Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer.
Loss of E-cadherin is associated with acquisition of metastatic capacity. Numerous studies suggest that histone deacetylation and/or hypermethylation of CpG islands in E-cadherin gene (CDH1) are major mechanisms responsible for E-cadherin silencing in different tumors and cancer cell lines. The hepatitis B virus (HBV)-encoded X antigen, HBx, contributes importantly to the development of hepatocellular carcinoma using multiple mechanisms. Experiments were designed to test if in addition to CDH1 hypermethylation HBx promotes epigenetic modulation of E-cadherin transcriptional activity through histone deacetylation and miR-373. The relationships between HBx, E-cadherin, mSin3A, Snail-1 and miR-373 were evaluated in HBx expressing (HepG2X) and control (HepG2CAT) cells by western blotting, immunoprecipitation (IP), chromatin IP as well as by immunohistochemical staining of liver and tumor tissue sections from HBV-infected patients. In HepG2X cells, decreased levels of E-cadherin and elevated levels of mSin3A and Snail-1 were detected. Reciprocal IP with anti-HBx and anti-mSin3A demonstrated mutual binding. Furthermore, HBx-mSin3A colocalization was detected by immunofluorescent staining. HBx downregulated E-cadherin expression by the recruitment of the mSin3A/histone deacetylase complex to the Snail-binding sites in human CDH1. Histone deacetylation inhibition by Trichostatin-A treatment restored E-cadherin expression. Mir-373, a positive regulator of E-cadherin expression, was downregulated by HBx in HepG2X cells and tissue sections from HBV-infected patients. Thus, histone deacetylation of CDH1 and downregulation of miR-373, together with the previously demonstrated hypermethylation of CDH1 by HBx, may be important for the understanding of HBV-related carcinogenesis.


Microbial lag phase can be indicative of, or independent from, cellular stress.
Measures of microbial growth, used as indicators of cellular stress, are sometimes quantified at a single time-point. In reality, these measurements are compound representations of length of lag, exponential growth-rate, and other factors. Here, we investigate whether length of lag phase can act as a proxy for stress, using a number of model systems (Aspergillus penicillioides; Bacillus subtilis; Escherichia coli; Eurotium amstelodami, E. echinulatum, E. halophilicum, and E. repens; Mrakia frigida; Saccharomyces cerevisiae; Xerochrysium xerophilum; Xeromyces bisporus) exposed to mechanistically distinct types of cellular stress including low water activity, other solute-induced stresses, and dehydration-rehydration cycles. Lag phase was neither proportional to germination rate for X. bisporus (FRR3443) in glycerol-supplemented media (r2 = 0.012), nor to exponential growth-rates for other microbes. In some cases, growth-rates varied greatly with stressor concentration even when lag remained constant. By contrast, there were strong correlations for B. subtilis in media supplemented with polyethylene-glycol 6000 or 600 (r2 = 0.925 and 0.961), and for other microbial species. We also analysed data from independent studies of food-spoilage fungi under glycerol stress (Aspergillus aculeatinus and A. sclerotiicarbonarius); mesophilic/psychrotolerant bacteria under diverse, solute-induced stresses (Brochothrix thermosphacta, Enterococcus faecalis, Pseudomonas fluorescens, Salmonella typhimurium, Staphylococcus aureus); and fungal enzymes under acid-stress (Terfezia claveryi lipoxygenase and Agaricus bisporus tyrosinase). These datasets also exhibited diversity, with some strong- and moderate correlations between length of lag and exponential growth-rates; and sometimes none. In conclusion, lag phase is not a reliable measure of stress because length of lag and growth-rate inhibition are sometimes highly correlated, and sometimes not at all.


Visible light active nanofibrous membrane for antibacterial wound dressing.
Chronic wound infections, especially due to the emergence of multidrug resistance in bacteria, require the urgent development of alternative antibacterial therapies. Here, we developed a new class of hydrogel nanofibrous membranes that show visible light-induced disinfection. The presented photocatalytic disinfection is based on the generation of reactive singlet oxygen from a conjugated microporous polymer upon visible light irradiation. Therefore, sustained protection of the wound area can be provided in the presence of visible light. Fabrication of the photoactive wound dressing consists of first synthesizing photoactive conjugated microporous polymer nanoparticles by miniemulsion polymerization and subsequently embedding the nanoparticles in polyvinyl alcohol hydrogel nanofibers by colloid-electrospinning. The fibers were then crosslinked in glutaraldehyde/HCl vapor to be water-insoluble. This nanoparticle-in-nanofiber structure allows for a flexible combination of the properties of the nanoparticles and supporting nanofibers. The disinfecting properties of the membranes were evaluated with the inactivation of Escherichia coli K-12 and Bacillus subtilis as model systems of Gram-negative and Gram-positive bacteria, as well as the inhibition of biofilm growth under irradiation of visible light. Cytotoxicity tests on fibroblast cells revealed a high cytocompatibility of the membranes. Furthermore, the good mechanical properties of the membranes allow for their facile removal after use and prevent the leakage of the embedded nanoparticles into the wound, making the photoactive hydrogel membranes a promising candidate for active wound dressing materials.


Ultrahigh mass resolution and accurate mass measurements as a tool to characterize oligomers in secondary organic aerosols.
Organic aerosols are a major fraction, often more than 50%, of the total atmospheric aerosol mass. The chemical composition of the total organic aerosol mass is poorly understood, although hundreds of compounds have been identified in the literature. High molecular weight compounds have recently gained much attention because this class of compounds potentially represents a major fraction of the unexplained organic aerosol mass. Here we analyze secondary organic aerosols, generated in a smog chamber from alpha-pinene ozonolysis with ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). About 450 compounds are detected in the mass range of m/z 200-700. The mass spectrum is clearly divided into a low molecular weight range (monomer) and a high molecular weight range, where dimers and trimers are distinguishable. Using the Kendrick mass analysis, the elemental composition of about 60% of all peaks could be determined throughout the whole mass range. Most compounds have high O:C ratios between 0.4 and 0.6. Small compounds (i.e., monomers) have a higher maximum O:C ratio than dimers and trimers, suggesting that condensation reactions with, for example, the loss of water are important in the oligomer formation process. A program developed in-house was used to determine exact mass differences between peaks in the monomer, dimer, and trimer mass range to identify potential monomer building blocks, which form the co-oligomers observed in the mass spectrum. A majority of the peaks measured in the low mass region of the spectrum (m/z < 300) is also found in the calculated results. For the first time the elemental composition of the majority of peaks over a wide mass range was determined using advanced data analysis methods for the analysis of ultra-high-resolution MS data. Possible oligomer formation mechanisms in secondary organic aerosols were investigated.


Soliton dual frequency combs in crystalline microresonators.
We present a novel compact dual-comb source based on a monolithic optical crystalline MgF2 multi-resonator stack. The coherent soliton combs generated in the two microresonators of the stack with the repetition rate of 12.1 GHz and difference of 1.62 MHz provided after heterodyning a 300 MHz wide radio frequency comb. An analogous system can be used for dual-comb spectroscopy, coherent LIDAR applications, and massively parallel optical communications.


Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial.
We report the first results of a randomized trial assessing a new oral aminobisphosphonate, ibandronate, in patients with bone metastases from breast cancer. Patients (n = 435) received placebo, or oral ibandronate 20 mg or 50 mg once-daily for 96 weeks. The primary efficacy measure was the number of 12-week periods with new bone complications [skeletal morbidity period rate (SMPR)]. Multivariate Poisson regression analysis assessed the relative risk reduction of skeletal-related events. Secondary efficacy analyses included bone pain and analgesic use. Adverse events were monitored. SMPR was significantly reduced with oral ibandronate [placebo 1.2, 20 mg group 0.97 (P = 0.024), 50 mg group 0.98 (P = 0.037)]. Ibandronate 50 mg significantly reduced the need for radiotherapy (P = 0.005 versus placebo). The relative risk of skeletal events was reduced by 38% (20 mg dose) and 39% (50 mg dose) versus placebo (P = 0.009 and P = 0.005). The tolerability profile of ibandronate was similar to placebo. Oral ibandronate is an effective and well-tolerated treatment for metastatic bone disease. The 50 mg dose is being further evaluated in clinical trials, and this dose was recently approved in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases.


The genomic basis for colonizing the freezing Southern Ocean revealed by Antarctic toothfish and Patagonian robalo genomes.
The Southern Ocean is the coldest ocean on Earth but a hot spot of evolution. The bottom-dwelling Eocene ancestor of Antarctic notothenioid fishes survived polar marine glaciation and underwent adaptive radiation, forming >120 species that fill all water column niches today. Genome-wide changes enabling physiological adaptations and the rapid expansion of the Antarctic notothenioids remain poorly understood. We sequenced and compared 2 notothenioid genomes-the cold-adapted and neutrally buoyant Antarctic toothfish Dissostichus mawsoni and the basal Patagonian robalo Eleginops maclovinus, representing the temperate ancestor. We detected >200 protein gene families that had expanded and thousands of genes that had evolved faster in the toothfish, with diverse cold-relevant functions including stress response, lipid metabolism, protein homeostasis, and freeze resistance. Besides antifreeze glycoprotein, an eggshell protein had functionally diversified to aid in cellular freezing resistance. Genomic and transcriptomic comparisons revealed proliferation of selcys-transfer RNA genes and broad transcriptional upregulation across anti-oxidative selenoproteins, signifying their prominent role in mitigating oxidative stress in the oxygen-rich Southern Ocean. We found expansion of transposable elements, temporally correlated to Antarctic notothenioid diversification. Additionally, the toothfish exhibited remarkable shifts in genetic programs towards enhanced fat cell differentiation and lipid storage, and promotion of chondrogenesis while inhibiting osteogenesis in bone development, collectively contributing to the achievement of neutral buoyancy and pelagicism. Our study revealed a comprehensive landscape of evolutionary changes essential for Antarctic notothenioid cold adaptation and ecological expansion. The 2 genomes are valuable resources for further exploration of mechanisms underlying the spectacular notothenioid radiation in the coldest marine environment.


