulation, as revealed by a hormone-inducible Sox10 construct. These results suggest that Sox10 is involved in the specification of neural crest progenitors fated to form the pigment cell lineage.