Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells.
The CD16 receptor (Fc gamma R-III) is found on many tissue macrophages (M phi s), but its expression on circulating monocytes is restricted to a small, phenotypically distinct subset. The number of these CD16+ monocytes may be markedly increased in response to sepsis, human immunodeficiency virus infection, or metastatic malignancy. We have recently shown that the CD16+ monocyte population is selectively expanded by administration of recombinant human macrophage colony-stimulating factor (rhM-CSF). In the current study, we used the highly rhM-CSF-responsive cynomolgus primate model to further characterize this novel monocyte population. Animals treated with rhM-CSF underwent a progressive and essentially complete conversion to the CD16+ monocyte phenotype, with up to a 50-fold increase in the number of CD16+ cells. This increase was paralleled by the emergence of a population of circulating cells that morphologically resembled large granular lymphocytes (LGLs). However, quantitatively, this population corresponded closely to the number of CD16+ monocytes, and fluorescence-activated cell sorting (FACS) confirmed that they were the same. In addition to their LGL-like morphology, many rhM-CSF-induced CD16+ monocytes showed a pattern of size, granularity, and quantitative cell surface marker expression that closely resembled the pretreatment LGL/natural killer (NK) cell population but that did not resemble the pretreatment monocyte population. However, rhM-CSF-induced CD16+ monocytes could be distinguished from LGL/ NK cells by fact that they all expressed cell surface receptors for rhM-CSF, and many of them showed reduced but detectable phagocytic and respiratory burst activity. Studies of human subjects treated with rhM-CSF also showed an analogous population of "LGL-appearing" CD16+ mononuclear cells. Thus, our studies reveal a previously unsuspected ability of cells in the monocyte lineage to adopt a phenotype similar to that of LGL/NK cells. The extent of this phenotypic convergence suggests that the two lineages retain access to elements of a similar developmental pathway.


The fate and transformation of tetrabromobisphenol A in natural waters, mediated by oxidoreductase enzymes.
In this study, we examined the fate and transformation of tetrabromobisphenol A (TBBPA), mediated by the representative oxidoreductases (laccase and horseradish peroxidase (HRP)) in natural waters. Both enzymes could readily degrade TBBPA at environmentally relevant concentrations (e.g., 10 nmol L-1) in natural waters. After 2 hour treatment, 0.5-25% and 35-65% of TBBPA were degraded in municipal wastewater and natural surface waters by a laccase or HRP-catalyzed reaction, respectively. Enzyme kinetics evaluations indicated that the kCAT/KM ratio of HRP (1.01 μM-1 s-1) was much higher than that of laccase (0.032 μM-1 s-1) for TBBPA degradation, suggesting that the catalytic performance of HRP towards TBBPA was more efficient than that of laccase. The effects of pH and organic matter on the enzymatic degradation efficiency were explored. Organic matter in the water inhibited the enzymatic degradation efficiency and the degree of inhibition was proportional to the UV254 values of water. Product identification indicated that the product distribution of TBBPA at low concentration (10 nmol L-1) was similar to that of TBBPA at high concentration (10 μmol L-1). The degradation intermediates underwent further enzymatic reaction to yield higher molecular weight secondary products. Toxicity assessment showed that TBBPA toxicity was effectively eliminated by the oxidoreductase-catalyzed reaction.


Antitumor effects and normal-tissue toxicity of 111In-nuclear localization sequence-trastuzumab in athymic mice bearing HER-positive human breast cancer xenografts.
(111)In-nuclear localization sequence-trastuzumab is a radioimmunotherapeutic agent consisting of trastuzumab modified with NLS peptides (CGYGPKKKRKVGG) and labeled with the Auger electron emitter (111)In. Our objectives were to evaluate the tumor growth-inhibitory properties and normal-tissue toxicity of (111)In-NLS-trastuzumab in mice after intraperitoneal administration. The pharmacokinetics of (111)In-NLS-trastuzumab after intravenous (tail vein) or intraperitoneal injection in BALB/c mice were compared. Normal-tissue toxicity was determined in BALB/c mice at 2 wk after intraperitoneal injection of 3.7-18.5 MBq (4 mg/kg) of (111)In-NLS-trastuzumab by monitoring body weight, histopathologic examination of tissues, and hematology (white blood cell, platelet, red blood cell, and hemoglobin) or clinical biochemistry (alanine transaminase and creatinine) parameters. A no-observable-adverse-effect-level (NOAEL) dose was defined. Athymic mice bearing subcutaneous MDA-MB-361 or MDA-MB-231 human breast cancer xenografts (5.0 x 10(5) or 0.5 x 10(5) HER2/cell, respectively) were treated with a single NOAEL dose or 2 doses administered intraperitoneally and separated by 2 wk. Control groups were administered (111)In-trastuzumab, trastuzumab, nonspecific (111)In-NLS-human IgG (hIgG), or normal saline. The bioavailability of (111)In-NLS-trastuzumab after intraperitoneal injection was 0.7. The NOAEL dose was 9.25 MBq (4 mg/kg); doses greater than or equal to 18.5 MBq decreased white blood cell or platelet counts, and doses of 27.7 MBq decreased red blood cell counts. There was no increase in alanine transaminase or creatinine at any doses tested. There were no morphologic changes to the liver, kidneys, heart, or spleen or loss of body weight. A single dose of (111)In-NLS-trastuzumab (9.25 MBq)-compared with mice receiving (111)In-trastuzumab, trastuzumab, (111)In-NLS-hIgG, or normal saline-significantly slowed the rate of growth of MDA-MB-361 tumors over 60 d (0.014 d(-1) vs. 0.033 d(-1), 0.046 d(-1), 0.030 d(-1), and 0.061 d(-1), respectively; P < 0.05). (111)In-NLS-trastuzumab had no effect on the growth of MDA-MB-231 tumors. Two doses of (111)In-NLS-trastuzumab (9.25 MBq; 4 mg/kg) separated by 2 wk increased the survival of mice with MDA-MB-361 tumors, compared with mice treated with trastuzumab or normal saline (>140 d vs. 96 and 84 d, respectively; P < 0.001 or 0.027, respectively). (111)In-NLS-trastuzumab is a promising radioimmunotherapeutic agent that could be effective for treatment of HER2-overexpressing breast cancer in humans.


Computational identification of microRNAs in the strawberry (Fragaria x ananassa) genome sequence and validation of their precise sequences by miR-RACE.
In plants, microRNAs (miRNAs) play significant roles in post-transcriptional gene regulation and have been found to control many genes involved in different biological and metabolic processes. Extensive studies were carried out to discover miRNAs and analyze their functions in model plant species, such as in Arabidopsis and rice that have been reported. In this research, we used bioinformatics to predict microRNAs in an important strawberry rootstock cultivar to discover and validate precise sequences of microRNAs in strawberry. By adopting a range of filtering criteria, we obtained 59 potential miRNAs belonging to 40 miRNA families from the Fragaria vesca genome. Using two specific 5' and 3' miRNA RACE PCR reactions and a sequence-directed cloning method, we accurately determined 34 precise sequences of candidate miRNAs, while six other sequences exhibited some minor divergence in their termini nucleotides, and 19 miRNAs that could not be cloned owing to expression abundance may be too low or these mirRNAs predicted could not be existing in strawberry. Potential target genes were further predicted for the miRNAs above. The expression of the 16 miRNAs unreported and having exact sequences and their targets by experiment could be detected in different tissues of strawberry ranging from roots, stems, leaves, flowers and fruits by qRT-PCR and some of them showed differential expression in various tissues. The functional analysis of 16 miRNAs and their targets was carried out. Finally, we conclude that there are 34 mirRNAs in strawberry and their targets play vital roles not only in growth and development, but also in diverse physiological processes. These results show that regulatory miRNAs exist in agronomically important strawberry and might have an important function in strawberry growth and development.


Simultaneous determination of hormonal residues in treated waters using ultrahigh performance liquid chromatography-tandem mass spectrometry.
In the last years, hormone consumption has increased exponentially. Because of that, hormone compounds are considered emerging pollutants since several studies have determinted their presence in water influents and effluents of wastewater treatment plants (WWTPs). In this study, a quantitative method for the simultaneous determination of oestrogens (estrone, 17 β -estradiol, estriol, 17 α -ethinylestradiol, and diethylstilbestrol), androgens (testosterone), and progestogens (norgestrel and megestrol acetate) has been developed to determine these compounds in wastewater samples. Due to the very low concentrations of target compounds in the environment, a solid phase extraction procedure has been optimized and developed to extract and preconcentrate the analytes. Determination and quantification were performed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The method developed presents satisfactory limits of detection (between 0.15 and 9.35 ng·L(-1)), good recoveries (between 73 and 90% for the most of compounds), and low relative standard deviations (under 8.4%). Samples from influents and effluents of two wastewater treatment plants of Gran Canaria (Spain) were analyzed using the proposed method, finding several hormones with concentrations ranged from 5 to 300 ng·L(-1).