The role of natural products in modern drug discovery.
The global medicine market is about 1.1 trillion US dollars. About 35 percent of medicines have originated from natural products. Brazil presents the largest biodiversity in the world, with more than 50,000 species of higher plants. However, few innovative products have been developed in Brazil from active constituents derived from the Brazilian biodiversity. Scientific evidences on plants and venoms have been internationally published by Brazilian scientists over the last 4 decades; but few examples of innovative products are commercially available. Few examples include the anti-hypertensive drug captopril first identified in the venom of the Brazilian viper Bothrops jararaca by Professor Sergio Ferreira; and some phytotherapeutic agents such as Acheflan®, Syntocalmy® and Melagrião® produced by standardized plant extracts with scientific proof of safety, efficacy and quality. Still, only Acheflan® and Melagrião® are obtained from native Brazilian plants. Several issues contribute to the lack of innovative products from the Brazilian biodiversity, but in my opinion, the most challenging ones are i) the lack of specific regulations to allow researchers and companies to access biodiversity for the purposes of scientific and technological innovation; and ii) the absence of a long-term government program to support research and innovation in this field.


Molecular biology of the natriuretic peptides and their receptors.
After the description in the past 5 years of BNP and CNP, interest in the natriuretic peptide family has dramatically increased. Molecular characterization of the receptors for this hormone family has identified a heterogeneity in the receptor subtypes not previously alluded to by pharmacological or biochemical studies. Much has been published on the physiology of ANP, but the major roles for BNP and CNP remain to be elucidated. Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP. Localization studies have implied that CNP is the most prominent neuropeptide in the natriuretic peptide family, and the restriction of its receptor, NPR-B, to the nervous system suggests that CNP and NPR-B may act in the brain to coordinate the central aspects of body fluid homeostasis. Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP. The domain within these receptors that has high homology to protein kinases has been demonstrated to be essential for regulating this activity. No kinase activity has been measured in these proteins, but it is possible that this region is important for ATP regulation of guanylyl cyclase activity. This possibility raises interesting parallels with receptor-mediated cAMP signaling within cells. Seven transmembrane receptors, once activated by ligand, associate with G proteins to affect the activity of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical application of a combination therapy of lentinan, multi-electrode RFA and TACE in HCC.
Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide and there is a clear need for further treatment options. In this study, we assessed the efficacy of a combination of lentinan (a fungal extract), transcatheter arterial chemoembolisation (TACE) and radiofrequency ablation (RFA) in HCC patients. Seventy-eight patients with HCC confirmed by pathology and iconographical checks were used in this study. A total of 136 tumours with a mean diameter of 6.5 cm were detected (standard deviation [SD]+/-0.7). Subjects were divided into four groups, receiving either TACE only, RFA only, RFA and TACE, or the combination group - receiving lentinan, RFA and TACE. The tumour necrosis was significantly higher in the combination group (88.6%), compared to the TACE group (37.5%), the RFA group (47.8%) and the TACE/RFA group (60.3%; P<0.05). The tumour recurrence rate was significantly lower in the combination group (17.8%), compared to the TACE group (45.8%), the RFA group (34.7%) and the TACE/RFA group (29.0%; P<0.05). Finally, mean survival duration was significantly higher in the combination group (28.2 months; P<0.05). Combination therapy involving lentinan, RFA and TACE was beneficial in terms of increasing mean survival duration, tumour necrosis and reducing the recurrence rate. Lentinan may therefore be of benefit to HCC patients.


Introduction to the Special Issue: The role of seed dispersal in plant populations: perspectives and advances in a changing world.
Despite the importance of seed dispersal as a driving process behind plant community assembly, our understanding of the role of seed dispersal in plant population persistence and spread remains incomplete. As a result, our ability to predict the effects of global change on plant populations is hampered. We need to better understand the fundamental link between seed dispersal and population dynamics in order to make predictive generalizations across species and systems, to better understand plant community structure and function, and to make appropriate conservation and management responses related to seed dispersal. To tackle these important knowledge gaps, we established the CoDisperse Network and convened an interdisciplinary, NSF-sponsored Seed Dispersal Workshop in 2016, during which we explored the role of seed dispersal in plant population dynamics (NSF DEB Award # 1548194). In this Special Issue, we consider the current state of seed dispersal ecology and identify the following collaborative research needs: (i) the development of a mechanistic understanding of the movement process influencing dispersal of seeds; (ii) improved quantification of the relative influence of seed dispersal on plant fitness compared to processes occurring at other life history stages; (iii) an ability to scale from individual plants to ecosystems to quantify the influence of dispersal on ecosystem function; and (iv) the incorporation of seed dispersal ecology into conservation and management strategies.


Radiative transfer for a three-dimensional raining cloud.
Satellite-sensor-based microwave brightness temperatures for a three-dimensional raining cloud over a reflecting surface are computed by using a radiative transfer model based on the discrete-ordinates solution procedure. The three-dimensional model applied to a plane layer is validated by comparison with results from a one-dimensional model that is available in the literature. Results examining the effects of cloud height, rainfall rate, surface reflectance, rainfall footprint area, and satellite viewing position on one- and three-dimensional brightness temperature calculations are reported. The numerical experiments indicate that, under certain conditions, three-dimensional effects are significant in the analysis of satellite-sensor-based rainfall retrieval algorithms. The results point to the need to consider carefully three-dimensional effects as well as surface reflectance effects when interpreting satellitemeasured radiation data.


Managed care market share and primary treatment for cancer.
Increases in the market share of managed care are associated with decreases in expenditures in the fee-for-service sector. To understand utilization patterns responsible for such savings, we assessed whether increases in managed care market share were related to increases in receipt of equally effective but less costly primary cancer therapies. Cancer registry data linked to Medicare administrative data for a population-based sample of fee-for-service Medicare beneficiaries 66 years and older who were diagnosed with breast or prostate cancer during 1993-1999. We used fixed-effects regression models to assess whether county-level increases in the market share of managed care were associated with differences in receipt of cancer therapies that are similar in effectiveness but vary in cost. Increases in the market share of managed care were not associated with differences in the receipt of mastectomy versus breast-conserving surgery with radiation for women with early stage breast cancer (p=.47) or with the receipt of conservative therapy (versus surgery or radiation therapy) for men with local or regional prostate cancer (p=.30). Increases in the market share of managed care do not appear to influence the receipt of equally effective primary treatments for cancer in the fee-for-service sector.


The effect of a brief family intervention on primary carer's functioning and their schizophrenic relatives levels of psychopathology in India.
This study examined the short term effects of a brief familial intervention on schizophrenic the patient's levels of psychopathology and their primary caregiver's functioning in India. Caregiver functioning was measured by the caregiver's levels of burden and coping along with the patient's perceived level of expressed emotion (EE). The participants were 18 schizophrenic patients and their related primary carer from a medical facility in India. The patients' levels of psychopathology and EE were assessed at baseline and at completion of the study with the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) and the Family Emotional Involvement And Criticism Scale (FEICS; Shields et al., 1992), respectively. The primary caregiver's levels of burden and coping were also measured at baseline and upon completion of the study by the Burden Assessment Scale (BAS; Thara et al., 1998) and the Family Crisis Oriented Personal Evaluation Scale (F-COPES; McCubbin et al., 1981), respectively. The brief intervention was comprised of 3 one hour sessions aimed at educating the primary caregiver and patient about schizophrenia; along with improving their communication, problem solving skills and expression of emotions. A significant improvement was found between baseline and the final 3-month follow-up on measures of psychopathology for the patients, as well as family functioning for both the caregivers and patients. The implications of the findings are discussed, along with future research directions.


Connectivity sustains disease transmission in environments with low potential for endemicity: modelling schistosomiasis with hydrologic and social connectivities.
Social interaction and physical interconnections between populations can influence the spread of parasites. The role that these pathways play in sustaining the transmission of parasitic diseases is unclear, although increasingly realistic metapopulation models are being used to study how diseases persist in connected environments. We use a mathematical model of schistosomiasis transmission for a distributed set of heterogeneous villages to show that the transport of parasites via social (host movement) and environmental (parasite larvae movement) pathways has consequences for parasite control, spread and persistence. We find that transmission can be sustained regionally throughout a group of connected villages even when individual village conditions appear not to support endemicity. Optimum transmission is determined by an interplay between different transport pathways, and not necessarily by those that are the most dispersive (e.g. disperse social contacts may not be optimal for transmission). We show that the traditional targeting of villages with high infection, without regard to village interconnections, may not lead to optimum control. These findings have major implications for effective disease control, which needs to go beyond considering local variations in disease intensity, to also consider the degree to which populations are interconnected.


Exploring socio-cultural factors that mediate, facilitate, & constrain the health and empowerment of refugee youth.
Studies on youth health and well-being are predominantly quantitative and expert-driven with less attention given to how youth understand what it means to be healthy themselves and the role of socio-cultural factors in shaping this. Knowledge on the perceptions and experiences of refugee youth is particularly lacking and notable given their unique stressors related to migratory, settlement and integration experiences. We contribute a better understanding of how refugee youth themselves define and contextualize health, with particular emphasis given to socio-cultural factors that enable or constrain health promotion efforts and individual health agency. This research was undertaken at a downtown drop-in centre in Hamilton, Ontario, Canada that provided settlement and integration services to newcomer youth. We employ a grounded theory approach and draw upon participant observation, focus groups and in-depth interviews. Twenty-six youth (age 18-25 years), representing 12 different countries of origin participated. The youth defined health very broadly touching upon many typical determinants of health (e.g. education, income, etc.). Yet factors of most importance (as demonstrated by the frequency and urgency in which they were discussed by youth) included a sense of belonging, positive self-identity, emotional well-being, and sense of agency or self-determination. We conceptualize these as "mediating" factors given the youth argued they enabled or constrained their ability to cope with adversities related to other health determinant categories. The youth also discussed what we interpret as "facilitators" that encourage mediating factors to manifest positively (e.g. informal, non-biomedical settings and programs that nurture trust, break down access barriers, and promote a sense of community amongst peers, mentors, and health professionals). When creating health promotion strategies for refugee youth (and perhaps youth more generally) it is important to understand the factors that may mediate the magnitude of effects from various risks/stressors, in addition to those which facilitate health agency.


Flexible evaluation of surrogacy in platform studies.
Trial-level surrogates are useful tools for improving the speed and cost effectiveness of trials but surrogates that have not been properly evaluated can cause misleading results. The evaluation procedure is often contextual and depends on the type of trial setting. There have been many proposed methods for trial-level surrogate evaluation, but none, to our knowledge, for the specific setting of platform studies. As platform studies are becoming more popular, methods for surrogate evaluation using them are needed. These studies also offer a rich data resource for surrogate evaluation that would not normally be possible. However, they also offer a set of statistical issues including heterogeneity of the study population, treatments, implementation, and even potentially the quality of the surrogate. We propose the use of a hierarchical Bayesian semiparametric model for the evaluation of potential surrogates using nonparametric priors for the distribution of true effects based on Dirichlet process mixtures. The motivation for this approach is to flexibly model relationships between the treatment effect on the surrogate and the treatment effect on the outcome and also to identify potential clusters with differential surrogate value in a data-driven manner so that treatment effects on the surrogate can be used to reliably predict treatment effects on the clinical outcome. In simulations, we find that our proposed method is superior to a simple, but fairly standard, hierarchical Bayesian method. We demonstrate how our method can be used in a simulated illustrative example (based on the ProBio trial), in which we are able to identify clusters where the surrogate is, and is not useful. We plan to apply our method to the ProBio trial, once it is completed.


The incomplete natural history of mitochondria.
Mitochondrial DNA (mtDNA) has been used to study molecular ecology and phylogeography for 25 years. Much important information has been gained in this way, but it is time to reflect on the biology of the mitochondrion itself and consider opportunities for evolutionary studies of the organelle itself and its ecology, biochemistry and physiology. This review has four sections. First, we review aspects of the natural history of mitochondria and their DNA to show that it is a unique molecule with specific characteristics that differ from nuclear DNA. We do not attempt to cover the plethora of differences between mitochondrial and nuclear DNA; rather we spotlight differences that can cause significant bias when inferring demographic properties of populations and/or the evolutionary history of species. We focus on recombination, effective population size and mutation rate. Second, we explore some of the difficulties in interpreting phylogeographical data from mtDNA data alone and suggest a broader use of multiple nuclear markers. We argue that mtDNA is not a sufficient marker for phylogeographical studies if the focus of the investigation is the species and not the organelle. We focus on the potential bias caused by introgression. Third, we show that it is not safe to assume a priori that mtDNA evolves as a strictly neutral marker because both direct and indirect selection influence mitochondria. We outline some of the statistical tests of neutrality that can, and should, be applied to mtDNA sequence data prior to making any global statements concerning the history of the organism. We conclude with a critical examination of the neglected biology of mitochondria and point out several surprising gaps in the state of our knowledge about this important organelle. Here we limelight mitochondrial ecology, sexually antagonistic selection, life-history evolution including ageing and disease, and the evolution of mitochondrial inheritance.


Stereoscopic processing of absolute and relative disparity in human visual cortex.
Stereoscopic vision relies mainly on relative depth differences between objects rather than on their absolute distance in depth from where the eyes fixate. However, relative disparities are computed from absolute disparities, and it is not known where these two stages are represented in the human brain. Using functional MRI (fMRI), we assessed absolute and relative disparity selectivity with stereoscopic stimuli consisting of pairs of transparent planes in depth in which the absolute and relative disparity signals could be independently manipulated (at a local spatial scale). In experiment 1, relative disparity was kept constant, while absolute disparity was varied in one-half the blocks of trials ("mixed" blocks) and kept constant in the remaining one-half ("same" blocks), alternating between blocks. Because neuronal responses undergo adaptation and reduce their firing rate following repeated presentation of an effective stimulus, the fMRI signal reflecting activity of units selective for absolute disparity is expected to be smaller during "same" blocks as compared with "mixed" ones. Experiment 2 similarly manipulated relative disparity rather than absolute disparity. The results from both experiments were consistent with adaptation with differential effects across visual areas such that 1) dorsal areas (V3A, MT+/V5, V7) showed more adaptation to absolute than to relative disparity; 2) ventral areas (hV4, V8/V4alpha) showed an equal adaptation to both; and 3) early visual areas (V1, V2, V3) showed a small effect in both experiments. These results indicate that processing in dorsal areas may rely mostly on information about absolute disparities, while ventral areas split neural resources between the two types of stereoscopic information so as to maintain an important representation of relative disparity.


Significance of Dopaminergic Gene Variants in the Male Biasness of ADHD.
ADHD is frequently detected in boys though there is no established cause. One possibility is that genes predisposing to ADHD have sexually dimorphic effects. With an aim to find out the reason for this male biasness, contribution of 14 functional polymorphisms was investigated in ADHD subjects. Genomic DNA of probands, their parents, and ethnically matched controls was subjected to analysis of single-nucleotide polymorphisms and variable number of tandem repeats (VNTRs). Case-control analysis revealed significant higher occurrence of DAT1 intron 8 VNTR "5R" allele ( p = .028), DBH rs1108580 "A" allele ( p = .027), and MAOA-u VNTR-rs6323 3R-T haplotype ( p = .007) in male probands. Family-based analysis showed significant preferential transmission of Dopamine receptor D4 exon 3 VNTR-rs1800955 7R-T haplotype from parents to male probands ( p = .008). Interaction between DBH gene variants and low enzymatic activity was also noticed, especially in male probands. Data obtained may partly answer the male biasness of ADHD.


Three-sphere low-Reynolds-number swimmer with a passive elastic arm.
One of the simplest model swimmers at low Reynolds number is the three-sphere swimmer by Najafi and Golestanian. It consists of three spheres connected by two rods which change their lengths periodically in non-reciprocal fashion. Here we investigate a variant of this model in which one rod is periodically actuated while the other is replaced by an elastic spring. We show that the competition between the elastic restoring force and the hydrodynamic drag produces a delay in the response of the passive elastic arm with respect to the active one. This leads to non-reciprocal shape changes and self-propulsion. After formulating the equations of motion, we study their solutions qualitatively and numerically. The leading-order term of the solution is computed analytically. We then address questions of optimization with respect to both actuation frequency and swimmer's geometry. Our results can provide valuable conceptual guidance in the engineering of robotic microswimmers.


Impaired binding of standard initiation factors eIF3b, eIF4G and eIF4B to domain V of the live-attenuated coxsackievirus B3 Sabin3-like IRES--alternatives for 5'UTR-related cardiovirulence mechanisms.
Internal ribosome entry site (IRES) elements fold into highly organized conserved secondary and probably tertiary structures that guide the ribosome to an internal site of the RNA at the IRES 3'end. The composition of the cellular proteome is under the control of multiple processes, one of the most important being translation initiation. In each poliovirus Sabin vaccine strain, a single point mutation in the IRES secondary-structure domain V is a major determinant of neurovirulence and translation attenuation. Here we are extrapolating poliovirus findings to a genomic related virus named coxsackievirus B3 CVB3); a causative agent of viral myocarditis. We have previously reported that Sabin3-like mutation (U473 → C) introduced in the domain V sequence of the CVB3 IRES led to a defective mutant with a serious reduction in translation efficiency and ribosomal initiation complex assembly, besides an impaired RNA-protein binding pattern. With the aim to identify proteins interacting with both CVB3 wild-type and Sabin3-like domain V RNAs and to assess the effect of the Sabin3-like mutation on these potential interactions, we have used a proteomic approach. This procedure allowed the identification of three RNA-binding proteins interacting with the domain V: eIF4G (p220), eIF3b (p116) and eIF4B (p80). Moreover, we report that this single-nucleotide exchange impairs the interaction pattern and the binding affinity of these standard translation initiation factors within the IRES domain V of the mutant strain. Taken together, these data indicate how this decisive Sabin3-like mutation mediates viral translation attenuation; playing a key role in the understanding of the cardiovirulence attenuation within this construct. Hence, these data provide further evidence for the crucial role of RNA structure for the IRES activity, and reinforce the idea of a distribution of function between the different IRES structural domains. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6160165131045880.