Daclatasvir: A Review in Chronic Hepatitis C.
The hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (Daklinza(®)) is indicated for use in combination with sofosbuvir, with or without ribavirin, in a pangenotypic all-oral regimen. In patients with chronic HCV genotype 1 or 3 infection without cirrhosis, a 12-week regimen of daclatasvir plus sofosbuvir achieved high sustained virological response rates 12 weeks' post-treatment (SVR12), regardless of prior treatment experience, according to the results of the AI444040 and ALLY-3 trials. In the ALLY-3+ trial, high SVR12 rates were achieved with a 12- or 16-week regimen of daclatasvir plus sofosbuvir and ribavirin in patients with chronic HCV genotype 3 infection and advanced fibrosis or compensated cirrhosis. A daclatasvir plus sofosbuvir-based regimen demonstrated efficacy in patients with chronic HCV genotype 1, 3 or 4 infection and advanced cirrhosis or post-transplant recurrence in the ALLY-1 trial, and in patients co-infected with HCV genotype 1, 3 or 4 and HIV-1 in the ALLY-2 trial. Results of clinical trials were supported by real-world data from early-access programmes that included high numbers of patients who would have been excluded from phase 3 trials because of advanced disease and/or concomitant medical conditions. Daclatasvir plus sofosbuvir with or without ribavirin was generally well tolerated. In conclusion, an all-oral regimen comprising daclatasvir plus sofosbuvir with or without ribavirin is an important option for use in treatment-naive or treatment-experienced patients with chronic HCV genotype 1, 3 or 4 infection, including in patients with advanced liver disease, post-transplant recurrence and HIV-1 co-infection.


The ghosts of brain states past: remembering reactivates the brain regions engaged during encoding.
There is growing evidence that the brain regions involved in encoding an episode are partially reactivated when that episode is later remembered. That is, the process of remembering an episode involves literally returning to the brain state that was present during that episode. This article reviews studies of episodic and associative memory that provide support for the assertion that encoding regions are reactivated during subsequent retrieval. In the first section, studies are reviewed in which neutral stimuli were associated with different modalities of sensory stimuli or different valences of emotional stimuli. When the neutral stimuli were later used as retrieval cues, relevant sensory and emotion processing regions were reactivated. In the second section, studies are reviewed in which participants used different strategies for encoding stimuli. When the stimuli were later retrieved, regions associated with the different encoding strategies were reactivated. Together, these studies demonstrate not only that the encoding experience determines which regions are activated during subsequent retrieval but also that the same regions are activated during encoding and retrieval. In the final section, relevant questions are posed and discussed regarding the reactivation of encoding regions during retrieval.


Interpretable machine learning models for hospital readmission prediction: a two-step extracted regression tree approach.
Advanced machine learning models have received wide attention in assisting medical decision making due to the greater accuracy they can achieve. However, their limited interpretability imposes barriers for practitioners to adopt them. Recent advancements in interpretable machine learning tools allow us to look inside the black box of advanced prediction methods to extract interpretable models while maintaining similar prediction accuracy, but few studies have investigated the specific hospital readmission prediction problem with this spirit. Our goal is to develop a machine-learning (ML) algorithm that can predict 30- and 90- day hospital readmissions as accurately as black box algorithms while providing medically interpretable insights into readmission risk factors. Leveraging a state-of-art interpretable ML model, we use a two-step Extracted Regression Tree approach to achieve this goal. In the first step, we train a black box prediction algorithm. In the second step, we extract a regression tree from the output of the black box algorithm that allows direct interpretation of medically relevant risk factors. We use data from a large teaching hospital in Asia to learn the ML model and verify our two-step approach. The two-step method can obtain similar prediction performance as the best black box model, such as Neural Networks, measured by three metrics: accuracy, the Area Under the Curve (AUC) and the Area Under the Precision-Recall Curve (AUPRC), while maintaining interpretability. Further, to examine whether the prediction results match the known medical insights (i.e., the model is truly interpretable and produces reasonable results), we show that key readmission risk factors extracted by the two-step approach are consistent with those found in the medical literature. The proposed two-step approach yields meaningful prediction results that are both accurate and interpretable. This study suggests a viable means to improve the trust of machine learning based models in clinical practice for predicting readmissions through the two-step approach.


Endocrine effects of low dose aminoglutethimide alone in advanced postmenopausal breast cancer.
The site of action of aminoglutethimide (AG) has been investigated. An initial study was performed on 10 postmenopausal patients with advanced breast cancer who had taken 1000 mg AG per day and 20 mg hydrocortisone (HC) twice daily (b.d.) for greater than 3 months. There was a 15.5 +/- 5.6 s.e.-fold rise in 17-OH progesterone and a 4.9 +/- 0.9 s.e.-fold rise in 4 delta androstenedione but no rise in cortisol or oestrone 30 min after short Synacthen tests. These results suggested that peripheral aromatisation was a more important site of AG action than adrenal desmolase, and that adrenal 11 beta hydroxylase was inhibited. Since aromatase is more sensitive than desmolase to AG in vitro, lower doses of AG alone (i.e. without HC) were assessed for endocrine effects in 13 further post-menopausal women with advanced breast cancer. All of these patients tolerated 125 mg AG b.d., but 3 could not tolerate the conventional maximum dose. Oestrone levels on 125 mg AG b.d. were suppressed below pretreatment levels and were not significantly different from those on 500 mg AG b.d. alone, or with the addition of HC. Oestradiol levels were suppressed to a similar extent. Dehydroepiandrosterone sulphate (DHA-S) levels were not suppressed by AG alone, but fell on addition of HC. The endocrine results show low dose AG alone is an effective and well tolerated inhibitor of the peripheral production of oestrogens in postmenopausal patients. Therapeutic trials are now possible. DHA-S is not a marker of AG effect.


Phenotypic and functional heterogeneity of human peripheral blood T lymphocytes producing colony stimulating factor. A clonal and precursor frequency analysis.
In this report we describe the precursor frequency and the subset distribution of peripheral blood human T cells producing lymphokine(s) acting on the proliferation and differentiation of bone marrow precursors of the granulocyte/macrophage series, as assessed in a liquid microculture assay. Because the sensitivity of this system was similar to that of the classic colony formation assay in semi-solid (methylcellulose) medium, it is likely that the lymphokine activity measured in this assay corresponds to the colony-stimulating factor (CSF) activity. Single human T lymphocytes, isolated from peripheral blood by E rosetting and Ficoll-Hypaque gradients, were seeded into microculture wells by limiting dilution or micromanipulation techniques and were incubated under culture conditions that allow clonal expansion of essentially all T cells. After 15 to 20 days, microcultures were stimulated with PHA and CSF activity was assayed in culture supernatants 24 hr thereafter. About 45% (1/2.3) of peripheral blood T cells were found to give rise to CSF-producing progenies. Moreover, when fluorescence-activated cell sorter-purified T4+ and T4- (or T8- and T8+) were analyzed, the frequency of the precursors of CSF-producing cells was 1/1.5 in the T4+ subset, whereas approximately one-third of the T8+ cells had this functional potential. To additionally characterize T cells responsible for CSF production, unfractionated T cells as well as T4+ and T4- cells were cloned by single cell micromanipulation. The resulting clones were analyzed simultaneously for the production of IL 2, production of CSF and for cytolytic activity in a lectin-dependent assay. It was found that 25/48 clones obtained from unfractionated T cells produced CSF, whereas 23/48 and 19/48 produced IL 2 or had cytolytic activity respectively. Six of the 25 CSF-producing clones had only this functional capability, whereas the remaining clones in addition displayed cytolytic activity (4/25), IL 2 production (10/25), or both (5/25). A similar functional heterogeneity was observed among T4+ and T4- clones, thus indicating that T cells producing CSF are functionally heterogeneous within both the T4+ and T8+ subsets.


The critical role of ants in the extensive dispersal of Acacia seeds revealed by genetic parentage assignment.
Ants are prominent seed dispersal agents in many ecosystems, and dispersal distances are small in comparison with vertebrate dispersal agents. However, the distance and distribution of ant-mediated dispersal in arid/semi-arid environments remains poorly explored. We used microsatellite markers and parentage assignment to quantify the distance and distribution of dispersed seeds of Acacia karina, retrieved from the middens of Iridomyrmex agilis and Melophorus turneri perthensis. From parentage assignment, we could not distinguish the maternal from each parent pair assigned to each seed, so we applied two approaches to estimate dispersal distances, one conservative (CONS), where the parent closest to the ant midden was considered to be maternal, and the second where both parents were deemed equally likely (EL) to be maternal, and used both distances. Parentage was assigned to 124 seeds from eight middens. Maximum seed dispersal distances detected were 417 m (CONS) and 423 m (EL), more than double the estimated global maximum. Mean seed dispersal distances of 40 m (±5.8 SE) (CONS) and 79 m (±6.4 SE) (EL) exceeded the published global average of 2.24 m (±7.19 SD) by at least one order of magnitude. For both approaches and both ant species, seed dispersal was predominantly (44-84% of all seeds) within 50 m from the maternal source, with fewer dispersal events at longer distances. Ants in this semi-arid environment have demonstrated a greater capacity to disperse seeds than estimated elsewhere, which highlights their important role in this system, and suggests significant novel ecological and evolutionary consequences for myrmecochorous species in arid/semi-arid Australia.


Co-response analysis: a new experimental strategy for metabolic control analysis.
The formulation of the standard summation and connectivity relationships as a statement that the matrix of all the elasticities in a system is the inverse of the matrix of all the control coefficients is completely general, provided that only control coefficients for independent fluxes and concentrations are considered, and that the elasticity matrix is written to take account of the stoichiometry of the pathway and the implied dependences between concentrations. This generally implies that co-response analysis is also general, i.e. that all of the elasticities and all of the control coefficients in any system, regardless of branching, feedback effects, moiety conservation or other complications, can be determined by comparing the effects of perturbations of the enzyme activities on the steady-state fluxes and concentrations of the pathway. The approach requires no quantitative information about the magnitudes of the effects on the individual enzyme activities, and consequently no enzymes need to be studied in isolation from the pathway.