Routine follow up of breast cancer in primary care: randomised trial.
To assess the effect on time to diagnosis of recurrence and on quality of life of transferring primary responsibility for follow up of women with breast cancer in remission from hospital to general practice. Randomised controlled trial with 18 month follow up in which women received routine follow up either in hospital or in general practice. 296 women with breast cancer in remission receiving regular follow up care at district general hospitals in England. Time between first presentation of symptoms to confirmation of recurrence; quality of life measured by specific dimensions of the SF-36 schedule, the EORTC symptom scale, and hospital anxiety and depression scale. Most recurrences (18/26, 69%) presented as interval events, and almost half (7/16, 44%) of the recurrences in the hospital group presented first to general practice. The median time to hospital confirmation of recurrence was 21 days in the hospital group (range 1-376 days) and 22 days in the general practice group (range 4-64). The differences between groups in the change in SF-36 mean scores from baseline were small: -1.8 (95% confidence interval -7.2 to 3.5) for social functioning, 0.5 (-4.1 to 5.1) for mental health, and 0.6 (-3.6 to 4.8) for general health perception. The change from baseline in the mean depression score was higher in the general practice group at the mid-trial assessment (difference 0.6, 0.1 to 1.2) but there was no significant difference between groups in the anxiety score or the EORTC scales. General practice follow up of women with breast cancer in remission is not associated with increase in time to diagnosis, increase in anxiety, or deterioration in health related quality of life. Most recurrences are detected by women as interval events and present to the general practitioner, irrespective of continuing hospital follow up.


Iranian and Swedish adolescents: differences in personality traits and well-being.
Introduction. This study addresses the need to further contextualize research on well-being (e.g., Kjell, 2011) in terms of cross-cultural aspects of personality traits among adolescents and by examining two different conceptualizations of well-being: subjective well-being (i.e., life satisfaction, positive and negative affect) and psychological well-being (i.e., positive relations with others, environmental mastery, self-acceptance, autonomy, personal growth, and life purpose). Methods. Iranian (N = 122, mean age 15.23 years) and Swedish (N = 109, mean age 16.69 years) adolescents were asked to fill out a Big Five personality test, as well as questionnaires assessing subjective well-being and psychological well-being. Results. Swedes reported higher subjective and psychological well-being, while Iranians reported higher degree of Agreeableness, Openness and Conscientiousness. Neuroticism and Extraversion did not differ between cultures. Neuroticism was related to well-being within both cultures. Openness was related to well-being only among Iranians, and Extraversion only among Swedes. A mediation analysis within the Swedish sample, the only sample meeting statistical criteria for mediation analysis to be conducted, demonstrated that psychological well-being mediated the relationship between Neuroticism and subjective well-being as well as between Extraversion and subjective well-being. Conclusions. Certain personality traits, such as Extraversion, Openness, and Conscientiousness, relate differently to well-being measures across cultures. Meanwhile, Neuroticism seems to relate similarly across cultures at least with regard to subjective well-being. Furthermore, the results give an indication on how psychological well-being might mediate the relationship between certain personality traits and subjective well-being. Overall, the complexity of the results illustrates the need for more research whilst supporting the importance of contextualizing well-being research.


Electrophysiology of pancreatic β-cells in intact mouse islets of Langerhans.
When exposed to intermediate glucose concentrations (6-16 mol/l), pancreatic β-cells in intact islets generate bursts of action potentials (superimposed on depolarised plateaux) separated by repolarised electrically silent intervals. First described more than 40 years ago, these oscillations have continued to intrigue β-cell electrophysiologists. To date, most studies of β-cell ion channels have been performed on isolated cells maintained in tissue culture (that do not burst). Here we will review the electrophysiological properties of β-cells in intact, freshly isolated, mouse pancreatic islets. We will consider the role of ATP-regulated K⁺-channels (K(ATP)-channels), small-conductance Ca²⁺-activated K⁺-channels and voltage-gated Ca²⁺-channels in the generation of the bursts. Our data indicate that K(ATP)-channels not only constitute the glucose-regulated resting conductance in the β-cell but also provide a variable K⁺-conductance that influence the duration of the bursts of action potentials and the silent intervals. We show that inactivation of the voltage-gated Ca²⁺-current is negligible at voltages corresponding to the plateau potential and consequently unlikely to play a major role in the termination of the burst. Finally, we propose a model for glucose-induced β-cell electrical activity based on observations made in intact pancreatic islets.


The contribution of astrocytes to the 18F-2-deoxyglucose signal in PET activation studies.
With the development of functional brain imaging techniques such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) it has become possible to visualize brain areas that are activated by a variety of sensory, motor or cognitive tasks. This technological progress has permitted a kind of in vivo functional neuroanatomy which has led to the identification of neural circuits subserving specific brain functions. Metabolic processes linked to neuronal activity--such as blood flow, glucose utilization and oxygen consumption--provide the signals detected with most functional brain-imaging techniques. These metabolic indices have been examined in a variety of psychiatric and neurological disorders. This article focuses on the use of (18F)fluoro-2-deoxyglucose (FDG)-PET in the study of psychiatric disorders; it is mainly intended to bring a novel perspective, based on recent experimental data, on the cellular and molecular mechanisms that underlie the FDG-based PET imaging. These new observations point to a critical role of a particular glial cell type, the astrocyte, in coupling neuronal activity to glucose utilization. Indeed it appears that in response to glutamate released by active neurons, glucose is predominantly taken up by specialized astrocytic processes, the end-feet, which surround brain capillaries; glucose is then metabolized to lactate, which provides a preferred energy substrate for neurons. These data support the notion that astrocytes markedly contribute to the FDG-PET signal. This perspective may also provide renewed insights for the interpretation of FDG-PET studies in psychiatric disorders.


Tetracycline-inducible packaging cell line for production of flavivirus replicon particles.
We have previously developed replicon vectors derived from the Australian flavivirus Kunjin that have a unique noncytopathic nature and have been shown to direct prolonged high-level expression of encoded heterologous genes in vitro and in vivo and to induce strong and long-lasting immune responses to encoded immunogens in mice. To facilitate further applications of these vectors in the form of virus-like particles (VLPs), we have now generated a stable BHK packaging cell line, tetKUNCprME, carrying a Kunjin structural gene cassette under the control of a tetracycline-inducible promoter. Withdrawal of tetracycline from the medium resulted in production of Kunjin structural proteins that were capable of packaging transfected and self-amplified Kunjin replicon RNA into the secreted VLPs at titers of up to 1.6 x 10(9) VLPs per ml. Furthermore, secreted KUN replicon VLPs from tetKUNCprME cells could be harvested continuously for as long as 10 days after RNA transfection, producing a total yield of more than 10(10) VLPs per 10(6) transfected cells. Passaging of VLPs on Vero cells or intracerebral injection into 2- to 4-day-old suckling mice illustrated the complete absence of any infectious Kunjin virus. tetKUNCprME cells were also capable of packaging replicon RNA from closely and distantly related flaviviruses, West Nile virus and dengue virus type 2, respectively. The utility of high-titer KUN replicon VLPs was demonstrated by showing increasing CD8(+)-T-cell responses to encoded foreign protein with increasing doses of KUN VLPs. A single dose of 2.5 x 10(7) VLPs carrying the human respiratory syncytial virus M2 gene induced 1,400 CD8 T cells per 10(6) splenocytes in an ex vivo gamma interferon enzyme-linked immunospot assay. The packaging cell line thus represents a significant advance in the development of the noncytopathic Kunjin virus replicon-based gene expression system and may be widely applicable to the basic studies of flavivirus RNA packaging and virus assembly as well as to the development of gene expression systems based on replicons from different flaviviruses.


Mood, anxiety and psychotic phenomena measure a common psychopathological factor.
Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying 'common mental distress' (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information. We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state. In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was significantly associated with the prior parental measure. Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.


Antimicrobial resistance of bacteria isolated from patients with bloodstream infections at a tertiary care hospital in the Democratic Republic of the Congo.
Bloodstream infection (BSI) is a life-threatening condition that requires rapid antimicrobial treatment. We determined the prevalence of bacterial isolates associated with BSI at Bukavu General Hospital (BGH), South Kivu Province, Democratic Republic of the Congo, and their patterns of susceptibility to antimicrobial drugs, from February 2013 to January 2014. We cultured 112 clinically relevant isolates from 320 blood cultures. Of these isolates, 104 (92.9%) were Gram-negative bacteria (GNB), with 103 bacilli (92.0%) and one coccus (0.9%). Among GNB, Escherichia coli (51.9%), Klebsiella spp. (20.2%), Enterobacter spp. (6.7%), Shigella spp. (5.8%) and Salmonella spp. (4.8%) were the most frequent agents causing BSIs. Other GNB isolates included Proteus spp., Citrobacter spp. and Pseudomonas aeruginosa (both 2.9%), and Acinetobacter spp. and Neisseria spp. (both 0.9%). High rates of resistance to co-trimoxazole (100%), erythromycin (100%) and ampicillin (66.7-100%) and moderate to high resistance to ciprofloxacin, ceftazidime, ceftriaxone, cefuroxime and cefepime were observed among GNB. Furthermore, there were high rates of multidrug resistance and of extended-spectrum β-lactamase (ESBL) production phenotype among Enterobacteriaceae. Gram-positive bacteria included three Staphylococcus aureus isolates (2.7%), four oxacillin-resistant coagulase-negative staphylococci (CoNS) isolates (3.6%) and one Streptococcus pneumoniae (0.9%). No oxacillin-resistant S. aureus was isolated. Among clinically relevant staphylococci, susceptibility to co-trimoxazole and ampicillin was low (0-25%). In addition, 58 contaminant CoNS were isolated from blood cultures, and the calculated ratio of contaminants to pathogens in blood cultures was 1:2. Multidrug-resistant and ESBL-producing GNB are the leading cause of BSI at BGH.