Amino acid transport in thermophiles: characterization of an arginine-binding protein in Thermotoga maritima. 2. Molecular organization and structural stability.
ABC transport systems provide selective passage of metabolites across cell membranes and typically require the presence of a soluble binding protein with high specificity to a specific ligand. In addition to their primary role in nutrient gathering, the binding proteins associated with bacterial transport systems have been studied for their potential to serve as design scaffolds for the development of fluorescent protein biosensors. In this work, we used Fourier transform infrared spectroscopy and molecular dynamics simulations to investigate the physicochemical properties of a hyperthermophilic binding protein from Thermotoga maritima. We demonstrated preferential binding for the polar amino acid arginine and experimentally monitored the significant stabilization achieved upon binding of ligand to protein. The effect of temperature, pH, and detergent was also studied to provide a more complete picture of the protein dynamics. A protein structure model was obtained and molecular dynamic experiments were performed to investigate and couple the spectroscopic observations with specific secondary structural elements. The data determined the presence of a buried beta-sheet providing significant stability to the protein under all conditions investigated. The specific amino acid residues responsible for arginine binding were also identified. Our data on dynamics and stability will contribute to our understanding of bacterial binding protein family members and their potential biotechnological applications.


Urinary tract infection, inflammation, and cognition in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study.
Schizophrenia is associated with an increased prevalence of infections throughout the life span. Previous studies have found an association between urinary tract infection (UTI) and acute psychosis. We investigated the prevalence and correlates of UTI in a large cohort of patients with schizophrenia. We estimated the prevalence of UTI at the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We then investigated associations between UTI and inflammatory markers, psychopathology, and cognition, controlling for potential confounding factors. The prevalence of probable UTI at baseline in the CATIE trial was 1.2% (n = 13 of 1,061 participants). Compared with participants with a normal urinalysis (n = 387), after controlling for potential confounders, UTI was a significant predictor of greater impairments (approximately 1 standard deviation difference) in the cognition composite score (beta = -0.153, P = .002), and poorer working memory (beta = -0.190, P < .001). There were no differences in psychopathology scores between participants with probable UTI and those with a normal urinalysis. Urinary tract infections in patients with schizophrenia may have an impact on cognition. Findings provide additional evidence regarding infectious disease comorbidity, which may be clinically relevant in the treatment of patients with schizophrenia.


Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis.
To evaluate association between biomarkers and outcomes in COVID-19 hospitalised patients. COVID-19 pandemic has been a challenge. Biomarkers have always played an important role in clinical decision making in various infectious diseases. It is crucial to assess the role of biomarkers in evaluating severity of disease and appropriate allocation of resources. Systematic review and meta-analysis. English full text observational studies describing the laboratory findings and outcomes of COVID-19 hospitalised patients were identified searching PubMed, Web of Science, Scopus, medRxiv using Medical Subject Headings (MeSH) terms COVID-19 OR coronavirus OR SARS-CoV-2 OR 2019-nCoV from 1 December 2019 to 15 August 2020 following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Studies having biomarkers, including lymphocyte, platelets, D-dimer, lactate dehydrogenase (LDH), C reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, procalcitonin (PCT) and creatine kinase (CK), and describing outcomes were selected with the consensus of three independent reviewers. Composite poor outcomes include intensive care unit admission, oxygen saturation <90%, invasive mechanical ventilation utilisation, severe disease, in-hospital admission and mortality. The OR and 95% CI were obtained and forest plots were created using random-effects models. Publication bias and heterogeneity were assessed by sensitivity analysis. 32 studies with 10 491 confirmed COVID-19 patients were included. We found that lymphopenia (pooled-OR: 3.33 (95% CI: 2.51-4.41); p<0.00001), thrombocytopenia (2.36 (1.64-3.40); p<0.00001), elevated D-dimer (3.39 (2.66-4.33); p<0.00001), elevated CRP (4.37 (3.37-5.68); p<0.00001), elevated PCT (6.33 (4.24-9.45); p<0.00001), elevated CK (2.42 (1.35-4.32); p=0.003), elevated AST (2.75 (2.30-3.29); p<0.00001), elevated ALT (1.71 (1.32-2.20); p<0.00001), elevated creatinine (2.84 (1.80-4.46); p<0.00001) and LDH (5.48 (3.89-7.71); p<0.00001) were independently associated with higher risk of poor outcomes. Our study found a significant association between lymphopenia, thrombocytopenia and elevated levels of CRP, PCT, LDH, D-dimer and COVID-19 severity. The results have the potential to be used as an early biomarker to improve the management of COVID-19 patients, by identification of high-risk patients and appropriate allocation of healthcare resources in the pandemic.


The path to universal health coverage in five African and Asian countries: examining the association between insurance status and health-care use.
Despite major efforts to achieve universal health coverage (UHC), progress has lagged in many African and Asian countries. A key strategy pursued by many countries is the use of health insurance to increase access and affordability. However, evidence on insurance coverage and on the association between insurance and UHC is mixed. We analysed nationally representative cross-sectional data collected between 2022 and 2023 in Ethiopia, Kenya, South Africa, India, and Laos. We described public and private insurance coverage by sociodemographic factors and used logistic regression to examine the associations between insurance status and seven health-care use outcomes. Health insurance coverage ranged from 25% in India to 100% in Laos. The share of private insurance ranged from 1% in Ethiopia to 13% in South Africa. Relative to the population with private insurance, the uninsured population had reduced odds of health-care use (adjusted odds ratio 0·68, 95% CI 0·50-0·94), cardiovascular examinations (0·63, 0·47-0·85), eye and dental examinations (0·54, 0·42-0·70), and ability to get or afford care (0·64, 0·48-0·86); private insurance was not associated with unmet need, mental health care, and cancer screening. Relative to private insurance, public insurance was associated with reduced odds of health-care use (0·60, 0·43-0·82), mental health care (0·50, 0·31-0·80), cardiovascular examinations (0·62, 0·46-0·84), and eye and dental examinations (0·50, 0·38-0·65). Results were highly heterogeneous across countries. Public health insurance appears to be only weakly associated with access to health services in the countries studied. Further research is needed to improve understanding of these associations and to identify the most effective financing strategies to achieve UHC.


Glyphosate's impact on vegetative growth in leafy spurge identifies molecular processes and hormone cross-talk associated with increased branching.
Leafy spurge (Euphorbia esula) is a perennial weed that is considered glyphosate tolerant, which is partially attributed to escape through establishment of new vegetative shoots from an abundance of underground adventitious buds. Leafy spurge plants treated with sub-lethal concentrations of foliar-applied glyphosate produce new vegetative shoots with reduced main stem elongation and increased branching. Processes associated with the glyphosate-induced phenotype were determined by RNAseq using aerial shoots derived from crown buds of glyphosate-treated and -untreated plants. Comparison between transcript abundance and accumulation of shikimate or phytohormones (abscisic acid, auxin, cytokinins, and gibberellins) from these same samples was also done to reveal correlations. Transcriptome assembly and analyses confirmed differential abundance among 12,918 transcripts (FDR ≤ 0.05) and highlighted numerous processes associated with shoot apical meristem maintenance and stem growth, which is consistent with the increased number of actively growing meristems in response to glyphosate. Foliar applied glyphosate increased shikimate abundance in crown buds prior to decapitation of aboveground shoots, which induces growth from these buds, indicating that 5-enolpyruvylshikimate 3-phosphate (EPSPS) the target site of glyphosate was inhibited. However, abundance of shikimate was similar in a subsequent generation of aerial shoots derived from crown buds of treated and untreated plants, suggesting EPSPS is no longer inhibited or abundance of shikimate initially observed in crown buds dissipated over time. Overall, auxins, gibberellins (precursors and catabolites of bioactive gibberellins), and cytokinins (precursors and bioactive cytokinins) were more abundant in the aboveground shoots derived from glyphosate-treated plants. Based on the overall data, we propose that the glyphosate-induced phenotype resulted from complex interactions involving shoot apical meristem maintenance, hormone biosynthesis and signaling (auxin, cytokinins, gibberellins, and strigolactones), cellular transport, and detoxification mechanisms.


Organocatalytic asymmetric Michael/hemiketalization/acyl transfer reaction of 1,3-propanediones with (E)-2-(2-nitrovinyl)phenols.
An organocatalytic asymmetric cascade Michael/hemiketalization/acyl transfer reaction between (E)-2-(2-nitrovinyl)phenols and 1,3-propanediones is disclosed. A cinchona alkaloid derived bifunctional thiourea catalyst was found to be the most effective for this reaction and provided the desired products in moderate to good yields with good to high enantioselectivities.