Prevalence and social correlates of cardiovascular disease risk factors in Harlem.
This study examined the prevalence, social correlates, and clustering of cardiovascular disease risk factors in a predominantly Black, poor, urban community. Associations of risk factor prevalences with sociodemographic variables were examined in a population-based sample of 695 men and women aged 18 to 65 years living in Central Harlem. One third of the men and women were hypertensive, 48% of the men and 41% of the women were smokers, 25% of the men and 49% of the women were overweight, and 23% of the men and 35% of the women reported no leisure-time physical activity over the past month. More than 80% of the men and women had at least 1 of these risk factors, and 9% of the men and 19% of the women had 3 or more risk factors. Income and education were inversely related to hypertension, smoking, and physical inactivity. Having 3 or more risk factors was associated with low income and low education (extreme odds ratio [OR] = 10.2, 95% confidence interval [CI] = 3.0, 34.5 for education; OR = 3.7, CI = 1.6, 8.9 for income) and with a history of unstable work or of homelessness. Disadvantaged, urban communities are at high risk for cardiovascular disease. These results highlight the importance of socioenvironmental factors in shaping cardiovascular risk.


Effects of hepatic function on vancomycin pharmacokinetics in patients with cancer.
Vancomycin is widely used in the prophylaxis and treatment of infections in neutropenic patients with cancer. The objective of this study was to analyze liver damage effects on vancomycin pharmacokinetics and determine the necessity for liver function evaluation when selecting vancomycin dosing schedules in these patients. A population pharmacokinetic analysis was performed using the global two-stage method. To this purpose serum vancomycin concentrations from 154 cancer patients were measured and individual vancomycin pharmacokinetic parameters were estimated by the Sawchuk and Zaske method. Mean and standard deviation of the vancomycin pharmacokinetic parameters were estimated for various subgroups of patients classified according to the degree of liver damage. Then a multiple linear regression analysis was performed to select the best predictive models for vancomycin clearance (Clvan) and steady state distribution volume (V). Results revealed that Clvan is not influenced by liver failure. Differences in V between patients with and without hepatic failure were initially observed, but these disappeared when patients with ascites were excluded. In conclusion, vancomycin dosing schedule does not need to be modified for patients with liver failure, with the exception of patients with ascites.


Side-chain repacking calculations for predicting structures and stabilities of heterodimeric coiled coils.
An important goal in biology is to predict from sequence data the high-resolution structures of proteins and the interactions that occur between them. In this paper, we describe a computational approach that can make these types of predictions for a series of coiled-coil dimers. Our method comprises a dual strategy that augments extensive conformational sampling with molecular mechanics minimization. To test the performance of the method, we designed six heterodimeric coiled coils with a range of stabilities and solved x-ray crystal structures for three of them. The stabilities and structures predicted by the calculations agree very well with experimental data: the average error in unfolding free energies is <1 kcal/mol, and nonhydrogen atoms in the predicted structures superimpose onto the experimental structures with rms deviations <0.7 A. We have also tested the method on a series of homodimers derived from vitellogenin-binding protein. The predicted relative stabilities of the homodimers show excellent agreement with previously published experimental measurements. A critical step in our procedure is to use energy minimization to relax side-chain geometries initially selected from a rotamer library. Our results show that computational methods can predict interaction specificities that are in good agreement with experimental data.


Biomarkers in maternal and newborn blood indicate heightened fetal susceptibility to procarcinogenic DNA damage.
Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) are widespread air contaminants released by transportation vehicles, power generation, and other combustion sources. Experimental evidence indicates that the developing fetus is more susceptible than the adult to carcinogenic effects of PAHs, although laboratory studies in rodents suggest that the dose to fetal tissues is an order of magnitude lower than that to maternal tissues. To assess fetal versus adult susceptibility to PAHs and environmental tobacco smoke (ETS), we compared carcinogen-DNA adducts (a biomarker associated with increased cancer risk) and cotinine (a biomarker of tobacco smoke exposure) in paired blood samples collected from mothers and newborns in New York City. We enrolled 265 nonsmoker African-American and Latina mother-newborn pairs in New York City between 1997 and 2001 (estimated average ambient air BaP concentrations < 0.5 ng/m3). Despite the estimated 10-fold lower fetal dose, mean levels of BaP-DNA adducts as determined by high-performance liquid chromatography-fluorescence were comparable in paired New York City newborn and maternal samples (0.24 adducts per 10(8) nucleotides, 45% of newborns with detectable adducts vs. 0.22 per 10(8) nucleotides, 41% of mothers with detectable adducts). However, by the Wilcoxon signed-rank test, the levels in newborns were higher (p = 0.02). Mean cotinine was higher in newborns than in mothers (1.7 ng/mL, 47% detectable vs. 1.28 ng/mL, 44% detectable). Consistent with our prior study in a Caucasian Polish population, these results indicate increased susceptibility of the fetus to DNA damage and reduced ability to clear ETS constituents. The findings have implications for risk assessment, given the need to protect children as a sensitive subset of the population.


A device for sampling of human alveolar breath for the measurement of expired volatile organic compounds.
This report describes the development of a portable spirometer capable of collecting primarily alveolar breath into 1.8-L canisters for subsequent gas chromatographic/mass spectrometric (GC/MS) analysis. Based on CO2 measurements, greater than 97% of the breath collected is alveolar in origin. Sample collection takes place in approximately two minutes. Clean air for inhalation is provided by two organic vapor respirator cartridges. Studies of the breakthrough volume of test compounds at both the 5- and 50-micrograms/m3 levels indicate that each cartridge filter can be used to sample over 300 L of air and that this volume is not altered by intermittent use and storage of the filter for up to five days. In experiments designed to mimic human breathing, recoveries of test compounds through the device at the 5-mu/m3 level ranged from 87 to 112%. Essentially no volatile organic compound (VOC) memory (i.e., adsorption carryover by the device) was measured at the 50-micrograms/m3 level. The data suggest that the device can be used successfully for organic compounds with volatilities greater than that of p-dichlorobenzene.


Tomographic Imaging of a Forested Area By Airborne Multi-Baseline P-Band SAR.
In recent years, various attempts have been undertaken to obtain information about the structure of forested areas from multi-baseline synthetic aperture radar data. Tomographic processing of such data has been demonstrated for airborne L-band data but the quality of the focused tomographic images is limited by several factors. In particular, the common Fourierbased focusing methods are susceptible to irregular and sparse sampling, two problems, that are unavoidable in case of multi-pass, multi-baseline SAR data acquired by an airborne system. In this paper, a tomographic focusing method based on the time-domain back-projection algorithm is proposed, which maintains the geometric relationship between the original sensor positions and the imaged target and is therefore able to cope with irregular sampling without introducing any approximations with respect to the geometry. The tomographic focusing quality is assessed by analysing the impulse response of simulated point targets and an in-scene corner reflector. And, in particular, several tomographic slices of a volume representing a forested area are given. The respective P-band tomographic data set consisting of eleven flight tracks has been acquired by the airborne E-SAR sensor of the German Aerospace Center (DLR).


A novel method for reliable and fast extraction of neuronal EEG/MEG oscillations on the basis of spatio-spectral decomposition.
Neuronal oscillations have been shown to underlie various cognitive, perceptual and motor functions in the brain. However, studying these oscillations is notoriously difficult with EEG/MEG recordings due to a massive overlap of activity from multiple sources and also due to the strong background noise. Here we present a novel method for the reliable and fast extraction of neuronal oscillations from multi-channel EEG/MEG/LFP recordings. The method is based on a linear decomposition of recordings: it maximizes the signal power at a peak frequency while simultaneously minimizing it at the neighboring, surrounding frequency bins. Such procedure leads to the optimization of signal-to-noise ratio and allows extraction of components with a characteristic "peaky" spectral profile, which is typical for oscillatory processes. We refer to this method as spatio-spectral decomposition (SSD). Our simulations demonstrate that the method allows extraction of oscillatory signals even with a signal-to-noise ratio as low as 1:10. The SSD also outperformed conventional approaches based on independent component analysis. Using real EEG data we also show that SSD allows extraction of neuronal oscillations (e.g., in alpha frequency range) with high signal-to-noise ratio and with the spatial patterns corresponding to central and occipito-parietal sources. Importantly, running time for SSD is only a few milliseconds, which clearly distinguishes it from other extraction techniques usually requiring minutes or even hours of computational time. Due to the high accuracy and speed, we suggest that SSD can be used as a reliable method for the extraction of neuronal oscillations from multi-channel electrophysiological recordings.


Vitamin D deficiency is associated with hepatic decompensation and inflammation in patients with liver cirrhosis: A prospective cohort study.
Vitamin D is required to maintain the integrity of the intestinal barrier and inhibits inflammatory signaling pathways. Vitamin D deficiency might be involved in cirrhosis-associated systemic inflammation and risk of hepatic decompensation in patients with liver cirrhosis. Outpatients of the Hepatology Unit of the University Hospital Frankfurt with advanced liver fibrosis and cirrhosis were prospectively enrolled. 25-hydroxyvitamin D (25(OH)D3) serum concentrations were quantified and associated with markers of systemic inflammation / intestinal bacterial translocation and hepatic decompensation. A total of 338 patients with advanced liver fibrosis or cirrhosis were included. Of those, 51 patients (15%) were hospitalized due to hepatic decompensation during follow-up. Overall, 72 patients (21%) had severe vitamin D deficiency. However, patients receiving vitamin D supplements had significantly higher 25(OH)D3 serum levels compared to patients without supplements (37 ng/mL vs. 16 ng/ml, P<0.0001). Uni- and multivariate analyses revealed an independent association of severe vitamin D deficiency with the risk of hepatic decompensation during follow-up (multivariate P = 0.012; OR = 3.25, 95% CI = 1.30-8.2), together with MELD score, low hemoglobin concentration, low coffee consumption, and presence of diabetes. Of note, serum levels of C-reactive protein, IL-6 and soluble CD14 were significantly higher in patients with versus without severe vitamin D deficiency, and serum levels of soluble CD14 levels declined in patients with de novo supplementation of vitamin D (median 2.15 vs. 1.87 ng/mL, P = 0.002). In this prospective cohort study, baseline vitamin D levels were inversely associated with liver-cirrhosis related systemic inflammation and the risk of hepatic decompensation.