Culturable phylogenetic diversity of the phylum 'Bacteroidetes' from river epilithon and coastal water and description of novel members of the family Flavobacteriaceae: Epilithonimonas tenax gen. nov., sp. nov. and Persicivirga xylanidelens gen. nov., sp. nov.
Members of the phylum 'Bacteroidetes' are important heterotrophs involved in cycling organic carbon in aquatic habitats. Their diversity has been studied by molecular methods in both freshwater and marine habitats and many novel genera and species within this phylum have been characterized in recent years. In this study, we examined the diversity of members of the 'Bacteroidetes' that could be readily isolated on solid media from river epilithon and coastal sea water. Most (93 %) of the 55 isolates confirmed as members of the 'Bacteroidetes' and examined by phylogenetic analysis of 16S rRNA gene sequences belonged to the Flavobacteriaceae. Furthermore, most (62 %) of these were almost certainly members of the genus Flavobacterium and all but one were from river epilithon. Conversely, the sea-water isolates were more widely distributed in clades containing other genera. Some of the isolates were deep-branching within phylogenetic trees and so could not be assigned to putative genera. Two of these deep-branching isolates were characterized by polyphasic taxonomy and are proposed as novel species within two new genera of the family Flavobacteriaceae. These are Epilithonimonas tenax gen. nov., sp. nov. (type strain EP105T = NCIMB 14026T = DSM 16811T) and Persicivirga xylanidelens gen. nov., sp. nov. (type strain SW256T = NCIMB 14027T = DSM 16809T).


Dispersal dynamics in food webs.
Studies of food webs suggest that limited nonrandom dispersal can play an important role in structuring food webs. It is not clear, however, whether density-dependent dispersal fits empirical patterns of food webs better than density-independent dispersal. Here, we study a spatially distributed food web, using a series of population-dispersal models that contrast density-independent and density-dependent dispersal in landscapes where sampled sites are either homogeneously or heterogeneously distributed. These models are fitted to empirical data, allowing us to infer mechanisms that are consistent with the data. Our results show that models with density-dependent dispersal fit the α, β, and γ tritrophic richness observed in empirical data best. Our results also show that density-dependent dispersal leads to a critical distance threshold beyond which site similarity (i.e., β tritrophic richness) starts to decrease much faster. Such a threshold can also be detected in the empirical data. In contrast, models with density-independent dispersal do not predict such a threshold. Moreover, preferential dispersal from more centrally located sites to peripheral sites does not provide a better fit to empirical data when compared with symmetric dispersal between sites. Our results suggest that nonrandom dispersal in heterogeneous landscapes is an important driver that shapes local and regional richness (i.e., α and γ tritrophic richness, respectively) as well as the distance-decay relationship (i.e., β tritrophic richness) in food webs.


The association between carotid intima media thickness and individual dietary components and patterns.
To review: 1) the correlation between individual dietary components and carotid intima media thickness (cIMT); 2) the relationship between dietary patterns and cIMT; 3) the effect of dietary interventions on cIMT progression. An electronic search for epidemiological and intervention trials investigating the association between dietary components or patterns of intake and cIMT was performed in PUBMED, EMBASE and the Cochrane Library. Epidemiological data shows that a higher intake of fruit, wholegrains and soluble fibre and lower consumption of saturated fat in favour of polyunsaturated fat is associated with lower cIMT. In people at high risk of cardiovascular disease >93 g/day of fruit is associated with lower cIMT. Lower cIMT has also been observed when >0.79 serves/day of wholegrains and >25 g/day of fibre, predominately in the soluble form is consumed. Saturated fat is positively associated with cIMT, for every 10 g/day increase in saturated fat cIMT is 0.03 mm greater. Olive oil is inversely associated with cIMT, with a benefit seen when >34 g/day is consumed. While there are many epidemiological studies exploring the association between dietary intake and cIMT there are few intervention studies. Intervention studies show that a Mediterranean diet may reduce cIMT progression, especially in those with a higher cIMT. A Mediterranean style dietary pattern, which is high in fruits, wholegrains, fibre and olive oil and low in saturated fat, may reduce carotid atherosclerosis development and progression. However further research from randomised controlled trials is required to understand the association between diet and cIMT and the underlying mechanisms.


Pyruvate Treatment Restores the Effectiveness of Chemotherapeutic Agents in Human Colon Adenocarcinoma and Pleural Mesothelioma Cells.
Emerging evidence supports the idea that a dysfunction in cell metabolism could sustain a resistant phenotype in cancer cells. As the success of chemotherapeutic agents is often questioned by the occurrence of multidrug resistance (MDR), a multiple cross-resistance towards different anti-cancer drugs represent a major obstacle to cancer treatment. The present study has clarified the involvement of the carbon metabolites in a more aggressive tumor colon adenocarcinoma phenotype and in a chemoresistant mesothelioma, and the role of pyruvate treatment in the reversion of the potentially related resistance. For the first time, we have shown that human colon adenocarcinoma cells (HT29) and its chemoresistant counterpart (HT29-dx) displayed different carbon metabolism: HT29-dx cells had a higher glucose consumption compared to HT29 cells, whereas human malignant mesothelioma (HMM) cells showed a lower glucose consumption compared to HT29 cells, accompanied by a lower pyruvate production and, consequently, a higher production of lactate. When treated with pyruvate, both HT29-dx and HMM cells exhibited a re-established accumulation of doxorubicin and a lower survival ability, a decreased activity of multidrug resistance protein 1 (MRP1) and a restored mitochondrial respiratory chain function, improving the effectiveness of the chemotherapeutic agents in these resistant cancer cells.


Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis.
Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.


Global operating theatre distribution and pulse oximetry supply: an estimation from reported data.
Surgery is an essential part of health care, but resources to ensure the availability of surgical services are often inadequate. We estimated the global distribution of operating theatres and quantified the availability of pulse oximetry, which is an essential monitoring device during surgery and a potential measure of operating theatre resources. We calculated ratios of the number of operating theatres to hospital beds in seven geographical regions worldwide on the basis of profiles from 769 hospitals in 92 countries that participated in WHO's safe surgery saves lives initiative. We used hospital bed figures from 190 WHO member states to estimate the number of operating theatres per 100,000 people in 21 subregions throughout the world. To estimate availability of pulse oximetry, we sent surveys to anaesthesia providers in 72 countries selected to ensure a geographically and demographically diverse sample. A predictive regression model was used to estimate the pulse oximetry need for countries that did not provide data. The estimated number of operating theatres ranged from 1·0 (95% CI 0·9-1·2) per 100,000 people in west sub-Saharan Africa to 25·1 (20·9-30·1) per 100,000 in eastern Europe. High-income subregions all averaged more than 14 per 100,000 people, whereas all low-income subregions, representing 2·2 billion people, had fewer than two theatres per 100,000. Pulse oximetry data from 54 countries suggested that around 77,700 (63,195-95,533) theatres worldwide (19·2% [15·2-23·9]) were not equipped with pulse oximeters. Improvements in public-health strategies and monitoring are needed to reduce disparities for more than 2 billion people without adequate access to surgical care. WHO.


ACTIVE IMMUNITY PRODUCED BY SO CALLED BALANCED OR NEUTRAL MIXTURES OF DIPHTHERIA TOXIN AND ANTITOXIN.
The foregoing and earlier data taken together demonstrate that an active immunity lasting several years can be produced in guinea-pigs, by the injection of toxin-antitoxin mixtures which have no recognizable harmful effect either immediate or remote. They also show, what might have been anticipated, that under the same conditions mixtures which produce local lesions and which, therefore, contain an excess of toxin produce a much higher degree of immunity than the neutral mixtures, and that an excess of antitoxin reduces the possibility of producing an active immunity, and may extinguish it altogether. There is, therefore, a certain definite relation between the components of the mixture and the degree of immunity producible. Furthermore, toxin-antitoxin mixtures do not change materially within five days at room temperature. They are apparently more efficacious at the end of forty-eight hours than immediately after preparation. The experiments finally prove that a relatively high degree of active immunity can be induced by a harmless procedure, whereas the use of toxin alone leading to very severe local lesions is incapable of producing more than an insignificant protection. The method, therefore, invites further tests in regard to its ultimate applicability to the human being. Unless the subcutis of the guinea-pig reacts to toxin-antitoxin mixtures in a manner peculiar to itself, a practical, easily controlled method for active immunization can be worked out which should afford a larger protection than the serum alone and avoid the complications associated with horse serum. That proportion of toxin and antitoxin which would produce the highest desirable immunity consistent with the least discomfort would have to be carefully worked out for the human subject. From the nature of the immunity induced it is obvious, however, that such a method of immunization cannot take the place of a large dose of antitoxin in exposed individuals who must be protected at once. It would be applicable only as a general protective measure without reference to any immediate danger, since it would take several weeks, perhaps longer, to perfect the attainable immunity. Passing to the theoretical aspects of the facts observed, we find no publications bearing directly upon the subject before us. Madsen has, however, approached it very closely in his experiments on the immunization of animals with mixtures not fully balanced, or, in other words, in which the "toxones" were still free. He found that the injection of such mixtures in rabbits, goats and horses produces an active immunity. He makes the significant remark that perhaps in the immunizing capacity we may possess the keenest reagent for a poison which is not able to exert any toxic action in the body. This is fully borne out by the experiments described, for in these we pass beyond the visible spectrum, so to speak, of the toxin-antitoxin effects, and we are able to recognize toxic action only by the lasting immunizing effects. Another publication which touches upon some phases of the same problem is that of Morgenroth on the union between toxin and antitoxin. Morgenroth brought out the fact that a given toxin-antitoxin mixture is more toxic when injected directly into the circulation than when injected under the skin. Thus, an L(+) dose of 0.78 c.c. toxin + one unit antitoxin applied subcutaneously was of the same toxicity as 0.68 c.c. toxin + one unit antitoxin injected into the circulation. When the mixture had stood twenty-four hours this (L(+)) dose was still 0.78 c.c. subcutaneously, but it had risen to 0.74 c.c. when introduced by the intracardiac route. The author makes two deductions from these results. He assumes that the velocity of reaction between toxin and antitoxin is slow, and that the union is not completed until the mixture has stood twenty-four hours. Hence, the L(+) dose of toxin injected into the blood is higher after twenty-four hours than immediately after mixing the toxin and antitoxin. He furthermore explains the fact that the subcutaneous L(+) dose remains the same whether the mixture is injected at once or after twenty-four hours, by assuming that in the subcutis of the guinea-pig there is a catalytic acceleration of the union of toxin and antitoxin. In view of the writer's results it seems that not only immediately, but four to five days after the preparation of the mixture of toxin and antitoxin, there are still toxic substances available for the production of immunity in the body of the guinea-pig, when the dose of toxin in the mixture is far below the L(0) or neutral level. These toxins may be free, either because uncombined in vitro, or else because the mixture is partially dissociated in vivo, or there may be a third possibility. It is obvious that Morgenroth's investigations, however extensive and thorough, have not exhausted the subject, for both these inferences are incompatible with his. Perhaps his recent important studies on the recovery of toxin from its combination with antitoxin with weak acids may throw more light on this subject. The only conclusion which we may safely draw at this time is that the toxin-antitoxin mixture produces two sets of effects, essentially identical, however. One is visible, as injury (oedema, loss of hair, superficial and deep necrosis of skin, paralysis and death), and corresponds to the toxin spectrum of Ehrlich. The other is invisible and manifests itself only in degrees of active immunity. At what ratio of toxin to antitoxin in the mixture active immunity is no longer produced will vary somewhat with the guinea-pig used, but it is evident that traces of immunity are still transmitted to the young when the amount of toxin approaches half the L(0) dose.