234Th and 7Be as tracers for transport and sources of particle-associated contaminants in the Hudson River Estuary.
The natural radionuclides 234Th and 7Be have known sources in estuaries and strongly and rapidly associate with particles. They are thus good tracers of the transport and sources of particles in the suspended sediment reservoir, and, by implication, of particle-associated contaminants such as heavy metals. In the Hudson River estuary, 234Th is produced from decay of dissolved 238U, which varies linearly with salinity, while 7Be is added directly to the estuary from the atmosphere. The 234Th/7Be activity ratio eliminates variations in radionuclide specific activities that result from changes in sediment grain size or composition. Sampling in the Hudson under conditions of low and high river flow shows that 234Th/7Be in suspended sediment increases from low salinity to higher salinity waters at all sampling times. The Th/Be activity ratio may thus be used as a tracer of where particles are labeled with these radionuclides in the estuary and of the relative importance of resuspension and particle transport through the estuary. The distribution of heavy metals in the suspended sediment reservoir can be compared with that of 234Th/7Be by normalizing the metals to Fe. Iron and Al are well correlated in suspended sediments of the Hudson, indicating that either element can be used to normalize grain size effects on specific concentrations of metals. Ratios of Ag and Pb to Fe in suspended particles generally increase down-estuary at all sampling times, whereas Cu, Zn and Cd-to-Fe ratios show more scatter and less consistency in trends. Both source(s) and chemical behavior affect the metal/Fe ratios. The strongest positive correlation with 234Th/7Be is seen for Ag/Fe, reflecting the dominance of lower estuary sources of this trace metal to the Hudson. Relationships between Pb/Fe, Cu/Fe and 234Th/7Be are less strong, reflecting multiple sources of these elements. No correlation is seen for Cd/Fe with 234Th/7Be, indicating either a source up-river or release of Cd as its Kd decreases with increasing salinity.


Childhood trauma as a risk factor for the onset of subclinical psychotic experiences: Exploring the mediating effect of stress sensitivity in a cross-sectional epidemiological community study.
Childhood trauma is a risk factor for the onset of schizophrenic psychosis. Because the psychosis phenotype can be described as a continuum with varying levels of severity and persistence, childhood trauma might likewise increase the risk for psychotic experiences below the diagnostic threshold. But the impact of stressful experiences depends upon its subjective appraisal. Therefore, varying degrees of stress sensitivity possibly mediate how childhood trauma impacts in the end upon the occurrence of subclinical psychotic experiences. We investigated this research question in a representative community cohort of 1500 participants. A questionnaire, comprising five domains of physical and emotional neglect, as well as physical, emotional, and sexual abuse, was used to assess childhood trauma. Based on different symptoms of subclinical psychotic experiences, we conducted a latent profile analysis (LPA) to derive distinct profiles for such experiences. Path modeling was performed to identify the direct and indirect (via stress sensitivity) pathways from childhood trauma to subclinical psychotic experiences. The LPA revealed four classes - unaffected, anomalous perceptions, odd beliefs and behavior, and combined anomalous perceptions/odd beliefs and behavior, that - except for sexual abuse - were all linked to childhood trauma. Moreover, except for physical abuse, childhood trauma was significantly associated with stress sensitivity. Thus, our results revealed that the pathways from emotional neglect/abuse and physical neglect to subclinical psychotic experiences were mediated by stress sensitivity. In conclusion, we can state that subclinical psychotic experiences are affected by childhood traumatic experiences in particular through the pathway of a heightened subjective stress appraisal.


Pseudo-Mannosylated DC-SIGN Ligands as Immunomodulants.
DC-SIGN, a C-type lectin mainly expressed by DCs, mediates antigen uptake and can induce specific immune responses, depending on the ligand involved. Owing to these properties, DC-SIGN is an attracting target for approaches aimed at tailoring the immune response towards specific immunologic outcomes. A multivalent DC-SIGN ligand (Polyman26), containing at its core a fluorescent "rod-like" spacer and able to inhibit DC-SIGN mediated HIV infection in nanomolar concentration, has been recently developed by our group. We investigated the internalization pattern and the ability of Polyman26 to elicit innate immune responses. Results obtained by confocal microscopy indicate that Polyman26 is internalized by DCs via receptor- mediated endocytosis and is then routed to endolysosomal compartments, thus being presented together with MHC class II molecules, with important implications for the development of vaccines. Moreover, Polyman26 up-regulated the production of β-chemokines and pro-inflammatory cytokines (including IL-1β, IL-6, IL-12, and TNFα) as well as the expression of TLR9 and CD40L. These results indicate that glycomimetic DC-SIGN ligands should be further investigated and suggest that these compounds could be used to differentially stimulate immune responses.


The interplay between protein L-isoaspartyl methyltransferase activity and insulin-like signaling to extend lifespan in Caenorhabditis elegans.
The protein L-isoaspartyl-O-methyltransferase functions to initiate the repair of isomerized aspartyl and asparaginyl residues that spontaneously accumulate with age in a variety of organisms. Caenorhabditis elegans nematodes lacking the pcm-1 gene encoding this enzyme display a normal lifespan and phenotype under standard laboratory growth conditions. However, significant defects in development, egg laying, dauer survival, and autophagy have been observed in pcm-1 mutant nematodes when deprived of food and when exposed to oxidative stress. Interestingly, overexpression of this repair enzyme in both Drosophila and C. elegans extends adult lifespan under thermal stress. In this work, we show the involvement of the insulin/insulin-like growth factor-1 signaling (IIS) pathway in PCM-1-dependent lifespan extension in C. elegans. We demonstrate that reducing the levels of the DAF-16 downstream transcriptional effector of the IIS pathway by RNA interference reduces the lifespan extension resulting from PCM-1 overexpression. Using quantitative real-time PCR analysis, we show the up-regulation of DAF-16-dependent stress response genes in the PCM-1 overexpressor animals compared to wild-type and pcm-1 mutant nematodes under mild thermal stress conditions. Additionally, similar to other long-lived C. elegans mutants in the IIS pathway, including daf-2 and age-1 mutants, PCM-1 overexpressor adult animals display increased resistance to severe thermal stress, whereas pcm-1 mutant animals survive less long under these conditions. Although we observe a higher accumulation of damaged proteins in pcm-1 mutant nematodes, the basal level of isoaspartyl residues detected in wild-type animals was not reduced by PCM-1 overexpression. Our results support a signaling role for the protein L-isoaspartyl methyltransferase in lifespan extension that involves the IIS pathway, but that may be independent of its function in overall protein repair.


Factors influencing nursing staff members' participation in continuing education.
The purpose was to determine the effect of personal and professional factors, as well as motivational orientations, on the participation of nursing staff in continuing education at two health institutions, one public and another private. Descriptive, comparative, correlational design. Probabilistic sampling, random estimation, error limit 0.05, confidence level 95%. Participants were 105 subjects from the private institution and 200 subjects from the public institution. Two instruments were applied: Scale of Reasons for Participation (SRP) and instrument of Participation in Continuing Education (PCE). The internal consistency of the instruments was acceptable. Among personal factors, the income demonstrated effect on the participation (p=.007) in continuing education. Academic level (p=.004) and staff position (p=.005) are professional factors that predict participation in continuing education, as well as the development factor and professional enhancement among motivational orientations (p=.005). The labor institution, whether private or public, did not show any significant effect.


Doping palladium with tellurium for the highly selective electrocatalytic reduction of aqueous CO2 to CO.
Designing highly selective and energy-efficient electrocatalysts to minimize the competitive hydrogen evolution reaction in the electrochemical reduction of aqueous CO2 remains a challenge. In this study, we report that doping Pd with a small amount of Te could selectively convert CO2 to CO with a low overpotential. The PdTe/few-layer graphene (FLG) catalyst with a Pd/Te molar ratio of 1 : 0.05 displayed a maximum CO faradaic efficiency of about 90% at -0.8 V (vs. a reversible hydrogen electrode, RHE), CO partial current density of 4.4 mA cm-2, and CO formation turnover frequency of 0.14 s-1 at -1.0 V (vs. a RHE), which were 3.7-, 4.3-, and 10-fold higher than those of a Pd/FLG catalyst, respectively. Density functional calculations showed that Te adatoms preferentially bind at the terrace sites of Pd, thereby suppressing undesired hydrogen evolution, whereas CO2 adsorption and activation occurred on the high index sites of Pd to produce CO.


Enhanced tissue factor expression by blood eosinophils from patients with hypereosinophilia: a possible link with thrombosis.
Thrombotic risk is increased in eosinophil-mediated disorders, and several hypotheses have been proposed to link eosinophilia and thrombosis. In particular, eosinophils have been described as source of tissue factor (TF), the main initiator of blood coagulation; however, this aspect is still controversial. This study was aimed to evaluate whether TF expression varies in eosinophils isolated from normal subjects and patients with different hypereosinophilic conditions. Eosinophils were immunologically purified from peripheral blood samples of 9 patients with different hypereosinophilic conditions and 9 normal subjects. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were performed to test eosinophil TF expression. For comparison, TF expression was evaluated in monocytes from blood donors and in human endothelial (ECV304) and fibroblast (IMR90) cell lines. Western blot analysis revealed a major band of 47,000 corresponding to native TF in homogenates of purified eosinophils with a higher intensity in the 9 patients than in the 9 controls (p<0.0001). According to RT-PCR cycle threshold (Ct), TF gene expression was higher in eosinophils from patients than in those from controls, median (range) 35.10 (19.45-36.50) vs 37.17 (35.33-37.87) (p = 0.002), and was particularly abundant in one patient with idiopathic hypereosinophilic syndrome and ischemic heart attacks (Ct: 19.45). TF gene expression was moderate in monocytes, Ct: 31.32 (29.82-33.49) and abundant in endothelial cells, Ct: 28.70 (27.79-29.57) and fibroblasts, Ct: 22.77 (19.22-25.05). Our results indicate that human blood eosinophils contain variable amounts of TF. The higher TF expression in patients with hypereosinophilic disorders may contribute to increase the thrombotic risk.


An Update on Artemisinin Resistance.
While the precise mode of action of artemisinin (ART) derivatives remains obscure, it is nonetheless commonly accepted that ART generates reactive oxygen intermediates that contribute to cell death. Also, numerous studies confirm that point mutations in the propeller domain of K13 protein play a key role in resistance to ART derivatives. Because of its homology with the KEAP1 protein, it is thought that this protein may have a role in the polyubiquitination of proteins and that its alteration may cause resistance of young parasite stages to the drug. In this chapter, we present our current knowledge of K13-related resistance to ART and its spread in Southeast Asia and discuss its possible emergence and/or diffusion in Africa.


Terminal exon definition occurs cotranscriptionally and promotes termination of RNA polymerase II.
Analysis of nascent transcription from the human epsilon- and beta-globin genes shows that transcriptional termination occurs within 1.5 kb of the poly(A) site and is dependent on the presence of functional poly(A) signals. Even so, transcripts that have not been cleaved at the poly(A) site are detected up to the termination region, suggesting that there is a kinetic lag between transcription over the poly(A) signal and its effect on transcriptional termination. Surprisingly, mutation of the splice acceptor (SA) of the beta-globin IVS2 also abolishes transcriptional termination. Our results emphasize the interconnection of transcription and RNA processing by showing that the enhancement of 3' end processing by the terminal splice acceptor occurs cotranscriptionally.


Holographic particle velocimeter using forward scattering with filtering.
We propose a new approach, forward-scattering holography with a filter, to holographic particle velocimetry for significant improvement in terms of increased effective aperture, modest laser power requirement, simple geometric setup, improved signal-to-noise ratio, and higher seeding density. We achieve this result by using a smooth (Guassian-like) high-pass filter during recording.


Cementless acetabular revision with the Harris-Galante porous prosthesis. Results after a minimum of ten years of follow-up.
Revisions of the acetabular component of a total hip arthroplasty have a higher rate of complications, particularly loosening and dislocation, than do primary procedures. The purpose of this study, in which the results of a consecutive series of revisions performed with the Harris-Galante Porous acetabular component by a single surgeon were evaluated at an average of twelve years, was to quantify the complications and outcomes of acetabular revision. Clinical and radiographic results were evaluated to assess loosening, lysis, radiolucencies, and trochanteric union in 188 hips (170 patients) treated between 1984 and 1990. One hundred and twenty-two hips in 110 patients were followed for at least ten years, which was required for inclusion in the study. Thirty-one patients (thirty-six hips) died less than ten years postoperatively, and twenty-nine patients (thirty hips) were lost to or refused to return for follow-up. The average Harris hip score was 78 points at an average of 12.5 years after revision, which was a 29-point improvement compared with the preoperative score. The rate of repeat revision because of aseptic loosening of the acetabular shell was 4% (five of 122). The rate of repeat revision of the shell for any reason was 15% (eighteen of 122). Eight unrevised sockets were loose radiographically, for a total rate of aseptic loosening of 11% (thirteen of 122). This study demonstrated that most acetabular revisions with this cementless hemispherical socket were successful. Few structural grafts and no cages were used. Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.


Effects of the Financial Crisis on Psychotropic Drug Consumption in a Cohort from a Semi-Urban Region in Catalonia, Spain.
Evidence of whether the recent economic crisis has or has not had an effect on psychotropic drug consumption is very scarce. Our objective was to determine if there had in fact been an increase in psychotropic drug use as a result of the financial crisis. In our study a retrospective cohort (between January 1, 2005, and December 31, 2012) was made up of individuals from the general population in a region in the northeast of Catalonia, Spain. We specified a generalized linear mixed model along with combined 'selection on observables' as (propensity scoring) matching and 'selection on unobservables' as (random coefficient) the panel data model methods, and performed inferences using a Bayesian framework. In the period following the economic crisis (post 2009), there was an increase in the consumption of psychotropic drugs which was significantly higher among those who had already been consuming psychotropic drugs prior to 2009 and those most likely to be unemployed. The increase was of greater significance when consumption was measured by the number of drugs being taken, rather than by the defined daily dose (DDD), with the greatest increase occurring in 2011; the very year in which Spain was most affected by the crisis. Once the financial crisis had ended, there was an increase in the severity, rather than the intensity, of mental health disorders in individuals who had already had disorders before the crisis. This increase occurred in those most likely to be unemployed, and the severity was accentuated in the toughest year of the economic crisis.


Measurement of residual stress for ITO/PET substrates by the double beam shadow moiré interferometer.
This study constructed a measurement system that can quickly and accurately analyze the residual stress of flexible electronics. A double beam shadow moiré interferometer was set up to measure and evaluate the residual stress of tin-doped indium oxide films on a polyethylene terephthalate substrate. However, this system required only two symmetrical fringes to evaluate the residual stress of transparent conductive oxide films on flexible substrate. Applying the grating translation techniques to the double beam shadow moiré interferometer greatly improved the measurement resolution and accuracy, and the relative error was reduced to 1.2%.


Spontaneous Spiritual Awakenings: Phenomenology, Altered States, Individual Differences, and Well-Being.
Spontaneous Spiritual Awakenings (SSAs) are subjective experiences characterised by a sudden sense of direct contact, union, or complete nondual merging (experience of oneness) with a perceived ultimate reality, the universe, "God," or the divine. These profound transformative experiences have scarcely been researched, despite extensive anecdotal evidence suggesting their potential to catalyse drastic, long-term, and often positive shifts in perception, world-view, and well-being. The aims of this study were to investigate the phenomenological variances of these experiences, including the potential differences between SSAs and Spontaneous Kundalini Awakenings (SKAs), a subset of awakening experiences that the authors postulate may produce a higher likelihood of both physical and negative effects; to explore how these experiences compare to other altered states of consciousness (ASCs), including those mediated by certain psychedelic substances; and understand their impact on well-being. Personality trait absorption and temporal lobe lability (TLL) were assessed as predictors of Spontaneous Spiritual and Kundalini Awakenings (SSA/SKAs). A mixed within and between-participants self-report survey design was adopted. A total of 152 participants reporting their most powerful SSA/SKAs completed questionnaires measuring nondual, kundalini, and mystical experience, as well as depth of ASC, and trait absorption and TLL. Spontaneous Kundalini Awakenings were found to be significantly more physical, but not significantly more negative than SSAs, and overall, both sets of experiences were perceived to be overwhelmingly more positive than negative, even in cases where the experience was initially challenging. The phenomenological distribution of SSA/SKAs was similar to other measured ASCs although greater in magnitude, and appeared most similar in distribution and in magnitude to drug-induced ASCs, particularly classic psychedelics DMT and psilocybin. Temporal lobe lability and trait absorption were found to predict the SSA/SKA experience. The limitations and implications of these findings are discussed.


Antimicrobial resistance in the subgingival microflora in patients with adult periodontitis. A comparison between The Netherlands and Spain.
The widespread use of antibiotics for prophylaxis and treatment of bacterial infections has lead to the emergence of resistant human pathogens. Great differences have been documented between European countries in the use of systemic antibiotics. In parallel, significant differences in levels of resistant pathogens have been documented. To investigate whether differences in antibiotic use influence the level of antimicrobial resistance of the subgingival microflora of untreated patients with adult periodontitis in The Netherlands and Spain. Blood agar plates containing breakpoint concentrations of penicillin, amoxicillin, amoxicillin and clavunalate, metronidazole, erythromycin, azithromycin, clindamycin and tetracycline were used to determine the proportion of bacteria from the subgingival plaque that was resistant to these antibiotics. In the Spanish patients, statistically significant higher mean levels of resistance were found for penicillin, amoxicillin, metronidazole, clindamycin and tetracycline. The mean number of different bacterial species growing on the selective plates was higher in the Spanish patients, as was the % of resistant strains of most periodontal pathogens. A striking difference was observed in the frequency of occurrence of tetracycline-resistant periodontal pathogens. In Spain, 5 patients had > or =3 tetracycline resistant periodontal pathogens, whereas this was not observed in any of the Dutch patients. The widespread use of antibiotics in Spain is reflected in the level of resistance of the subgingival microflora of adult patients with periodontitis.


Psychometric Properties of Eight-Item Physical Activity Enjoyment Scale in a Chinese Population.
This study examined the psychometric properties of the eight-item Physical Activity Enjoyment Scale (PACES) in Hong Kong older adults. Study 1 assessed the scale's factor validity and test-retest reliability, whereas Study 2 examined its convergent validity in Hong Kong older adults. A total of 168 (Study 1) older adults completed the PACES twice over a 2-week interval, and 57 (Study 2) older adults completed both the eight-item PACES and a measure of quality of life. The results of both studies showed that the eight-item PACES had a high degree of internal consistency. Both the composite reliability and average variance extracted from Study 1 were high, suggesting that as a set, the eight items of the PACES reliably measured the construct. The observed test-retest reliability was satisfactory over a 2-week interval. This eight-item PACES is an expedited and reliable instrument for assessing physical activity enjoyment in Chinese older adults.