Distinct vestibular effects on early and late somatosensory cortical processing in humans.
In non-human primates several brain areas contain neurons that respond to both vestibular and somatosensory stimulation. In humans, vestibular stimulation activates several somatosensory brain regions and improves tactile perception. However, less is known about the spatio-temporal dynamics of such vestibular-somatosensory interactions in the human brain. To address this issue, we recorded high-density electroencephalography during left median nerve electrical stimulation to obtain Somatosensory Evoked Potentials (SEPs). We analyzed SEPs during vestibular activation following sudden decelerations from constant-velocity (90°/s and 60°/s) earth-vertical axis yaw rotations and SEPs during a non-vestibular control period. SEP analysis revealed two distinct temporal effects of vestibular activation: An early effect (28-32ms post-stimulus) characterized by vestibular suppression of SEP response strength that depended on rotation velocity and a later effect (97-112ms post-stimulus) characterized by vestibular modulation of SEP topographical pattern that was rotation velocity-independent. Source estimation localized these vestibular effects, during both time periods, to activation differences in a distributed cortical network including the right postcentral gyrus, right insula, left precuneus, and bilateral secondary somatosensory cortex. These results suggest that vestibular-somatosensory interactions in humans depend on processing in specific time periods in somatosensory and vestibular cortical regions.


Patient blood management knowledge and practice among clinicians from seven European university hospitals: a multicentre survey.
The aim of this survey was to evaluate the knowledge about Patient Blood Management (PBM) principles and practices amongst clinicians working in seven European hospitals participating in a European Blood Alliance (EBA) project. A web-based questionnaire was sent to 4952 clinicians working in medical, surgery and anaesthesiology disciplines. The responses were analysed, and the overall results as well as a comparison between hospitals are presented. A total of 788 responses (16%) were obtained. About 24% of respondents were not aware of a correlation between preoperative anaemia (POA) and perioperative morbidity and mortality. For 22%, treatment of POA was unlikely to favourably influence morbidity and mortality even before surgery with expected blood loss. More than half of clinicians did not routinely treat POA. 29%, when asked which is the best way to treat deficiency anaemia preoperatively, answered that they did not have sufficient knowledge and 5% chose to 'do nothing'. Amongst those who treated POA, 38% proposed red cell transfusion prior to surgery as treatment. Restrictive haemoglobin triggers for red blood cell transfusion, single unit policy and reduction of number and volumes of blood samples for diagnostic purposes were only marginally implemented. Overall, the responses indicated poor knowledge about PBM. Processes to diagnose and treat POA were not generally and homogeneously implemented. This survey should provide further impetus to implement programmes to improve knowledge and practice of PBM.


Aberrant light directly impairs mood and learning through melanopsin-expressing neurons.
The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep-wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.


Review of risk and protective factors of substance use and problem use in emerging adulthood.
This review examines the evidence for longitudinal predictors of substance use and abuse in emerging adulthood. Nationally representative data from the 2007 National Survey on Drug use and Health suggest that many substance use problems reach their peak prevalence during emerging adulthood (usually defined as the period from age 18 to age 26). This stage of development is characterized by rapid transitions into new social contexts that involve greater freedom and less social control than experienced during adolescence. Concurrent with this newfound independence is an increase in rates of substance use and abuse. Understanding the risk and protective factors associated with emerging adult substance use problems is an important step in developing interventions targeting those problems. While multiple reviews have examined risk and protective factors for substance use during adolescence, and many of these earlier predictors may predict emerging adult substance use, few studies have focused primarily on the emerging adult outcomes examining predictors from both adolescence and emerging adulthood. This review used the databases PubMed and PsycInfo to identify articles pertaining to longitudinal predictors of substance use problems in emerging adulthood, building from the conceptual framework presented in a review on risk and protective factors for adolescent substance abuse by Hawkins and colleagues (Hawkins, Catalano, & Miller, 1992). Predictors identified as predictors of substance use in adolescence, sometimes decreased in strength and in one case reversed direction. Unique predictors in emerging adulthood were also identified. Implications for prevention science during adolescence and emerging adulthood are discussed as well as suggestions for future research.


Dual pathways for regulation of root branching by nitrate.
Root development is extremely sensitive to variations in nutrient supply, but the mechanisms are poorly understood. We have investigated the processes by which nitrate (NO3-), depending on its availability and distribution, can have both positive and negative effects on the development and growth of lateral roots. When Arabidopsis roots were exposed to a locally concentrated supply of NO3- there was no increase in lateral root numbers within the NO3--rich zone, but there was a localized 2-fold increase in the mean rate of lateral root elongation, which was attributable to a corresponding increase in the rate of cell production in the lateral root meristem. Localized applications of other N sources did not stimulate lateral root elongation, consistent with previous evidence that the NO3- ion is acting as a signal rather than a nutrient. The axr4 auxin-resistant mutant was insensitive to the stimulatory effect of NO3-, suggesting an overlap between the NO3- and auxin response pathways. High rates of NO3- supply to the roots had a systemic inhibitory effect on lateral root development that acted specifically at the stage when the laterals had just emerged from the primary root, apparently delaying final activation of the lateral root meristem. A nitrate reductase-deficient mutant showed increased sensitivity to this systemic inhibitory effect, suggesting that tissue NO3- levels may play a role in generating the inhibitory signal. We present a model in which root branching is modulated by opposing signals from the plant's internal N status and the external supply of NO3-.


Strong impact on the polycyclic aromatic hydrocarbon (PAH)-degrading community of a PAH-polluted soil but marginal effect on PAH degradation when priming with bioremediated soil dominated by mycobacteria.
Bioaugmentation of soil polluted with polycyclic aromatic hydrocarbons (PAHs) is often disappointing because of the low survival rate and low activity of the introduced degrader bacteria. We therefore investigated the possibility of priming PAH degradation in soil by adding 2% of bioremediated soil with a high capacity for PAH degradation. The culturable PAH-degrading community of the bioremediated primer soil was dominated by Mycobacterium spp. A microcosm containing pristine soil artificially polluted with PAHs and primed with bioremediated soil showed a fast, 100- to 1,000-fold increase in numbers of culturable phenanthrene-, pyrene-, and fluoranthene degraders and a 160-fold increase in copy numbers of the mycobacterial PAH dioxygenase gene pdo1. A nonpolluted microcosm primed with bioremediated soil showed a high rate of survival of the introduced degrader community during the 112 days of incubation. A nonprimed control microcosm containing pristine soil artificially polluted with PAHs showed only small increases in the numbers of culturable PAH degraders and no pdo1 genes. Initial PAH degradation rates were highest in the primed microcosm, but later, the degradation rates were comparable in primed and nonprimed soil. Thus, the proliferation and persistence of the introduced, soil-adapted degraders had only a marginal effect on PAH degradation. Given the small effect of priming with bioremediated soil and the likely presence of PAH degraders in almost all PAH-contaminated soils, it seems questionable to prime PAH-contaminated soil with bioremediated soil as a means of large-scale soil bioremediation.


Stunting and lead: using causal mediation analysis to better understand how environmental lead exposure affects cognitive outcomes in children.
Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead's adverse effects on neurodevelopment are caused in part by lead's effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure's adverse effect on cognitive development. Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20-40 months. Stunting was determined using the World Health Organization's standards. Neurodevelopment was assessed at age 20-40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification). Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 μg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2-3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (β = - 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 μg/dL, β = - 0.45, SE = 0.49, P = 0.360). We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead's effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.