Regulation of carbon and electron flow in Propionispira arboris: relationship of catabolic enzyme levels to carbon substrates fermented during propionate formation via the methylmalonyl coenzyme A pathway.
A detailed study of the glucose fermentation pathway and the modulation of catabolic oxidoreductase activities by energy sources (i.e., glucose versus lactate or fumarate) in Propionispira arboris was performed. 14C radiotracer data show the CO2 produced from pyruvate oxidation comes exclusively from the C-3 and C-4 positions of glucose. Significant specific activities of glyceraldehyde-3-phosphate dehydrogenase and fructose-1,6-bisphosphate aldolase were detected, which substantiates the utilization of the Embden-Meyerhoff-Parnas path for glucose metabolism. The methylmalonyl coenzyme A pathway for pyruvate reduction to propionate was established by detection of significant activities (greater than 16 nmol/min per mg of protein) of methylmalonyl coenzyme A transcarboxylase, malate dehydrogenase, and fumarate reductase in cell-free extracts and by 13C nuclear magnetic resonance spectroscopic demonstration of randomization of label from [2-13C]pyruvate into positions 2 and 3 of propionate. The specific activity of pyruvate-ferredoxin oxidoreductase, malate dehydrogenase, fumarate reductase, and transcarboxylase varied significantly in cells grown on different energy sources. D-Lactate dehydrogenase (non-NADH linked) was present in cells of P. arboris grown on lactate but not in cells grown on glucose or fumarate. These results indicate that growth substrates regulate synthesis of enzymes specific for the methylmalonyl coenzyme A path and initial substrate transformation.


At the Edge of US Immigration's "Halt of Folly:" Data, Information, and Research Needs in the Event of Legalization.
Virtually all accounts of the state of the US immigration system point to its patently broken condition, with the presence of almost 12 million people without legal status paramount to this characterization. Because of several recent developments including continued and renewed interest in regularizing the status of most unauthorized migrants in executive and legislative branch agendas, the Center for Migration Studies of New York, with support from the John D. and Catherine T. MacArthur Foundation, convened a group of immigration specialists, researchers, scholars, and advocates in Washington, DC in September 2013 to discuss potential data, information, and research needs in the event of the enactment of large-scale legalization programs for the unauthorized population. This paper describes the results of this one-and-a-half day discussion. It begins with a description of the contours of a legalization program if it were to follow a similar form as S. 744, the Border Security, Economic Opportunity, and Immigration Modernization Act passed by the Senate in June 2013. In addition to being the most recent effort in this area, S. 744 includes a relatively complex set of conditions for "earning" legalization. A number of data, information, and research needs would need to be met to ensure the proper implementation of such a program. First, planning for effective local outreach and service delivery efforts requires estimating the eligible population at finer-scale geographies; understanding financial and time disincentives to apply and adhere to the program and skill levels required; assessing capacity in service delivery relative to the size and service needs of the local eligible population; tracking the progress of applicants through the legalization process; and understanding effective forms of outreach and service delivery. Second, assessing the effects of legalization on immigrant integration, future immigration, and fiscal and economic life in the United States would include anticipating the effects of legalization on eligibility and use of locally- and state-provided services by the legalized and their families. Within the discussion of these issues, the paper describes recent and potential efforts to develop methodologies, partnerships, and evaluation and tracking systems by different stakeholders and organizations to ensure and assess the short- and long-term effectiveness of legalization efforts. In doing this, a highly volatile climate make a full-fledged legalization program unlikely in the near future, waiting to plan for such a possibility until after legislation passes would be ill-advised. Because such a discussion may also help shape the parameters of how legalization takes place, fora like that provided by this meeting are valuable vehicles to organize and mobilize knowledge, and should be thus continued and expanded.


A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing.
X-chromosome inactivation is the process that evolved in mammals to equalize levels of X-linked gene expression in XX females relative to XY males. Silencing of a single X chromosome in female cells is mediated by the non-coding RNA Xist. Although progress has been made toward identifying factors that function in the maintenance of X inactivation, the primary silencing factors are largely undefined. We developed an shRNA screening strategy to produce a ranked list of candidate primary silencing factors. Validation experiments performed on several of the top hits identified the SPOC domain RNA binding proteins Rbm15 and Spen and Wtap, a component of the m6A RNA methyltransferase complex, as playing an important role in the establishment of Xist-mediated silencing. Localization analysis using super-resolution 3D-SIM microscopy demonstrates that these factors co-localize with Xist RNA within the nuclear matrix subcompartment, consistent with a direct interaction.


Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid.
To evaluate the clinical utility of frozen section in patients with follicular neoplasms of the thyroid in a randomized prospective trial. The finding of a follicular neoplasm on fine-needle aspiration prompts many surgeons to perform intraoperative frozen section during thyroid lobectomy. However, the focal distribution of key diagnostic features of malignancy contributes to a high rate of noninformative frozen sections. The series comprised 68 consecutive patients with a solitary thyroid nodule in whom fine-needle aspiration showed a follicular neoplasm. Patients were excluded for bilateral or nodal disease, extrathyroidal extension, or a definitive fine-needle aspiration diagnosis. Final pathologic findings were compared with frozen sections, and cost analyses were performed. Sixty-one patients met the inclusion criteria. Twenty-nine were randomized to the frozen-section group and 32 to the non-frozen-section group. In the non-frozen-section group, one patient was excluded when gross examination of the specimen was suggestive of malignancy and a directed frozen section was diagnostic of follicular carcinoma. Frozen-section analysis rendered a definitive diagnosis of malignancy in 1 of 29 (3.4%) patients, who then underwent a one-stage total thyroidectomy. In the remaining 28 patients, frozen section showed a "follicular or Hürthle cell neoplasm." Permanent histology demonstrated well-differentiated thyroid cancer in 6 of these 28 patients (21%). Of the 31 patients in the non-frozen-section group, 3 (10%) showed well-differentiated thyroid carcinoma on permanent histology. Complications were limited to one transient unilateral vocal cord dysfunction. All but one patient had a 1-day hospital stay. There were no significant differences between the groups in surgical time or total hospital charges; however, the charge per informative frozen section was approximately $12,470. For the vast majority of patients (96.4%) with follicular neoplasms of the thyroid, frozen section is neither informative nor cost-effective.


The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels.
Voltage- and store-operated calcium (Ca(2+)) channels are the major routes of Ca(2+) entry in mammalian cells, but little is known about how cells coordinate the activity of these channels to generate coherent calcium signals. We found that STIM1 (stromal interaction molecule 1), the main activator of store-operated Ca(2+) channels, directly suppresses depolarization-induced opening of the voltage-gated Ca(2+) channel Ca(V)1.2. STIM1 binds to the C terminus of Ca(V)1.2 through its Ca(2+) release-activated Ca(2+) activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. This establishes a previously unknown function for STIM1 and provides a molecular mechanism to explain the reciprocal regulation of these two channels in cells.


Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants.
Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.


StcE, a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor.
Escherichia coli O157:H7 causes diarrhoea, haemorrhagic colitis, and the haemolytic uraemic syndrome. We have identified a protein of previously unknown function encoded on the pO157 virulence plasmid of E. coli O157:H7, which is the first described protease that specifically cleaves C1 esterase inhibitor (C1-INH), a member of the serine protease inhibitor family. The protein, named StcE for secreted protease of C1 esterase inhibitor from EHEC (formerly Tagn), cleaves C1-INH to produce (unique) approximately 60-65 kDa fragments. StcE does not digest other serine protease inhibitors, extracellular matrix proteins or universal protease targets. We also observed that StcE causes the aggregation of cultured human T cells but not macrophage-like cells or B cells. Substitution of aspartic acid for glutamic acid at StcE position 435 within the consensus metalloprotease active site ablates its abilities to digest C1-INH and to aggregate T cells. StcE is secreted by the etp type II secretion pathway encoded on pO157, and extracellular StcE levels are positively regulated by the LEE-encoded regulator, Ler. StcE antigen and activity were detected in the faeces of a child with an E. coli O157:H7 infection, demonstrating the expression of StcE during human disease. Cleavage of C1-INH by StcE could plausibly cause localized pro-inflammatory and coagulation responses resulting in tissue damage, intestinal oedema and thrombotic abnormalities.


Pregnancy and Guillain-Barré syndrome: a nationwide register cohort study.
In this study, we determined the relationship between Guillain-Barré syndrome (GBS) and pregnancy. By taking advantage of several nationwide registers and the availability of personal identification numbers, we calculated person-years for Swedish females aged 15-49 years in the following categories: (1) neither pregnant nor postpartum; (2) pregnant; (3) in the first month postpartum, or (4) in the first 3 months postpartum during 1973-1983. For these women, we determined the corresponding exposure status of hospital-registered GBS cases. Medical records were examined for GBS cases hospitalized during the 2-week period postpartum and 1-month period after the last menstruation. Poisson regression analysis yielded age-adjusted relative risks (RRs) of 0.86 (95% CI 0.40-1.84) for pregnant women, and 1.47 (0.54-3.99) and 2.21 (0.55-8.94) for females during the 3-month and the 30-day period after delivery. The risk for GBS seems to be lower during pregnancy and increases after delivery.