Decreasing diversity of rare bacterial subcommunities relates to dissolved organic matter along permafrost thawing gradients.
Dissolved organic matter (DOM) released from permafrost thaw greatly influences the biogeochemical cycles of, among others, downstream carbon, nitrogen and phosphorus cycles; yet, knowledge of the linkages between bacterial communities with permafrost DOM heterogeneity is limited. Here, we aim at unravelling the responses of bacterial diversities and metabolic profiles to DOM quantity and composition across permafrost thawing gradients by coupling an extensive field investigation with bio-incubation experiments. Richness, evenness and dissimilarities of the whole and rare communities decreased from thermokarst pits to headstreams and to downstream rivers. The assemblages of the abundant subcommunities were mainly determined by ecological drift-driven stochastic processes. Both the optical and the molecular composition of DOM were significantly related to the changes of the whole (rare) bacterial communities (Mantel's correlation > 0.5, p < 0.01). Diversity indices of the whole and rare communities decreased with decreasing relative abundance of tannins, condensed aromatics and more aromatic and oxidized lignins as well as with decreased dissolved organic carbon and intensities of all fluorescence components. Laboratory DOM bio-incubation experiments further confirmed microbial consumption of more aromatic and oxidized compounds as well as decreasing metabolic diversities in terms of microbial degradation and production along permafrost thawing gradients. Our findings suggest that changes in the sources of permafrost-derived DOM induced by global warming can have different influences on the diversity and metabolism of bacterial communities and thus on permafrost carbon climate feedbacks along permafrost thawing gradients.


Does melatonin treatment change emotional processing? Implications for understanding the antidepressant mechanism of agomelatine.
The antidepressant, agomelatine, has a novel pharmacological profile, with agonist properties at M1 and M2 receptors and antagonist properties at 5HT2C receptors. Whether the antidepressant effects of this treatment are mediated by the drug's effects at the M1 and M2 receptors or the 5HT2C receptor or a synergy between these actions remains unclear. In the present study, a healthy volunteer model of emotional processing, which discriminates between effective and non-effective antidepressant compounds, was used to assess the contribution of melatonin agonism to the efficacy of agomelatine. Fifty-eight healthy volunteers were randomised to receive 7 days of once daily treatment with either 1 mg melatonin, 3 mg melatonin or placebo. Seven days treatment with 3 mg melatonin resulted in earlier bedtimes consistent with a phase advance in circadian rhythm. Some marginal effects of melatonin were observed on emotional processing; however, these were neither consistent with nor comparable to those seen following conventional antidepressant treatment or with agomelatine itself. These data suggest that the antidepressant action of agomelatine cannot be accounted for solely by its action at the M1 and M2 receptors.


Emergency therapy of maternal and fetal arrhythmias during pregnancy.
Atrial premature beats are frequently diagnosed during pregnancy (PR); supraventricular tachycardia (SVT) (atrial tachycardia, AV-nodal reentrant tachycardia, circus movement tachycardia) is less frequently diagnosed. For acute therapy, electrical cardioversion with 50-100 J is indicated in all unstable patients (pts). In stable SVT, the initial therapy includes vagal maneuvers to terminate tachycardias. For short-term management, when vagal maneuvers fail, intravenous adenosine is the first choice drug and may safely terminate the arrhythmia. Ventricular premature beats are also frequently present during PR and benign in most of the pts; however, malignant ventricular tachyarrhythmias (sustained ventricular tachycardia [VT], ventricular flutter [VFlut] or ventricular fibrillation [VF]) may occur. Electrical cardioversion is necessary in all pts who are in hemodynamically unstable situation with life-threatening ventricular tachyarrhythmias. In hemodynamically stable pts, initial therapy with ajmaline, procainamide or lidocaine is indicated. In pts with syncopal VT, VF, VFlut or aborted sudden death, an implantable cardioverter-defibrillator is indicated. In pts with symptomatic bradycardia, a pacemaker can be implanted using echocardiography at any stage of PR. The treatment of the pregnant patient with cardiac arrhythmias requires important modifications of the standard practice of arrhythmia management. The goal of therapy is to protect the patient and fetus through delivery, after which chronic or definitive therapy can be administered.


Reducing earthquake-related fears in victim and nonvictim children.
In this study, the authors investigated the fears of earthquake victim and nonvictim elementary school students and the effectiveness of an activity-based cognitive fear reduction (ABCF) procedure developed by the authors. To measure fear, the authors collected data from 266 participants using a modified version of the Fear Survey Schedule for Children (FSSC; W. Yule, O. Udwin, & K. Murdoch, 1990). Results demonstrated that earthquake victim children were more fearful on 2 subtests of the FSSC than were nonvictim children and that girls had significantly stronger fears on all subscales than did boys. The ABCF procedure was not an effective approach for reducing the fears of earthquake victims. However, the control group did demonstrate a significant reduction in fears. The authors suggest that the activity designed for this group may have been an intervention in itself. The authors discuss this finding and offer suggestions for researchers and therapists.


Automatic analysis of cerebral asymmetry: an exploratory study of the relationship between brain torque and planum temporale asymmetry.
Leftward occipital and rightward frontal lobe asymmetry (brain torque) and leftward planum temporale asymmetry have been consistently reported in postmortem and in vivo neuroimaging studies of the human brain. Here automatic image analysis techniques are applied to quantify global and local asymmetries, and investigate the relationship between brain torque and planum temporale asymmetries on T1-weighted magnetic resonance (MR) images of 30 right-handed young healthy subjects (15 male, 15 female). Previously described automatic cerebral hemisphere extraction and 3D interhemispheric reflection-based methods for studying brain asymmetry are applied with a new technique, LowD (Low Dimension), which enables automatic quantification of brain torque. LowD integrates extracted left and right cerebral hemispheres in columns orthogonal to the midsagittal plane (2D column maps), and subsequently integrates slices along the brain's anterior-posterior axis (1D slice profiles). A torque index defined as the magnitude of occipital and frontal lobe asymmetry is computed allowing exploratory investigation of relationships between this global asymmetry and local asymmetries found in the planum temporale. LowD detected significant torque in the 30 subjects with occipital and frontal components found to be highly correlated (P<0.02). Significant leftward planum temporale asymmetry was detected (P<0.05), and the torque index correlated with planum temporale asymmetry (P<0.001). However, torque and total brain volume were not correlated. Therefore, although components of cerebral asymmetry may be related, their magnitude is not influenced by total hemisphere volume. LowD provides increased sensitivity for detection and quantification of brain torque on an individual subject basis, and future studies will apply these techniques to investigate the relationship between cerebral asymmetry and functional laterality.


Protection Against Necrotic Enteritis in Broiler Chickens by Regulated Delayed Lysis Salmonella Vaccines.
Necrotic enteritis (NE), caused by Gram-positive Clostridium perfringens type A strains, has gained more attention in the broiler industry due to governmental restrictions affecting the use of growth-promoting antibiotics in feed. To date, there is only one commercial NE vaccine available, based on the C. perfringens alpha toxin. However, recent work has suggested that the NetB toxin, not alpha toxin, is the most critical virulence factor for causing NE. These findings notwithstanding, it is clear from prior research that immune responses against both toxins can provide some protection against NE. In this study, we delivered a carboxyl-terminal fragment of alpha toxin and a GST-NetB fusion protein using a novel attenuated Salmonella vaccine strain designed to lyse after 6-10 rounds of replication in the chicken host. We immunized birds with vaccine strains producing each protein individually, a mixture of the two strains, or with a single vaccine strain that produced both proteins. Immunization with strains producing either of the single proteins was not protective, but immunization with a mixture of the two or with a single strain producing both proteins resulted in protective immunity. The vaccine strain synthesizing both PlcC and GST-NetB was able to elicit strong production of intestinal IgA, IgY, and IgM antibodies and significantly protect broilers against C. perfringens challenge against both mild and severe challenges. Although not part of our experimental plan, the broiler chicks we obtained for these studies were apparently contaminated during transit from the hatchery with group D Salmonella. Despite this drawback, the vaccines worked well, indicating applicability to real-world conditions.


Why the activity of a gene depends on its neighbors.
Sixty years ago, the position of a gene on a chromosome was seen to be a major determinant of gene activity; however, position effects are rarely central to current discussions of gene expression. We describe a comprehensive and simplifying view of how position in 1D sequence and 3D nuclear space underlies expression. We suggest that apparently-different regulatory motifs including enhancers, silencers, insulators, barriers, and boundaries act similarly - they are active promoters that tether target genes close to, or distant from, appropriate transcription sites or 'factories'. We also suggest that any active transcription unit regulates the firing of its neighbors - and thus can be categorized as one or other type of motif; this is consistent with expression quantitative trait loci (eQTLs) being widely dispersed.


Complementing the inflammasome.
The innate immune system is an ancient surveillance system able to sense microbial invaders as well as aberrations in normal cell function. No longer viewed as a static and non-specific part of immunity, the innate immune system employs a plethora of specialized pattern recognition sensors to monitor and achieve homeostasis; these include the Toll-like receptors, the retinoic acid-inducible gene-like receptors, the nucleotide-binding oligomerization domain receptors (NLRs), the C-type lectins and the complement system. In order to increase specificity and diversity, innate immunity uses homotypic and heterotypic associations among these different components. Multi-molecular assemblies are formed both on the cell surface and in the cytosol to respond to pathogen and danger signals. Diverse, but tailored, responses to a changing environment are orchestrated depending on the the nature of the challenge and the repertoire of interacting receptors and components available in the sensing cell. It is now emerging that innate immunity operates a system of 'checks and balances' where interaction among the sensors is key in maintaining normal cell function. Complement sits at the heart of this alarm system and it is becoming apparent that it is capable of interacting with all the other pathways to effect a tailored immune response. In this review, we will focus on complement interactions with NLRs, the so-called 'inflammasomes', describing the molecular mechanisms that have been revealed so far and discussing the circumstantial evidence that exists for these interactions in disease states.


MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation.
A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca(2+) current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF. The miRNA transcriptome was analyzed by microarray and verified by real-time reverse-transcription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by >2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca(2+) channel α1c- and β1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca(2+) current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca(2+) channel protein subunits. miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca(2+) channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.


Determination of size and position of fast moving gas bubbles in liquids by digital 3-D image processing of hologram reconstructions.
An experimental setup for digital 3-D image processing from hologram reconstructions is described. The real image as obtained upon reconstruction of the hologram with its conjugated reference wave is scanned by a movable image dissector camera without imaging optics and serves as analog 3-D picture input storage to the computer. This scheme has been developed to analyze automatically fast moving bubble fields in liquids recorded by high speed holographic techniques. A computer code has been written combining standard methods like gradient filtering from the field of image processing with specially developed algorithms for speckle noise suppression to locate and count the bubbles in the image volume and to determine their morphological data.


Experimental transvitreal cyanoacrylate retinopexy in a primate model.
We evaluated the use of transvitreal cyanoacrylate retinopexy in the treatment of experimental rhegmatogenous retinal detachment during vitreous surgery in the cynomolgus monkey. The chorioretinal adhesions produced with cyanoacrylate tissue adhesive as compared with those produced by transscleral retinal cryopexy were more rapid in onset as well as stronger. To test the efficacy of cyanoacrylate retinopexy further, a 360-degree peripheral retinectomy was created in five eyes with circumferential cyanoacrylate application to the posterior retinal edge. The cyanoacrylate retinopexy did not prevent the development of proliferative vitreoretinopathy with traction retinal detachment, but in three of the eyes the tissue adhesive continued to maintain retinal apposition to the retinal pigment epithelium at the retinotomy edge. Histologic examination of the retinas disclosed a foreign body reaction adjacent to the cyanoacrylate sites, but there was no evidence of any distant effects caused by the tissue adhesive.


Effect of temperature and pressure on surface tension of polystyrene in supercritical carbon dioxide.
The surface tension of polymers in a supercritical fluid is one of the most important physicochemical parameters in many engineering processes, such as microcellular foaming where the surface tension between a polymer melt and a fluid is a principal factor in determining cell nucleation and growth. This paper presents experimental results of the surface tension of polystyrene in supercritical carbon dioxide, together with theoretical calculations for a corresponding system. The surface tension is determined by Axisymmetric Drop Shape Analysis-Profile (ADSA-P), where a high pressure and temperature cell is designed and constructed to facilitate the formation of a pendent drop of polystyrene melt. Self-consistent field theory (SCFT) calculations are applied to simulate the surface tension of a corresponding system, and good qualitative agreement with experiment is obtained. The physical mechanisms for three main experimental trends are explained by using SCFT, and none of the explanations quantitatively depend on the configurational entropy of the polymer constituents. These calculations therefore rationalize the use of simple liquid models for the quantitative prediction of surface tensions of polymers. As pressure and temperature increase, the surface tension of polystyrene decreases. A linear relationship is found between surface tension and temperature, and between surface tension and pressure; the slope of surface tension change with temperature is dependent on pressure.


Physical Activities That Cause High Friction Moments at the Cup in Hip Implants.
High friction moments in hip implants contribute to the aseptic loosening of cementless cups, of which there are approximately 100,000 cases per year; sustained joint loading may cause such high moments. The most "critical" physical activities associated with sustained joint loading were identified in this study. Friction moments in the cup were telemetrically measured about 33,000 times in the endoprostheses of 9 subjects during >1,400 different activities. The highest moments were compared with the cup's fixation stability limit of approximately 4 Nm. A total of 124 different activities caused friction moments meeting or exceeding the critical limit, with the highest value of 11.5 Nm. Most involved sustained high contact forces before or during the activity. The highest peak moments (6.3 to 11.5 Nm) occurred when moving the contralateral leg during 1-legged stance, during breaststroke swimming, muscle stretching, 2-legged stance with muscle contraction, and during static 1-legged stance. The median moments were highest (3.4 to 3.9 Nm) for unstable 1-legged stance, whole-body vibration training, 2-legged stance with an unexpected push at the upper body, 1-legged stance while exercising the contralateral leg, and running after 2-legged stance. Frequent unloading plus simultaneous movement of the joint are required to maintain good joint lubrication and keep the friction moments low. Frequent, sustained high loads before or during an activity may cause or contribute to aseptic cup loosening. During the first months after hip arthroplasty, such activities should be avoided or reduced as much as possible. This especially applies during postoperative physiotherapy. Whether these guidelines also apply for subjects with knee implants or arthrotic hip or knee joints requires additional investigation. The risk of aseptic cup loosening may be reduced by avoiding sustained loading of hip implants without periodic joint movement.


[Transplantation of neural stem cells into the cochlea].
Stem cell therapy is especially interesting for inner ear related diseases, since the hair cells are very sensitive and do not regenerate. Hair cell loss is therefore irreversible and is accompanied by hearing loss. In the last few years, different research groups have transplanted stem cells into the inner ear with promising results. In the presented study, our aim was to gain insight into how neuronal stem cells behave when they are transplanted, both in vitro and in vivo, into a damaged inner ear. Neuronal stem cells from E9.5 day old mouse embryos were collected and infected with an adenoviral vector encoding green fluorescent protein (GFP). GFP+ cells were then transplanted into a damaged organ of Corti in vitro or into a damaged mouse inner ear in vivo. We were able to detect GFP+ cells close to the organ of Corti in vitro and in the organ of Corti in vivo. The GFP+ cells do not seem to be randomly distributed in either the in vitro or in vivo situation. Most interestingly, GFP+ cells could be detected close to places where hair cells had been lost in vivo. Neuronal stem cells are interesting candidates to replace lost hair cells. However, a great deal of research is still needed before they can enter clinical trials.


Cloning and expression of gamma-adaptin, a component of clathrin-coated vesicles associated with the Golgi apparatus.
Adaptins are the major components of adaptors, the protein complexes that link clathrin to transmembrane proteins (e.g., receptors) in coated pits and vesicles. The plasma membrane adaptor contains an alpha-adaptin subunit and a beta-adaptin subunit, while the Golgi adaptor contains a gamma-adaptin subunit and a beta'-adaptin subunit. A partial cDNA clone encoding gamma-adaptin was isolated from a bovine brain expression library by screening with antibodies, and was used to obtain a cDNA clone from a mouse brain library containing the full coding sequence. The identity of the clones was confirmed by protein sequencing. The deduced amino acid sequence of gamma-adaptin was found to be homologous to that of alpha-adaptin, with several stretches of identical amino acids or conservative substitutions in the first approximately 70 kD, and 25% identity overall. Weaker homology was seen between gamma- and beta-adaptins. Like both alpha- and beta-adaptins, gamma-adaptin has a proline and glycine-rich hinge region, dividing it into NH2- and COOH-terminal domains. A chimeric gamma-adaptin was constructed from the mouse and bovine cDNAs and transfected into Rat 1 fibroblasts. Immunofluorescence microscopy was carried out using an mAb which recognizes an epitope present on the chimera but not found on the rodent protein. The construct was found to have a distribution typical of endogenous gamma-adaptin. Using this transfection system, it should now be possible to exchange domains between alpha- and gamma-adaptins, to try to find out how adaptors are targeted to the appropriate membrane compartment of the cell, and how they recruit the appropriate receptors into the coated vesicle.


Creative user-centered visualization design for energy analysts and modelers.
We enhance a user-centered design process with techniques that deliberately promote creativity to identify opportunities for the visualization of data generated by a major energy supplier. Visualization prototypes developed in this way prove effective in a situation whereby data sets are largely unknown and requirements open - enabling successful exploration of possibilities for visualization in Smart Home data analysis. The process gives rise to novel designs and design metaphors including data sculpting. It suggests: that the deliberate use of creativity techniques with data stakeholders is likely to contribute to successful, novel and effective solutions; that being explicit about creativity may contribute to designers developing creative solutions; that using creativity techniques early in the design process may result in a creative approach persisting throughout the process. The work constitutes the first systematic visualization design for a data rich source that will be increasingly important to energy suppliers and consumers as Smart Meter technology is widely deployed. It is novel in explicitly employing creativity techniques at the requirements stage of visualization design and development, paving the way for further use and study of creativity methods in visualization design.


Environmental radioactivity and high incidence rates of stomach and esophagus cancer in the Van Lake region: a causal relationship?
This study examined the incidence rates of cancer cases (averages for 2006-2010) and relationships with environmental radioactivity levels. Soil and water samples were collected from provincial and district centers of Van city and the outdoor gamma doses were determined using a portable gamma scintillation detector. Gross alpha and beta, (226)Ra, (232)Th, and (40)K activities were measured in both tap water and soil samples. Although high rates of stomach and esophagus cancers have been reported previously in Van the underlying reasons have not hitherto been defined. Incidences of cancers were highest in the Gurpinar (326.0) and Ozalp (377.1) counties (p<0.001). As to the results of the gross alpha and gross beta radioactivity measurements in the drinking water, these two counties also had high beta radionuclide levels: Gurpinar (140 mBq/dm3) and Ozalp (206 mBq/dm3). Even if within the normal range, a relation between the higher rate of the incidence of stomach and esophagus cancers with that of the higher rate of beta radionuclide activity was clear. On Spearman correlation analysis, the relation between higher beta radionuclide levels and cancer incidence was found to be statistically significant (p<0.01). According to the results of the analysis, Van residents receive an average 1.86 mSv/y annual dose from outdoor gamma radiation, ingestion of radionuclides in the drinking water, and indoor 222Rn activity. Moreover, gross alpha and beta activities were found to be extremely high in all of the lakes around the city of Van, Turkey. Further investigations with long-term detailed environmental radiation measurements are needed regarding the relationship between cancer cases and environmental radioactivity in the city of Van.


The pipid root.
The estimation of phylogenetic relationships is an essential component of understanding evolution. Accurate phylogenetic estimation is difficult, however, when internodes are short and old, when genealogical discordance is common due to large ancestral effective population sizes or ancestral population structure, and when homoplasy is prevalent. Inference of divergence times is also hampered by unknown and uneven rates of evolution, the incomplete fossil record, uncertainty in relationships between fossil and extant lineages, and uncertainty in the age of fossils. Ideally, these challenges can be overcome by developing large "phylogenomic" data sets and by analyzing them with methods that accommodate features of the evolutionary process, such as genealogical discordance, recurrent substitution, recombination, ancestral population structure, gene flow after speciation among sampled and unsampled taxa, and variation in evolutionary rates. In some phylogenetic problems, it is possible to use information that is independent of fossils, such as the geological record, to identify putative triggers for diversification whose associated estimated divergence times can then be compared a posteriori with estimated relationships and ages of fossils. The history of diversification of pipid frog genera Pipa, Hymenochirus, Silurana, and Xenopus, for instance, is characterized by many of these evolutionary and analytical challenges. These frogs diversified dozens of millions of years ago, they have a relatively rich fossil record, their distributions span continental plates with a well characterized geological record of ancient connectivity, and there is considerable disagreement across studies in estimated evolutionary relationships. We used high throughput sequencing and public databases to generate a large phylogenomic data set with which we estimated evolutionary relationships using multilocus coalescence methods. We collected sequence data from Pipa, Hymenochirus, Silurana, and Xenopus and the outgroup taxon Rhinophrynus dorsalis from coding sequence of 113 autosomal regions, averaging ∼300 bp in length (range: 102-1695 bp) and also a portion of the mitochondrial genome. Analysis of these data using multiple approaches recovers strong support for the ((Xenopus, Silurana)(Pipa, Hymenochirus)) topology, and geologically calibrated divergence time estimates that are consistent with estimated ages and phylogenetic affinities of many fossils. These results provide new insights into the biogeography and chronology of pipid diversification during the breakup of Gondwanaland and illustrate how phylogenomic data may be necessary to tackle tough problems in molecular systematics. [Coalescence; gene tree; high-throughout sequencing; lineage sorting; pipid; species tree; Xenopus.].


Utility elicitation in adults and children for allergic rhinoconjunctivitis and associated health states.
Allergic rhinitis and asthma symptoms are detrimental to health-related quality of life (HRQoL). Health technology appraisal agencies often require cost-utility analysis when assessing new interventions. Appropriate utility estimates, which quantify the value of different conditions in cost-utility analyses, are scarce for allergic rhinitis and asthma health states. This study aimed to generate utilities for allergic rhinitis and asthma health states from a European general population sample of adults and children. Health state descriptions incorporating symptoms, impact of symptoms on daily life and symptom treatment were developed using clinical guidelines. Descriptions were amended with clinician and patient input, and incorporated into a survey in which each health state was followed by a standard gamble (adults) or visual analogue scale (children) item. The survey was distributed to samples of adults and children aged 8 to 11 from four European countries that were stratified to represent the general population within that country. 1454 adults and 1082 children completed the survey. Mean health utilities ranged from 0.635 to 0.880 and those elicited in children were lower (0.635 to 0.705) than those elicited in adults (0.812 to 0.880). Disutilities assessing the impact of increased allergic rhinitis severity and comorbidities were also greater in children than in adults. Symptoms of allergic rhinitis and asthma were valued as having a clinically meaningful impact on HRQoL. Children valued health states as poorer than adults, and further research should investigate whether this reflects true preferential differences or results from methodological and/or comprehension differences between the two groups.


Efficacy of Epidural Injections in Managing Chronic Spinal Pain: A Best Evidence Synthesis.
Epidural injections have been used since 1901 in managing low back pain and sciatica. Spinal pain, disability, health, and economic impact continue to increase, despite numerous modalities of interventions available in managing chronic spinal pain. Thus far, systematic reviews performed to assess the efficacy of epidural injections in managing chronic spinal pain have yielded conflicting results. To evaluate and update the clinical utility of the efficacy of epidural injections in managing chronic spinal pain. A systematic review of randomized controlled trials of epidural injections in managing chronic spinal pain. In this systematic review, randomized trials with a placebo control or an active-control design were included. The outcome measures were pain relief and functional status improvement. The quality of each individual article was assessed by Cochrane review criteria, as well as the Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB). Best evidence synthesis was conducted based on the qualitative level of evidence (Level I to V). Data sources included relevant literature identified through searches of PubMed for a period starting in 1966 through August 2015; Cochrane reviews; and manual searches of the bibliographies of known primary and review articles. A total of 52 trials met inclusion criteria. Meta-analysis was not feasible. The evidence in managing lumbar disc herniation or radiculitis is Level II for long-term improvement either with caudal, interlaminar, or transforaminal epidural injections with no significant difference among the approaches. The evidence is Level II for long-term management of cervical disc herniation with interlaminar epidural injections. The evidence is Level II to III in managing thoracic disc herniation with an interlaminar approach. The evidence is Level II for caudal and lumbar interlaminar epidural injections with Level III evidence for lumbar transforaminal epidural injections for lumbar spinal stenosis. The evidence is Level III for cervical spinal stenosis management with an interlaminar approach. The evidence is Level II for axial or discogenic pain without facet arthropathy or disc herniation treated with caudal or lumbar interlaminar injections in the lumbar region; whereas it is Level III in the cervical region treated with cervical interlaminar epidural injections. The evidence for post lumbar surgery syndrome is Level II with caudal epidural injections and for post cervical surgery syndrome it is Level III with cervical interlaminar epidural injections. Even though this is a large systematic review with inclusion of a large number of randomized controlled trials, the paucity of high quality randomized trials literature continues to confound the evidence. This systematic review, with an assessment of the quality of manuscripts and outcome parameters, shows the efficacy of epidural injections in managing a multitude of chronic spinal conditions.


Word production inconsistency of Singaporean-English-speaking adolescents with Down Syndrome.
The nature of speech disorders in individuals with Down Syndrome (DS) remains controversial despite various explanations put forth in the literature to account for the observed speech profiles. A high level of word production inconsistency in children with DS has led researchers to query whether the inconsistency continues into adolescence, and if the inconsistency stems from inconsistent phonological disorder (IPD) or childhood apraxia of speech (CAS). Of the studies that have been published, most suggest that the speech profile of individuals with DS is delayed, while a few recent studies suggest a combination of delayed and disordered patterns. However, no studies have explored the nature of word production inconsistency in this population, and the relationship between word production inconsistency, receptive vocabulary and severity of speech disorder. To investigate in a pilot study the extent of word production inconsistency in adolescents with DS and to examine the correlations between word production inconsistency, measures of receptive vocabulary, severity of speech disorder and oromotor skills in adolescents with DS. The participants were 32 native speakers of Singaporean-English adolescents, comprising 16 participants with DS and 16 typically developing (TD) participants. The participants completed a battery of standardized speech and language assessments, including The Diagnostic Evaluation of Articulation and Phonology (DEAP) assessment. Results from each test were correlated to determine relationships. Qualitative analyses were also carried out on all the data collected. In this study, seven out of 16 participants with DS scored above 40% on word production inconsistency, a diagnostic criterion for IPD. In addition, all participants with DS performed poorly on the oromotor assessment of DEAP. The overall speech profile observed did not exactly correspond with the cluster symptoms observed in children with IPD or CAS. Word production inconsistency is a noticeable feature in the speech of individuals with DS. In addition, the speech profiles of individuals with DS consist of atypical and unusual errors alongside developmental errors. Significant correlations were found between the measures investigated, suggesting that speech disorder in DS is multifactorial. The results from this study will help to improve differential diagnosis of speech disorders and individualized treatment plans in the population with DS.


Mechanochemical solid state anion-exchange of lead(II) coordination polymers via an intermediate coordination polymer; new precursors for the preparation of PbBr2/Pb3O2Br2, PbBr(OH) and PbO nanoparticles.
The reversible crystal-to-crystal transformations of a 1D lead(II) coordination polymer with the ligand 2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene (4-bpdh), from [Pb(4-bpdh)Br2]n () to intermediate [Pb(4-bpdh)(Br)(NO3)]n () and [Pb(4-bpdh)(NO3)2(H2O)]n () by a solid state anion-replacement processes under mechanochemical reactions, have been studied. The reversible solid state structural transformation of compound to compound and then by anion replacement have been verified by PXRD and IR measurements. PbBr2, PbBr(OH), Pb3O2Br2 and PbO nanoparticles were obtained by the thermal decomposition of compounds , and in oleic acid at 180 °C in an air atmosphere, respectively. These nanoparticles were characterized by powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM).