Biomedical ontology alignment: an approach based on representation learning.
While representation learning techniques have shown great promise in application to a number of different NLP tasks, they have had little impact on the problem of ontology matching. Unlike past work that has focused on feature engineering, we present a novel representation learning approach that is tailored to the ontology matching task. Our approach is based on embedding ontological terms in a high-dimensional Euclidean space. This embedding is derived on the basis of a novel phrase retrofitting strategy through which semantic similarity information becomes inscribed onto fields of pre-trained word vectors. The resulting framework also incorporates a novel outlier detection mechanism based on a denoising autoencoder that is shown to improve performance. An ontology matching system derived using the proposed framework achieved an F-score of 94% on an alignment scenario involving the Adult Mouse Anatomical Dictionary and the Foundational Model of Anatomy ontology (FMA) as targets. This compares favorably with the best performing systems on the Ontology Alignment Evaluation Initiative anatomy challenge. We performed additional experiments on aligning FMA to NCI Thesaurus and to SNOMED CT based on a reference alignment extracted from the UMLS Metathesaurus. Our system obtained overall F-scores of 93.2% and 89.2% for these experiments, thus achieving state-of-the-art results. Our proposed representation learning approach leverages terminological embeddings to capture semantic similarity. Our results provide evidence that the approach produces embeddings that are especially well tailored to the ontology matching task, demonstrating a novel pathway for the problem.


Genomewide association analysis of coronary artery disease.
Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.


Medical complications of prematurity.
The improved survival of extremely premature infants has generated intense interest in the quality of life of the survivors. This review focuses on the major long-term complications of prematurity (developmental disability, retinopathy of prematurity, chronic lung disease) and concludes with an overview of the broader spectrum of morbidity. Severe impairment (cerebral palsy, mental retardation, retrolental fibroplasia, severe chronic lung disease) fortunately occurs in a small proportion of survivors. However, the prevalence of the lesser morbidities (minimal cerebral dysfunction/learning disability, poor growth, postneonatal illnesses, rehospitalization) is less clearly defined. These problems all have an impact on families, and on medical and educational services.


Acute effect of different stretching methods on Illinois agility test in soccer players.
The purpose of this study was to examine the effects of static, dynamic, and the combination of static and dynamic stretching within a pre-exercise warm-up on the Illinois agility test (IAT) in soccer players. Nineteen professional soccer players (age = 22.5 ± 2.5 years, height = 1.79 ± 0.003 m, body mass = 74.8 ± 10.9 kg) were tested for agility performance using the IAT after different warm-up protocols consisting of static, dynamic, combined stretching, and no stretching. The players were subgrouped into less and more experienced players (5.12 ± 0.83 and 8.18 ± 1.16 years, respectively). There were significant decreases in agility time after no stretching, among no stretching vs. static stretching; after dynamic stretching, among static vs. dynamic stretching; and after dynamic stretching, among dynamic vs. combined stretching during warm-ups for the agility: mean ± SD data were 14.18 ± 0.66 seconds (no stretch), 14.90 ± 0.38 seconds (static), 13.95 ± 0.32 seconds (dynamic), and 14.50 ± 0.35 seconds (combined). There was significant difference between less and more experienced players after no stretching and dynamic stretching. There was significant decrease in agility time following dynamic stretching vs. static stretching in both less and more experienced players. Static stretching does not appear to be detrimental to agility performance when combined with dynamic warm-up for professional soccer players. However, dynamic stretching during the warm-up was most effective as preparation for agility performance. The data from this study suggest that more experienced players demonstrate better agility skills due to years of training and playing soccer.


Evaluation of the Effectiveness of a Primary Preventive Dental Health Education Programme Implemented Through School Teachers for Primary School Children in Mysore City.
The present study was conducted with the aim of evaluating the effectiveness of a Primary Preventive Dental Health Education Programme conducted for 6-12-year-old primary school children in Mysore City. A total of 12 schools, one each in the category of Government, Aided, and Unaided, were randomly selected per zone viz., North, South, East, and West. These 12 schools constituted the study group where the Primary Preventive School Dental Health Education Programme (PPSDHEP) was implemented. Two additional schools were selected at random from the four zones to serve as the control. A total of 926 children participated in the study. The PPSDHEP involved the second-level transfer of preventive package wherein the oral health education was imparted to the school children by schoolteachers trained by the investigator. Among the parameters for evaluating the outcome of the programme were the pre and post-programme assessment (at the baseline and at follow-up, i.e., after 6 months) of knowledge, attitude, and practice (KAP), dental caries status, oral hygiene, and gingival health status. The results suggest that the PPSDHEP resulted in bringing about an enhancement in the KAP towards oral health and also an improvement in dental caries, oral hygiene, and gingival health status of the school children in the study group. The present study supports the implementation of similar programmes in schools and the contention that schoolteachers are suitable personnel for imparting dental health education to school children on a regular basis.


Molecular surface of JZTX-V (β-Theraphotoxin-Cj2a) interacting with voltage-gated sodium channel subtype NaV1.4.
Voltage-gated sodium channels (VGSCs; NaV1.1-NaV1.9) have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure-function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX)-V (also known as β-theraphotoxin-Cj2a) is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK) motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7-2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7) and two cationic (R20 and K22) residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.


A novel approach to design a multiepitope peptide as a vaccine candidate for Bordetella pertussis.
Bordetella pertussis is a very contagious pathogen in humans, causing pertussis disease. Pertussis is one of the 10 leading causes of death due to infectious diseases, especially among infants and children. Antibiotic-resistant strains have recently emerged in this bacterium, and despite the high vaccination coverage, the prevalence of this disease has been increasing recently in both developed and developing countries. The objective of this study is to introduce a novel in silico vaccine candidate aimed at countering B. pertussis effectively. Differing from other comparable studies, this research employed a computational screening methodology to assess the genome of 'Bordetella pertussis 18323.' The purpose was to identify an innovative antigen for the development of a vaccine against B. pertussis. Notably, our investigation introduces an innovative antigen distinguished by its elevated immunogenicity score. Importantly, this antigen lacks toxicity and allergenicity, making it recognizable to the immune system and thus capable of inducing a robust immune response. In the subsequent phase, our antigen was utilized to identify potential epitopes conducive to the construction of a B. pertussis vaccine. These epitopes, alongside linkers, his-tag and adjuvants, were amalgamated to form the vaccine candidate. Subsequently, a comprehensive evaluation of the vaccine was conducted, encompassing various computational tests such as secondary and tertiary structure analysis, physicochemical examination, and structural analysis involving docking and molecular dynamics simulations. Importantly, our vaccine successfully passed all in silico tests.Communicated by Ramaswamy H. Sarma.


Indoor noise exposure at home: a field study in the family of urban schoolchildren.
This article aims at evaluating indoor noise levels at home and investigating the factors that may influence their variability. An 8-day noise measurement campaign was conducted in the homes of 44 schoolchildren attending the public primary schools of Besançon (France). The presence of the inhabitants in the dwelling and the noisy events occurring indoors and outdoors was daily collected using a time-location-activity diary (TLAD); 902 time periods were analyzed. The indoor noise level increased significantly with the outdoor noise level, along with the duration of the presence or level of activity of the inhabitants at home. However, this effect may vary according to the period of day and the day of the week. Moreover, a significant part of the day and evening indoor noise level variability was explained when considering the TLAD variables: 46% and 45% in the bedroom, 54% and 39% in the main room, respectively. Our results highlight the complexity of the indoor environment in the dwellings of children living in an urban area. Combining the inhabitant presence and indoor noise source descriptors with outdoor noise levels and other dwelling or inhabitant characteristics could improve large-scale epidemiological studies. However, additional efforts are still needed, particularly during the night period.


Statistical association of dietary components with Simonsiella species residing in normal human mouths.
Members of the genus Simonsiella, aerobic, multicellular filamentous gliding bacteria, were detected in swabbings from the palates of 32% of 212 human subjects free of gross oral pathologies. Nutritional evaluations for 142 of the subjects showed a significantly greater daily intake among 53 Simonsiella carriers for 13 dietary variables, including four fat components, but there was no significantly greater daily intake for any of the carbohydrate components. Overall, there was a general excess dietary intake by Simonsiella carriers. The mean dietary intake of the carriers was numerically greater than that of the noncarriers for 70 of 74 dietary variables.


Antiarrhythmic action of beta-blockers: potential mechanisms.
Sympathetic nervous system overactivity has been linked to ventricular tachyarrhythmias and sudden death. It has been hypothesized that the extent and nature of the arrhythmogenic effect of sympathetic stimulation depends on the underlying myocardial substrate, the mechanism of the arrhythmia, and the integrated effects of sympathetic stimulation in the particular individual circumstance. Multiple direct and indirect mechanisms of adrenergic action on the heart may benefit from the known antiarrhythmic actions of beta-blocker therapy and other interventions that decrease sympathetic tone. The antiarrhythmic mechanism of beta-blockade (and possibly alpha-blockade) will depend on the specific mechanism of the individual arrhythmia and will differ for those arrhythmias caused by tachycardia and ischemia, those caused by reentry and promoted by decreased conduction velocity and shortened refractoriness, and those caused by early or delayed afterdepolarizations, usually in the context of prolonged action potential duration. Antagonism of cardiac adrenergic activity by beta-blockade in particular is the best-established drug therapy to prevent ventricular arrhythmias.


Older people's experience of falls: understanding, interpretation and autonomy.
This paper is a report of a study to explore the experiences of older people who suffered a recent fall and identify possible factors that could contribute to service development. Falls in older people are prevalent and are associated with morbidity, hospitalization and mortality, personal costs to individuals and financial costs to health services. A convenience sample of 27 older people (mean age 84 years; range 65-98) participated in semi-structured taped interviews. Follow-up interviews during 2003-2004 were undertaken to detect changes over time. Data were collected about experience of the fall, use of services, health and well-being, activities of daily living, informal care, support networks and prevention. Thematic content analysis was undertaken. Twenty-seven initial interviews and 18 follow-up interviews were conducted. The majority of people fell indoors (n = 23) and were alone (n = 15). The majority of falls were repeat falls (n = 22) and five were a first-ever fall. People who reflected on their fall and sought to understand why and how it occurred developed strategies to prevent future falls, face their fear, maintain control and choice and continue with activities of daily living. Those who did not reflect on their fall and did not know why it occurred restricted their activities and environments and remained in fear of falling. Assisting people to reflect on their falls and to understand why they happened could help with preventing future falls, allay fear, boost confidence and aid rehabilitation relating to their activities of daily living.


Positive and negative controls by protein kinases of sodium-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells stimulated by lysophosphatidic acid.
We previously found that lysophosphatidic acid (LPA), a bioactive phospholipid, induced Na+-dependent Ca2+ efflux from cultured bovine adrenal chromaffin cells, possibly by activating a Na+/Ca2+ exchanger. The present study on the structure-activity relationship of its action revealed that 1-acyl type LPAs were stronger stimulants than the corresponding 1-O-alkyl type LPAs having a long alkyl moiety with the same chain length. Lysophosphatidylglycerol, suramin and N-palmitoyl-tyrosine phosphoric acid have all been reported to inhibit the action of LPA in some animal cells and platelets, but only lysophosphatidylglycerol was found to inhibit selectively LPA-induced Ca2+ efflux from chromaffin cells. LPA-induced Ca2+ extrusion was suggested to be involved in both acceleration of return of intracellular Ca2+ in Fura 2-loaded bovine chromaffin cells after addition of carbachol, and inhibition of carbachol-induced catecholamine release when the cells were co-incubated with LPA. The Ca2+ efflux from chromaffin cells stimulated by LPA was augmented by their pretreatment with staurosporine or calphostin C, inhibitors of protein kinase C, but reduced by their preincubation with phorbol 12-myristate 13-acetate. Furthermore, the response to LPA was potentiated by sodium vanadate, a protein tyrosine phosphatase inhibitor, but inhibited by genistein, an inhibitor of protein tyrosine kinase. These results suggest that protein kinase C and protein tyrosine kinase are involved negatively and positively, respectively, in the signal transduction triggered by LPA, leading to activation of the Na+/Ca2+ exchanger.


The case view, a generic method of visualization of the case mix.
There is a worldwide consensus to use the diagnosis related groups (DRG) to consider hospital activity. This tool leads to the production of tables with numbers (case mix), the interpretation of which is difficult. The issue is to translate these tables of numbers into an image named Case view. It assimilates, in a way, each DRG to a "pixel", the set of the DRGs being an image, the case view. The methods consist of two phases: the first one is to define the reference set while the second one is to visualize data through the reference set. The "DRG-pixels" which constitute the reference set should be organized according to three criteria: medical/surgical, nosological and economic. This method is used to answer theoretical questions or to visualize activity at the level of a hospital or at the level of a department. It generates information of synthetic nature and ought to be used as a complement to existing methods. An important advantage of this method compared to the existing ones (DRGs listing, DRGs clustering, histograms em leader ) is that it presents data simultaneously at a global level (sets of DRGs) and at a local level (the DRG). We hope this method to be a supplementary step toward the creation of tools capable of eliciting the semantic content hidden in the medical data banks. The purpose of this paper is to explain the underlying general principles that define the graphic representation and to illustrate this model with the use of the French reference set.


Selective loss of regulatory T cells in thymomas.
Myasthenia gravis (MG) is the prime autoimmune manifestation of thymomas. We investigated the generation of T cells with a regulatory phenotype (T(R)) in thymomas with and without associated MG. In patients with MG(+) thymomas, maturation and export of T(R) cells but not of other T-cell subsets was significantly reduced. We conclude that imbalance between effector and regulatory T cells in thymomas may be involved in modulation of onset and/or severity of MG.


Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism.
Obstructive sleep apnoea (OSA) is a sleep disorder characterized by recurrent episodes of oxygen desaturation during sleep, representing an independent risk factor for cardiovascular disease, such as myocardial infarction, stroke, congestive heart failure and resistant hypertension. Several neurohormonal mechanisms have been suggested to account for blood pressure increases, such as sympathetic nervous system hyperactivity, oxidative stress, renin-angiotensin-aldosterone system (RAAS) activation, endothelin system activation, and endothelial dysfunction. The aim of this study was to evaluate the behaviour of RAAS and the presence of primary aldosteronism (PA) in these patients and possible correlations between RAAS and the severity of OSA. From October 2007 to November 2008 we studied 325 consecutive newly diagnosed hypertensive patients; 71 patients (21.8%) presented with clinical signs of sleep disorders, evaluated also through a specific questionnaire (Epworth Sleepiness Scale). In hypertensive patients with sleep disorders, 53 patients were affected by OSA; in this group 18 patients were affected by PA (five with aldosterone-producing adenoma (APA) and 13 with bilateral hyperplasia (IHA)); obesity was also demonstrated (BMI > 30 kg/m(2)). Overall, in patients with OSA PRA levels correlated positively with apnoea/hypopnoea index (AHI; r = 0.35; p<0.01), and in all groups the waist circumference and the neck circumference were correlated positively with AHI (r = 0.3 p<0.02 and r = 0.3 p<0.03, respectively). We revealed a high prevalence of PA in patients with OSA, and we can conclude that patients with hypertension and OSA, especially those who are newly diagnosed, must be evaluated for PA.


Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.
Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) content was reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin (5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway.


Algorithms and Applications to Weighted Rank-one Binary Matrix Factorization.
Many applications use data that are better represented in the binary matrix form, such as click-stream data, market basket data, document-term data, user-permission data in access control, and others. Matrix factorization methods have been widely used tools for the analysis of high-dimensional data, as they automatically extract sparse and meaningful features from data vectors. However, existing matrix factorization methods do not work well for the binary data. One crucial limitation is interpretability, as many matrix factorization methods decompose an input matrix into matrices with fractional or even negative components, which are hard to interpret in many real settings. Some matrix factorization methods, like binary matrix factorization, do limit decomposed matrices to binary values. However, these models are not flexible to accommodate some data analysis tasks, like trading off summary size with quality and discriminating different types of approximation errors. To address those issues, this article presents weighted rank-one binary matrix factorization, which is to approximate a binary matrix by the product of two binary vectors, with parameters controlling different types of approximation errors. By systematically running weighted rank-one binary matrix factorization, one can effectively perform various binary data analysis tasks, like compression, clustering, and pattern discovery. Theoretical properties on weighted rank-one binary matrix factorization are investigated and its connection to problems in other research domains are examined. As weighted rank-one binary matrix factorization in general is NP-hard, efficient and effective algorithms are presented. Extensive studies on applications of weighted rank-one binary matrix factorization are also conducted.


Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency.
Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes.


Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth.
The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.


Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used; however, they are also nephrotoxic with both acute and chronic effects on kidney function. Here we determined NSAID prescribing before and after estimated GFR (eGFR) reporting and evaluate renal function in patients who used NSAIDs but stopped these after their first eGFR report. A population-based longitudinal analysis using a record-linkage database was conducted with the GFR estimated using the four-variable equation from the MDRD study and analyzed by trend test, paired t-test, and logistic regression modeling. Prescriptions for NSAIDs significantly decreased from 39,459 to 35,415 after implementation of eGFR reporting from the second quarter of 2005 compared with the first quarter of 2007. Reporting eGFR was associated with reduced NSAID prescriptions (adjusted odds ratio, 0.78). NSAID prescription rates in the 6 months before April 2006 were 18.8, 15.4, and 7.0% in patients with CKD stages 3, 4, and 5 and 15.5, 10.7, and 6.3%, respectively, after eGFR reporting commenced. In patients who stopped NSAID treatment, eGFR significantly increased from 45.9 to 46.9, 23.9 to 27.1, and 12.4 to 26.4 ml/min per 1.73 m(2) in 1340 stage 3 patients, 162 stage 4 patients, and 9 stage 5 patients, respectively. Thus, NSAID prescribing decreased after the implementation of eGFR reporting, and there were significant improvements in estimated renal function in patients who stopped taking NSAIDs. Hence, eGFR reporting may result in safer prescribing.


Biochar amendment improves degraded pasturelands in Brazil: environmental and cost-benefit analysis.
Most deforested lands in Brazil are occupied by low-productivity cattle ranching. Brazil is the second biggest meat producer worldwide and is projected to increase its agricultural output more than any other country. Biochar has been shown to improve soil properties and agricultural productivity when added to degraded soils, but these effects are context-dependent. The impact of biochar, fertilizer and inoculant on the productivity of forage grasses in Brazil (Brachiaria spp. and Panicum spp.) was investigated from environmental and socio-economic perspectives. We showed a 27% average increase in Brachiaria production over two years but no significant effects of amendment on Panicum yield. Biochar addition also increased the contents of macronutrients, soil pH and CEC. Each hectare amended with biochar saved 91 tonnes of CO2eq through land sparing effect, 13 tonnes of CO2eq sequestered in the soil, equating to U$455 in carbon payments. The costs of biochar production for smallholder farmers, mostly because of labour cost, outweighed the potential benefits of its use. Biochar is 617% more expensive than common fertilizers. Biochar could improve productivity of degraded pasturelands in Brazil if investments in efficient biochar production techniques are used and biochar is subsidized by low emission incentive schemes.


The Functional Change and Deletion of FLC Homologs Contribute to the Evolution of Rapid Flowering in Boechera stricta.
Differences in the timing of vegetative-to-reproductive phase transition have evolved independently and repeatedly in different plant species. Due to their specific biological functions and positions in pathways, some genes are important targets of repeated evolution - independent mutations on these genes caused the evolution of similar phenotypes in distantly related organisms. While many studies have investigated these genes, it remains unclear how gene duplications influence repeated phenotypic evolution. Here we characterized the genetic architecture underlying a novel rapid-flowering phenotype in Boechera stricta and investigated the candidate genes BsFLC1 and BsFLC2. The expression patterns of BsFLC1 suggested its function in flowering time suppression, and the deletion of BsFLC1 is associated with rapid flowering and loss of vernalization requirement. In contrast, BsFLC2 did not appear to be associated with flowering and had accumulated multiple amino acid substitutions in the relatively short evolutionary timeframe after gene duplication. These non-synonymous substitutions greatly changed the physicochemical properties of the original amino acids, concentrated non-randomly near a protein-interacting domain, and had greater substitution rate than synonymous changes. Here we suggested that, after recent gene duplication of the FLC gene, the evolution of rapid phenology was made possible by the change of BsFLC2 expression pattern or protein sequences and the deletion of BsFLC1.


A Novel Rhoptry Protein as Candidate Vaccine against Eimeria tenella Infection.
Eimeria tenella (E. tenella) is a highly pathogenic and prevalent species of Eimeria that infects chickens, and it causes a considerable disease burden worldwide. The secreted proteins and surface antigens of E. tenella at the sporozoite stage play an essential role in the host-parasite interaction, which involves attachment and invasion, and these interactions are considered vaccine candidates based on the strategy of cutting off the invasion pathway to interrupt infection. We selected two highly expressed surface antigens (SAGs; Et-SAG13 and Et-SAG) and two highly expressed secreted antigens (rhoptry kinases Eten5-A, Et-ROPK-Eten5-A and dense granule 12, Et-GRA12) at the sporozoite stage. Et-ROPK-Eten5-A and Et-GRA12 were two unexplored proteins. Et-ROPK-Eten5-A was an E. tenella-specific rhoptry (ROP) protein and distributed in the apical pole of sporozoites and merozoites. Et-GRA12 was scattered in granular form at the sporozoite stage. To evaluate the potential of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG proteins as a coccidiosis vaccine, the protective efficacy was examined based on survival rate, lesion score, body weight gain, relative body weight gain and oocyst output. The survival rate was significantly improved in rEt-ROPK-Eten5-A (100%) and rEt-GRA12 (100%) immune chickens compared to the challenged control group (40%). The average body weight gains of rEt-ROPK-Eten5-A, rEt-GRA12, rEt-SAG13 and rEt-SAG immunized chickens were significantly higher than those of unimmunized chickens. The mean lesion score and oocyst output of the rEt-ROPK-Eten5-A immunized chickens were significantly reduced compared to unimmunized challenged chickens. These results suggest that the rEt-ROPK-Eten5-A protein effectively triggered protection against E. tenella in chickens and provides a useful foundation for future work developing anticoccidial vaccines.


Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method.
Amphotericin B (AMB) derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) retains the broad antifungal spectrum and potency of the parent antibiotic, whereas its toxicity towards mammalian cells is reduced by about two orders of magnitude. The purpose of this work was to find out whether the differences observed in the toxicity of MFAME and native AMB are due to the differential drugs affinity to fungal and mammalian cell membranes. Comparative studies on AMB and MFAME biological activity and their affinity to fungal, mammalian and bacterial cells were performed. The interaction of AMB and MFAME with cells have been studied by fluorescence method based on the energy transfer between membrane fluorescent probe (donor) and the polyenic chromophore of the antibiotic (acceptor) simultaneously present in the cell membrane. The amount of the antibiotic bound to cells was indicated by the extent of fluorescence quenching of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) or 1,6-diphenyl-1,3,5-hexatriene (DPH) by polyenic chromophore of the antibiotic. The results obtained indicate that binding extent and characteristics for both antibiotics are comparable in the three types of cells studied. Dramatically lower toxicity of MFAME as compared to AMB towards mammalian cells is not related to the antibiotic-cell affinity, but rather to different consequences of these interactions for cells, reflected in membrane permeabilization. MFAME is definitely less effective than parent AMB in the permeabilizing species formation in mammalian cell membrane.


Fluoride supplementation status, fractures and osteopenia in children with acute lymphoblastic leukemia.
Children with acute lymphoblastic leukemia (ALL) experience fractures on the basis of osteopenia related to chemotherapy administered for the maintenance of remission. It is likely that corticosteroids are the main cause of bone mineral loss in this circumstance. Because fluoride has been used as a therapeutic intervention in osteoporosis, including that induced by corticosteroid therapy, we explored the prospect that children with ALL who received fluoride supplementation (in drinking water or from other sources) may be relatively protected from iatrogenic skeletal morbidity. Children who completed therapy according to the Dana Farber Cancer Institute protocol 87-01 (n=35) were assessed by skeletal radiology and bone densitometry every 6 months from diagnosis. In addition, their families completed a questionnaire relating to fluoride supplementation. There was no correlation between such fluoride supplementation and either the prevalence of fractures or the severity of osteopenia. This outcome may reflect the mainly appendicular location of the fractures in this group of children. These findings, together with a consideration of the risk benefit ratio of fluoride administration to children at large, suggest that such intervention is unlikely to be beneficial in limiting skeletal morbidity during the treatment of ALL in childhood.


Estimating the latent number of types in growing corpora with reduced cost-accuracy trade-off.
The number of unique words in children's speech is one of most basic statistics indicating their language development. We may, however, face difficulties when trying to accurately evaluate the number of unique words in a child's growing corpus over time with a limited sample size. This study proposes a novel technique to estimate the latent number of words from a series of words uttered by children. This technique utilizes statistical properties of the number of types as a function of the number of sampled tokens. We tested the practical effectiveness of the proposed method in the empirical data analysis of the cross-sectional and longitudinal samples. The converging empirical evidence indicates that the proposed estimator improves the accuracy of vocabulary size estimation over a set of existing estimators. Utilizing this efficient estimator, we propose a new sampling scheme for vocabulary assessment that has lower cost and higher accuracy compared to existing methods.


Failing upwards: Genetics-based strategies to improve antibiotic discovery and efficacy in Mycobacterium tuberculosis.
Therapeutic advances in the 20th century significantly reduced tuberculosis (TB) mortality. Nonetheless, TB still poses a massive global health challenge with significant annual morbidity and mortality that has been amplified during the COVID-19 pandemic. Unlike most common bacterial infectious diseases, successful TB treatment requires months-long regimens, which complicates the ability to treat all cases quickly and effectively. Improving TB chemotherapy by reducing treatment duration and optimizing combinations of drugs is an important step to reducing relapse. In this review, we outline the limitations of current multidrug regimens against TB and have reviewed the genetic tools available to improve the identification of drug targets. The rational design of regimens that sterilize diverse phenotypic subpopulations will maximize bacterial killing while minimizing both treatment duration and infection relapse. Importantly, the TB field currently has all the necessary genetic and analytical tools to screen for and prioritize drug targets in vitro based on the vulnerability of essential and non-essential genes in the Mtb genome and to translate these findings in in vivo models. Combining genetic methods with chemical screens offers a formidable strategy to redefine the preclinical design of TB therapy by identifying powerful new targets altogether, as well as targets that lend new efficacy to existing drugs.


Intrarenal angiotensin I conversion at normal and reduced renal blood flow in the dog.
Intrarenal conversion of angiotensin I (ANG I) to angiotensin II (ANG II) under conditions of normal and reduced renal blood flow (RBF) elicited by constriction of the renal artery was examined in pentobarbital-anesthetized dogs. In eight animals, tracer doses of 125I-ANG I (5-12 pmol) were injected into the renal artery and 125I-ANG I, 125I-ANG II, and 125I-labeled metabolites were measured in renal venous effluent by high-voltage paper electrophoresis. The mean conversion of ANG I to ANG II during a single passage through the kidney was 21.8 +/- 2.1% at control RBF. When RBF was decreased by 25 and 53%, percent ANG I conversion was not altered significantly. In six dogs percent conversion of 125I-[Sar1, Ile5]ANG I, an ANG I analogue refractory to hydrolysis by aminopeptidases, was 18.1 +/- 1.7% at control RBF and did not change significantly when the RBF was reduced by 55%. Although there were severalfold increases in renal renin secretion rate and net ANG I generation rate during reduced RBF, net renal ANG II formation rate did not change significantly. These data indicate that there is substantial conversion of ANG I in a single passage through the dog kidney and that intrarenal ANG I conversion is independent of RBF even under conditions in which renin secretion rate and ANG I generation rate are increased severalfold.


Adipose Progenitor Cell Secretion of GM-CSF and MMP9 Promotes a Stromal and Immunological Microenvironment That Supports Breast Cancer Progression.
A cell population with progenitor-like phenotype (CD45-CD34+) resident in human white adipose tissue (WAT) is known to promote the progression of local and metastatic breast cancer and angiogenesis. However, the molecular mechanisms of the interaction have not been elucidated. In this study, we identified two proteins that were significantly upregulated in WAT-derived progenitors after coculture with breast cancer: granulocyte macrophage colony-stimulating factor (GM-CSF) and matrix metallopeptidase 9 (MMP9). These proteins were released by WAT progenitors in xenograft and transgenic breast cancer models. GM-CSF was identified as an upstream modulator. Breast cancer-derived GM-CSF induced GM-CSF and MMP9 release from WAT progenitors, and GM-CSF knockdown in breast cancer cells neutralized the protumorigenic activity of WAT progenitors in preclinical models. GM-CSF neutralization in diet-induced obese mice significantly reduced immunosuppression, intratumor vascularization, and local and metastatic breast cancer progression. Similarly, MMP9 inhibition reduced neoplastic angiogenesis and significantly decreased local and metastatic tumor growth. Combined GM-CSF neutralization and MMP9 inhibition synergistically reduced angiogenesis and tumor progression. High-dose metformin inhibited GM-CSF and MMP9 release from WAT progenitors in in vitro and xenograft models. In obese syngeneic mice, metformin treatment mimicked the effects observed with GM-CSF neutralization and MMP9 inhibition, suggesting these proteins as new targets for metformin. These findings support the hypothesis that GM-CSF and MMP9 promote the protumorigenic effect of WAT progenitors on local and metastatic breast cancer. Cancer Res; 77(18); 5169-82. ©2017 AACR.


Metaphyseal osteomyelitis in an immature Abyssinian cat.
Metaphyseal osteomyelitis is a rarely described condition in small animals, especially the cat. Infection, most commonly Staphylococcus sp, is considered to occur in the metaphyseal region of the immature animal due to vascular anomalies that predispose to the haematogenous seeding of bacteria in this area. There is also speculation that the characteristics of the bacteria that allow them to adhere to cartilage matrix, rather than vascular linings and erythrocytes, may provide an advantage for colonisation in the metaphysis, resulting in infection. This case describes the successful management of a case of distal radial metaphyseal osteomyelitis in an immature cat using surgical intervention and antibacterial therapy.


Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa.
Pseudomonas aeruginosa displays an impressive metabolic versatility, which ensures its survival in diverse environments. Reported herein is the identification of rare azetidine-containing alkaloids from P. aeruginosa PAO1, termed azetidomonamides, which are derived from a conserved, quorum-sensing regulated nonribosomal peptide synthetase (NRPS) pathway. Biosynthesis of the azetidine motif has been elucidated by gene inactivation, feeding experiments, and biochemical characterization in vitro, which involves a new S-adenosylmethionine-dependent enzyme to produce azetidine 2-carboxylic acid as an unusual building block of NRPS. The mutants of P. aeruginosa unable to produce azetidomonamides had an advantage in growth at high cell density in vitro and displayed rapid virulence in Galleria mellonella model, inferring functional roles of azetidomonamides in the host adaptation. This work opens the avenue to study the biological functions of azetidomonamides and related compounds in pathogenic and environmental bacteria.


Inhibition of antibody synthesis by histamine in concanavalin A-treated mice: the possible role of glucocorticosteroids.
Administration of histamine (50 mg/kg) to BALB/C mice injected with concanavalin A (Con A) (100 micrograms, i.v.) 24 hr previously, results in a marked decrease in antibody synthesis to sheep red blood cells (SRBC) injected 2 hr later. This phenomenon occurs with nonimmunosuppressive doses of Con A and is strain-specific. It does not take place in the response to the T-independent antigen polyvinylpyrrolidone (PVP) or if histamine is administered after the antigen. Adoptive transfer of normal syngeneic cells at the same time as antigen does not reverse this effect. Excess suppressor cell generation was excluded by co-cultivation of treated spleen cells with normal cells in vitro and by determining their antibody response to SRBC 5 days later. 2-Methylhistamine, a histamine type 1 (H1) receptor agonist, mimicks the effect of histamine whereas dimaprit, a histamine type 2 (H2) receptor agonist, does not. Because histamine interaction with H1 receptors causes the release of adrenocorticotropic hormone (ACTH), we examined the effects of ACTH and corticosterone in this system and found that both could mimick the effect of histamine. These results suggest that the interaction of histamine with H1 receptors causes the release of glucocorticosteroids that may interfere with either Con A-activated T helper cell function or macrophage processing of T-dependent antigen.


The Utility of the 5 Factor Modified Frailty Index in Outcome Prediction for Patients with Chronic Subdural Hematoma Treated with Surgical Drainage.
Increasing frailty is a significant determinant of perioperative morbidity and mortality within neurosurgical literature. This study investigates the predictive value of the modified frailty index 5 (mFI-5) for postoperative morbidity and mortality following surgical drainage of chronic subdural hematoma (cSDH). A retrospective cohort study was performed on patients who underwent surgical evacuation of a cSDH. The mFI-5 score was calculated for each patient and used to stratify patients: prefrail (mFI-5<2), frail (mFI-5 = 2), and severely frail (mFI-5>2). Multivariate Cox proportional hazards (CPH) regression analysis were used to identify factors associated with our primary outcomes: overall survival and 30-day readmission. Secondary outcomes included nonhome discharge, length of stay, hematoma accumulation, development of new postoperative neurologic deficits, resolution of preoperative neurologic deficits, and a modified Rankin score >2 at discharge. 118 patients with a mean age of 74.4 ± 11.9 years were analyzed. All baseline demographics were similar across the 3 groups. On multivariate analysis, severely frail patients (N = 24, 20.3%) had increased rates of 30-day readmission (hazard ratio [HR] 4.3, CPH regression P value<0.001) and postoperative mortality (HR 3.1, CPH regression P value<0.01) compared to the prefrail cohort. Severely frail patients had increased rates of nonhome disposition (HR 9.6, CPH regression P value< 0.001), development of new postoperative neurologic deficits (HR 2.75, CPH regression P value = 0.03), and hematoma reaccumulation (HR 4.07, CPH regression P value = 0.004). A novel scoring system accounting for patient age and frailty was predictive of 90-day mortality (area under the curve 0.77). Frailty, measured by the mFI-5, and our novel scoring system hold a predictive value regarding outcomes for patients undergoing surgical drainage of a cSDH.


Clarifying the interface between respectful leadership and intention to stay.
Considering that leaders play an important role in influencing the work environment and experiences of subordinates as well as the fact that employees like to be respected, the purpose of the current study was to explore supportive supervisor relations as a mediator of the relationship between respectful leadership and intention to stay. Data were collected from 389 hospital nurses based on authors' personal networks at three measurement points. This was done to avoid problems associated with collecting data for predictor and criterion variables from the same source at the same time. The direct and indirect effects were tested with ordinary least squares regression-based path analysis. Respectful leadership was found to be positively related to both supportive supervisor relations and intention to stay. In addition, supportive supervisor relations had a positive relationship with intention to stay. Finally, the relationship between respectful leadership and intention to stay was mediated by supportive supervisor relations. The sample were drawn from nurses only in a particularly region of a country and differences may exist among other occupational groups and geographical areas of the country in the way they perceive their leaders' behavior. Management of health facilities can utilize information from annual reviews and feedback from subordinates as performance evaluation criteria for rewarding leaders who treat their subordinates respectfully. However, leaders who are disrespectful toward their subordinates could be identified and subjected to mandatory training on respectful leadership. The current study extends the present state of research on the impact exerted by respectful leadership in an organizational context never examined heretofore; that is, health care context. This is also the first study linking respectful leadership, supportive supervisor relations and intention to stay in unison in a single study.


Skin compatibility of cyclodextrins and their derivatives: a comparative assessment using a corneoxenometry bioassay.
Few studies have been performed to assess the risk of skin damage by cyclodextrins (CD) and they have yielded contradictory results. The present study was conducted using the corneoxenometry bioassay on human stratum corneum to compare the skin compatibility of CD currently used in pharmaceutical preparations (betaCD, gammaCD, Rameb, Dimeb, Trimeb, HP-betaCD and HP-gammaCD) and that of new amphiphilic CD derivatives, namely, the phospholipidyl-CD (DMPE-Dimeb and DMPE-Trimeb). All the tested CD were well tolerated by the stratum corneum at a concentration of 5%. However, inter-individual reactivity was larger for DMPE-Dimeb, suggesting a more aggressive trend for this compound. Cutaneous Index of Mildness values obtained confirm that Dimeb is able to extract some skin components and shows that DMPE-Dimeb performs similarly.


Complications of pancreato-duodenectomy.
Pancreato-duodenectomy (PD) is the procedure of choice for management of resectable periampullary and pancreatic cancers and some patients with chronic pancreatitis. PD is one of the most major GI/ HPB surgical procedures performed involving resection of multiple organs and reconstruction with multiple anastomoses. While mortality of PD has been brought down to less than 5% morbidity still remains high.Patients undergoing PD are usually elderly with comorbidities - general complications of a major operation e.g. wound, chest, cardiac and venous thrombo-embolism, are common.The major intra-operative morbidity of PD is bleeding which can be from multiple sites viz. gall bladder bed, choledochal veins, gastro-colic trunk, pancreato-duodenal veins, jejunal veins, uncinate veins and cut surface of pancreas. An aberrant right hepatic artery (from the superior mesenteric artery) can be injured while dissecting the common bile duct.Pancreatic leak is defined as presence of amylase rich (>3x serum amylase) fluid in drain beyond 3 days. It is graded as A (no clinical impact), B (persists, infected) or C (systemic sepsis, reoperation). Investigation of choice is computed tomography; a localized collection can be drained percutaneously. Major leak requires reexploration at which lavage and drainage should be performed; no attempt should be made to repair or redo the anastomosis. Soft pancreas and undilated duct are the two most important risk factors for pancreatic anastomotic leak; role of octreotide to prevent the leak is debatable. Preoperative biliary drainage in the form of endoscopic stenting may reduce bleeding complications by controlling coagulopathy but increases the risk of infective complications.Postoperative bleed can be early or delayed and intra-luminal or intra-abdominal. Early intra-abdominal bleed is surgical - either a slipped ligature e.g. of the gastro-duodenal artery or one of the veins or from the pancreato-duodenal bed; reexploration should be done to control it if it is severe. Early intra-luminal bleed is from one of the anastomoses - commonest being the pancreatic. UGIE rules out bleed from the gastro/duodenal anastomosis (which if present, can be controlled endoscopically). Control of pancreatic stump bleed requires reoperation - taking down anterior layer of the anastomosis or a jejunotomy. Delayed intra-abdominal bleed is from a pseudo-aneurysm of an artery, usually gastro-duodenal caused by erosion by an abscess secondary to a leak; treatment of choice is angio-embolization. Delayed intra-luminal bleed is because of stress ulcers caused by systemic sepsis usually secondary to a leak and intra-abdominal sepsis.Other common complications include delayed gastric emptying and acute pancreatitis.Reoperations after PD are frequent - commonest cause is bleed, followed by leak; mortality of reexploration is high. Long term complications include anastomotic (PJ/ HJ) stricture, endocrine and exocrine insufficiency and inability to regain weight and poor quality of life. pancreato-duodenectomy complications.


Enhancing cAMP Levels as Strategy for the Treatment of Neuropsychiatric Disorders.
Phosphodiesterases (PDEs) have gained attention as potential pharmacological targets for neuropsychiatric diseases due to their ability to hydrolyze the second messengers, cGMP and/or cAMP. It is well-known the relationship between cAMP signaling and inflammation. Since neuroinflammation is considered to play an important role in the pathology of brain disorders, inhibition of PDEs highly expressed in brain has emerged as an innovative strategy for the treatment of these pathologies. PDE4, 7, 8 and 10 inhibitors are presented here as promising drug candidates to overcome the partial efficacy and adverse effects of the current therapy for neuropsychiatric illness such as depression, cognitive impairments or schizophrenia. Enhancing the intracellular concentration of cAMP underlies the effects of PDE inhibitors in the above mentioned disorders.


[Multimorbidity and comorbidity in the Dutch population--data from general practices].
To present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population. Data analysis. Data from the Netherlands Information Network of General Practice (LINH), a large representative network of general practices over a period of 7 years (2002-2008) were analysed. Multimorbidity was defined as a patient having been diagnosed with two or more of 29 chronic diseases in the general practitioner's electronic medical records system. The prevalence of chronic diseases and multimorbidity was calculated for the total population and subsequently by sex and age groups. For the 10 most prevalent diseases in the elderly, clustering and comorbidity of chronic diseases in patients 55 years and older were analysed. Almost 13% of the total Dutch population and 37% of patients 55 years and older had 2 or more chronic diseases. More than 70% of the patients aged 55 years and older who had 1 of the 10 specific chronic diseases also had an additional chronic disease. Most disease pairs occurred more frequently than expected based on independency (clustering), particularly the combinations depression and anxiety disorder, coronary heart disease and heart failure, and COPD and heart failure. The five most common combinations of conditions associated with a certain disease concerned only a limited portion (30%) of all disease comorbidity. This means that 70% of patients with a chronic disease had 1 or more additional diseases not included in the 5 most frequently occurring diseases. Multimorbidity was identified in over two-thirds of the elderly with frequently occurring chronic diseases. Comorbidity encompassed many different combinations of chronic diseases. In light of an ageing population, multimorbidity should increasingly be taken into account when delivering healthcare, in medical research and in defining healthcare policies.


Absorptance of nonferrous alloys to Nd:YLF and Nd:YAG laser light at room temperature.
The measurement of absorptance is important for the analysis and modeling of laser-material interactions. Unfortunately, most of the absorptance data currently available consider only polished pure metals rather than the commercially available (unpolished, oxidized) alloys that are actually being processed in manufacturing. We present the results of absorptance measurements carried out at room temperature on as-received engineering grade nonferrous metals (Al, Cu, and Zn alloys). The measurements were made using an integrating sphere with a Nd:YLF laser at two wavelengths (1053 and 527 nm, which means that the results are also valid for Nd:YAG radiation at 1064 and 532 nm). The absorptance results obtained differ considerably from the existing data for polished, pure metals and should help improve the accuracy of laser-material interaction models. Some clear trends were identified. For all 22 cases studied the absorptance was higher than for ideal pure, polished metals. For all Al and Cu samples the absorptance was higher for the green than it was for the infrared wavelength, while for all Zn coatings this trend was reversed. No clear correlation between absorptance and surface roughness was found at low roughness values (Sa 0.15-0.60), but one rougher set of samples (Sa 2.34) indicated a roughness-absorptance correlation at higher roughness levels.


[Glossary of terms and concepts used in scientific evidence based cardiology. Part I: diagnosis, therapy, iatrogenesis, generalities].
The papers published by the Revista about Evidence-Based Cardiology (EBC) have, so far, discussed general aspects of the theory as well as practice of EBC, using simple terms. We need a detailed description of the general, as well as specific, concepts applicable to EBC, in order to understand this methodology better and to facilitate the reading. In this first article we present a glossary of terms applicable to general aspects of the methodology, including terms found in papers about diagnosis, treatment, risk/harm, etc. A second paper, to be published in the next issue of the Revista, will present concepts regarding clinical trials (types, methodology, etc.) and systematic reviews.


More than support to court: Rape victims and specialist sexual violence services.
This article explores the involvement of specialist sexual violence services, including Independent Sexual Violence Advisers (ISVAs), in supporting victims/survivors of rape and sexual abuse to engage with the criminal justice system (CJS) in England and Wales. The underpinning research, conducted in one area of England, included referral data from the police and key specialist sexual violence services, interviews with 15 victims/survivors of sexual violence in contact with the police and specialist services, and interviews with 14 practitioners from sexual violence and related services. We examine the complex needs of victims/survivors of sexual violence (who have experienced historical child sexual abuse, acquaintance rape or rape in the context of intimate partner abuse), how their needs differ and vary over time, and the ways in which these diverse and changing needs are met by specialist sexual violence services. Non-specialist agencies, such as statutory mental health services, are unable to provide similarly targeted responses. The research found that specialist sexual violence services play particularly crucial roles through the use of approaches that can be characterised as flexible, enabling, holding and mending. However, this important work could easily be lost in the current climate of local service commissioning, to the great detriment of victims/survivors of sexual violence.


Evidence that cAMP-dependent protein kinase and a protein factor are involved in reactivation of triton X-100 models of sea urchin and starfish spermatozoa.
A fraction obtained from detergent-extract of sea urchin or starfish spermatozoa using DEAE-cellulose chromatography reactivated Triton X-100 models of the spermatozoa in a cAMP-dependent manner. The DEAE fraction contained cAMP-dependent protein kinase with a high level of specific activity. Rabbit muscle inhibitor protein highly specific for cAMP-dependent protein kinases inhibited the ability of the deae fraction to induce reactivation of Triton X-100 models.l This inhibition paralleled inhibition of cAMP-dependent protein kinase activity of the DEAE fraction, suggesting participation of the enzyme in the cAMP-dependent reactivation of Triton X-100 models. However, cAMP-dependent protein kinase further purified from the DEAE fraction was incapable of reactivating these models by itself. A protein factor which was separated from the protein kinase in the course of purification of the enzyme was found to also be necessary for the reactivation. When cAMP-dependent protein kinase was pretreated with protein kinase inhibitor before addition of the protein factor, the reactivation of Triton X-100 models was no longer detected. However, after the protein factor had been incubated with cAMP and cAMP-dependent protein kinase, protein kinase inhibitor did not repress reactivation of Triton X-100 models. We propose that the reactivation needs phosphorylation of the protein factor by cAMP-dependent protein kinase.


Self-assembly of hydrophobin protein rodlets studied with atomic force spectroscopy in dynamic mode.
We have investigated the self-assembling properties of the class I hydrophobin Vmh2 isolated from the fungus Pleurotus ostreatus. Five different hydrophobin self assembled samples including monolayers, bilayers, and rodlets have been prepared by Langmuir technique and studied at the nanoscale. Local wettability and visco-elasticity of the different hydrophobins samples were obtained from atomic force spectroscopy experiments in dynamic mode performed at different, controlled relative humidity (RH) values. It was found that hydrophobins assembled either in rodlets or in bilayer films, display similar hydropathicity and viscoelasticity in contrast to the case of monolayers, whose hydropathicity and viscoelasticity depend on the adopted preparation method (Langmuir-Blodgett or Langmuir-Schaeffer). The comparison with monolayers properties evidences a rearrangement of the bilayers adsorbed onto solid substrates. It is shown that this rearrangement leads to the formation of a stable hydrophobic film, and that the rodlets structure consists in fragments of restructured proteins bilayers. Our results support the hypothesis that the observed variations in the viscoelastic properties could be ascribed to the localization of the large flexible loop, typical of Class I hydrophobins which appears free at the air interface for LB monolayers but not for the other samples. These findings should now serve future developments and applications of hydrophobin films beyond the archetypal monolayer.


Characterization of memory profile in idiopathic REM sleep behavior disorder.
The present study aims to examine whether declarative memory dysfunction relates to impaired core memory mechanisms or attentional and executive dysfunction in idiopathic REM Sleep Behavior Disorder (iRBD). In this observational, cross-sectional study, were enrolled 82 individuals with the diagnosis of iRBD according to the International Classification of Sleep Disorders and 49-matched healthy controls fulfilling inclusion criteria. All participants underwent two memory tasks, namely the Rey Auditory Verbal Learning Test (RAVLT) and Memory Binding Test (MBT), which include conditions of varying degrees of dependence on executive functioning, as well as different indicators of core memory processes (e.g., learning, retention, relational binding). We used Bayesian multivariate generalized linear model analysis to evaluate the effect of iRBD on memory performance controlled for effects of age and sex. Individuals with iRBD displayed worse memory performance in the delayed free recall task (b = -0.37, 95% PPI [-0.69, -0.05]), but not on delayed recognition of the same material. Their performance in cued recall tasks both in immediate and delayed conditions was in comparison to controls relatively spared. Moreover, the deficit in delayed free recall was mediated by attention/processing speed. In iRBD, we replicated findings of reduced free recall based on inefficient retrieval (retrieval deficit), which was small in terms of effect size. Importantly, the memory profile across measures does not support the presence of core memory dysfunction, such as poor learning, retention or associative binding.


Notch signaling functions in lymphatic valve formation.
Collecting lymphatic ducts contain intraluminal valves that prevent backflow. In mice, lymphatic valve morphogenesis begins at embryonic day 15.5 (E15.5). In the mesentery, Prox1 expression is high in valve-forming lymphatic endothelial cells, whereas cells of the lymphatic ducts express lower levels of Prox1. Integrin α9, fibronectin EIIIA, Foxc2, calcineurin and the gap junction protein Cx37 are required for lymphatic valve formation. We show that Notch1 is expressed throughout the developing mesenteric lymphatic vessels at E16.5, and that, by E18.5, Notch1 expression becomes highly enriched in the lymphatic valve endothelial cells. Using a Notch reporter mouse, Notch activity was detected in lymphatic valves at E17.5 and E18.5. The role of Notch in lymphatic valve morphogenesis was studied using a conditional lymphatic endothelial cell driver either to delete Notch1 or to express a dominant-negative Mastermind-like (DNMAML) transgene. Deletion of Notch1 led to an expansion of Prox1(high) cells, a defect in Prox1(high) cell reorientation and a decrease in integrin α9 expression at sites of valve formation. Expression of DNMAML, which blocks all Notch signaling, resulted in a more severe phenotype characterized by a decrease in valves, failure of Prox1(high) cells to cluster, and rounding of the nuclei and decreased fibronectin-EIIIA expression in the Prox1(high) cells found at valve sites. In human dermal lymphatic endothelial cells, activation of Notch1 or Notch4 induced integrin α9, fibronectin EIIIA and Cx37 expression. We conclude that Notch signaling is required for proper lymphatic valve formation and regulates integrin α9 and fibronectin EIIIA expression during valve morphogenesis.


Production of semiconducting gold-DNA nanowires by application of DC bias.
There is considerable interest in using DNA nanowires or nanotubes in a wide variety of bioelectronic applications and microcircuitry. Various methods have been developed to construct DNA nanostructures. Here, we report a novel method to construct semiconducting DNA nanowires by applying a suitable DC bias to a gold plating solution containing double-stranded DNA. The self-assembled nanowires fabricated by this method contain attached gold nanoparticles. Further, we report that the dimensions of the nanowires can be easily manipulated by altering the applied DC bias. We also confirmed the semiconducting nature of the DNA nanowires by studying their resistance-temperature behavior from 25 to 65 degrees C in a microelectrode system. These studies describe a simple process by which gold-decorated, semiconducting DNA nanowires could be created and may lead to a breakthrough in the field of self-assembly of nanometer-scale circuits. The self-assembled structures do have some similarity with tube-like structures but in the present work we are using the term 'DNA nanowires' to define the structures.


Antibodies for prevention of mother-to-child transmission of HIV-1.
Although antiretroviral (ARV) prophylaxis can reduce mother-to-child transmission (MTCT) of HIV-1 to less than 2%, one-quarter of a million infants continue to be infected with HIV-1 annually. ARV prophylaxis alone will fail to eliminate infant HIV-1 infection because of issues of maternal adherence, toxicities, ARV-resistant virus strains, and acute maternal infection. Effective maternal and/or infant immunization will likely be required to achieve the goal of an HIV-free generation. This article describes recent studies of antibody responses that protect against vertical HIV-1 transmission. Studies have shown that maternal neutralization breadth is not a critical factor in MTCT, yet the ability of maternal plasma to neutralize autologous virus variants may be important in infant protection. There is also new evidence that infants mount robust and durable antibody responses to HIV-1 envelope following vaccination and can develop broad neutralization during infection. Finally, passive immunization of infants with highly potent and broad neutralizing antibodies may be an effective strategy to protect infants against infection with postnatally transmitted variants. Defining the characteristics of maternal and infant antibody responses that protect against MTCT will inform development of effective passive and active immunization strategies that will likely be required to eliminate pediatric HIV-1.


Unanticipated Nocturnal Oxygen Requirement during Positive Pressure Therapy for Sleep Apnea and Medical Comorbidities.
Home-based management of sleep-disordered breathing (SDB) generally excludes patients with significant medical comorbidities, but such an approach lacks scientific evidence. The current study examined whether significant medical comorbidities are associated with persistent hypoxia that requires unanticipated nocturnal O2 supplementation to positive airway pressure (PAP) therapy. Conceivably, in such patients, home-based management of SDB may not detect or therefore adequately treat persistent hypoxia. In this retrospective study of 200 patients undergoing laboratory-based polysomnography, we ascertained significant medical comorbidities (chronic obstructive pulmonary disease, congestive heart failure, and morbid obesity) and their association with the need for unanticipated O2 supplementation to PAP therapy. Postural oxygen (SpO2) desaturations between upright and reclining positions were determined during calm wakefulness. Postural change in SpO2 during calm wakefulness was greater in patients who eventually needed nocturnal O2 supplementation to PAP therapy than those needing PAP therapy alone (p < 0.0001). The presence of chronic obstructive pulmonary disease (odds ratio [OR] 6.0; 95% confidence interval [CI]; 2.1, 17.5; p = 0.001), morbid obesity (OR 3.6; 95% CI 1.9, 7.0; p < 0.0001), and age older than 50 y (OR 2.8; 95% CI 1.3, 5.9; p = 0.007) but not heart failure were associated with unanticipated need for nocturnal O2 supplementation. A clinical prediction rule of less than two determinants (age older than 50 y, morbid obesity, chronic obstructive pulmonary disease, and postural SpO2 desaturation greater than 5%) had excellent negative predictive value (0.92; 95% CI 0.85, 0.96) and likelihood ratio of negative test (0.08; 95% CI 0.04, 0.16). Medical comorbidities can predict persistent hypoxia that requires unanticipated O2 supplementation to PAP therapy. Such findings justify the use of medical comorbidities to exclude home management of SDB. A commentary on this article appears in this issue on page 7.


Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations.
A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min(1) with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 - 21 μg ml for TOLP μg / ml and 8 - 56 μg / ml for ETD. The detection limit of the proposed method was 0.16 μg / ml and 0.58 μg / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 μg / ml and 1.7 μg / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 - 101.15 for TOLP and 98.63 - 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form.


Gastric restrictive procedures: gastroplasty.
Gastroplasty for the treatment of morbid obesity has developed over the last 20 years from inconsistent suture technique operations to precisely constructed procedures. To date, the best results are achieved with the most recently developed techniques, vertical (mesh) banded gastroplasty, and silicone elastomer ring vertical gastroplasty. These operations produce a 33 to 37 per cent weight loss at 2 years with a failure rate of 6 to 8 per cent.


[Longevity and meaning of life. Philosophical-ethical considerations of the theme 'extension of life'].
The desire for the extension of life is not one out of many desire in life, but a form of the fundamental desire for life itself. This so called 'categorical desire' is a necessary condition for the many desires in life. The question why we desire for life (and for its extension), is the question for the meaning of life. The searching for a 'natural lifespan' is meaningless when it wants to find in nature a given norm for the duration of life. It can only have meaning when it tries to formulate the conditions for the experience of life as successful and meaningful. A long tradition in philosophy and religion associates the meaning of life with the acknowledgement of its finitude and mortality and with the acceptance of death. As far as the extension of life is motivated by a fear of death and by an effort to escape from it, it is a neglect of what makes life meaningful, and of what makes it (and its extension) worthwhile to desire.


The Alzheimer structural connectome: changes in cortical network topology with increased amyloid plaque burden.
To evaluate differences in the structural connectome among patients with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer disease (AD) and to determine associations between the structural connectome and cortical amyloid deposition. Patients enrolled in a multicenter biomarker study (Alzheimer's Disease Neuroimaging Initiative [ADNI] 2) who had both baseline diffusion-tensor (DT) and florbetapir positron emission tomography (PET) data at the time of data analyses in November 2012 were studied. All institutions received institutional review board approval. There were 102 patients in ADNI 2 who met criteria for analysis. Patients' T1-weighted images were automatically parcellated into cortical regions of interest. Standardized uptake value ratio (SUVr) was calculated from florbetapir PET images for composite cortical regions (frontal, cingulate, parietal, and temporal). Structural connectome graphs were created from DT images, and connectome topology was analyzed in each region by using graph theoretical metrics. Analysis of variance of structural connectome metrics and florbetapir SUVr across diagnostic group was performed. Linear mixed-effects models were fit to analyze the effect of florbetapir SUVr on structural connectome metrics. Diagnostic group (NC, MCI, or AD) was associated with changes in weighted structural connectome metrics, with decreases from the NC group to the MCI group to the AD group shown for (a) strength in the bilateral frontal, right parietal, and bilateral temporal regions (P < .05); (b) weighted local efficiency in the left temporal region (P < .05); and (c) weighted clustering coefficient in the bilateral frontal and left temporal regions (P < .05). Increased cortical florbetapir SUVr was associated with decreases in weighted structural connectome metrics; namely, strength (P = .00001), weighted local efficiency (P = .00001), and weighted clustering coefficient (P = .0006), independent of brain region. For every 0.1-unit increase in florbetapir SUVr, there was a 14% decrease in strength, an 11% decrease in weighted local efficiency, and a 9% decrease in weighted clustering coefficient, regardless of the analyzed cortical region or, in the case of weighted local efficiency and clustering coefficient, diagnostic group. Increased amyloid burden, as measured with florbetapir PET imaging, is related to changes in the topology of the large-scale cortical network architecture of the brain, as measured with graph theoretical metrics of DTI tractography, even in the preclinical stages of AD. Online supplemental material is available for this article.


Absence of correlation between IL-1 alpha intron 6 polymorphism and rheumatoid arthritis.
Several studies have implicated interleukin 1 alpha (IL-1 alpha) in the pathogenesis of rheumatoid arthritis (RA). We analysed IL-1 alpha intron 6 polymorphism in relation to RA (50 patients with RA and 50 healthy controls). The study of a healthy control population confirmed the existence of the different alleles with a frequency similar to that in the Caucasian populations of northern England. Allele and genotype distributions did not differ significantly between the normal and RA populations, although the allele corresponding to 8 repeats was over-represented in the RA population (8 and 14% in the healthy and RA populations respectively). This suggests that IL-1 alpha intron 6 polymorphism could be part of a complex process involving other unidentified genetic factors in the pathogenesis of RA.


Complement activation alters myocellular sodium homeostasis during polymicrobial sepsis.
To determine whether complement activation alters sodium homeostasis in fast-twitch skeletal muscles during sepsis, and if protein kinase-C is involved in this process. Prospective, randomized, controlled animal study. Research laboratory. Male Sprague-Dawley rats weighing 60-75 g. Rats underwent cecal ligation and puncture (CLP) or sham-operation with or without soluble complement receptor-1 treatment. Soluble complement receptor-1 (20 mg/kg) was administered intraperitoneally 5 mins before operation. Twenty-four hours after operation, fast-twitch extensor digitorum longus muscles were isolated and incubated in normal Krebs-Henseleit buffer (pH 7.4). In addition, extensor digitorum longus muscles isolated from normal rats were incubated for 1 hr in the Krebs-Henseleit buffer media containing normal rat sera, zymosan-activated (4 or 10 mg/mL) rat sera, or heat-inactivated rat sera. Ten percent diluted rat sera were used as a complement source in all groups. Last, extensor digitorum longus muscles isolated from normal rats were incubated for 1 hr in the Krebs-Henseleit buffer media containing zymosan-activated or heat-inactivated rat sera in the presence of protein kinase-C inhibitors (i.e., 4 microM GF109203X or 5 microM rottlerin). Soluble C5b-9 complex concentrations in zymosan-activated human sera were determined by enzyme-linked immunosorbent assay to evaluate the degree of complement activation induced by zymosan. Incubated extensor digitorum longus muscles from CLP, sham-operated, or normal rats were used to measure intracellular Na+ and K+ contents ([Na+]i or [K+]i). Polymicrobial sepsis, as produced by CLP, markedly increased [Na+]i and [Na+]i/[K+]i ratios in fast-twitch extensor digitorum longus muscles 24 hrs after CLP compared with sham operation. Administration of soluble recombinant complement receptor 1 before operation significantly decreased myocellular [Na+]i and [Na+]i/[K+]i ratios. Zymosan profoundly elevated soluble C5b-9 concentrations in human sera in vitro. Sublytic zymosan-activated rat sera significantly increased myocellular [Na+]i and [Na+]i/[K+]i ratios relative to heat-inactivated rat sera. No difference in myocellular [Na+]i and [Na+]i/[K+]i ratios was observed when we used 4 mg/mL compared with 10 mg/mL of zymosan for activation. Last, incubation of extensor digitorum longus muscles with GF109203X or rottlerin significantly attenuated increases in myocellular [Na+]i and [Na+]i/[K+]i ratios induced by sublytic zymosan-activated rat sera. Polymicrobial sepsis alters sodium homeostasis in fast-twitch skeletal muscles, which is significantly attenuated by administration of soluble complement receptor 1. Protein kinase-C inhibition completely blocks changes in myocellular [Na+]i and [Na+]i/[K+]i ratios induced by sublytic zymosan-activated rat sera. Collectively, these results suggest that an inappropriate activation of complement is, at least in part, responsible for changes in skeletal muscle sodium homeostasis during sepsis, and activation of PKC is one of the intracellular signaling pathways by which complement activation alters myocellular sodium homeostasis.


[Bacteriological evaluation of fresh tilapia (Oreochromis niloticus) coming from the northern region of Costa Rica].
The following work presents an evaluation of the normal and pathogenic flora associated to tilapia (Oreochromis niloticus), since there are no previous national studies referred to the microbiological quality of this product. The total aerobic plate count, lactic bacteria, Enterococcus sp and Aeromonas sp and fecal and total coliform count, and the presence of Listeria sp and Salmonella spp from the external surface of tilapias were evaluated. A total of 50 samples, coming from San Carlos and Cañas zones were transported in ice to the Food and Water Microbiology Laboratory, Universidad de Costa Rica, where the laboratory analysis were performed, according to the methodology presented by de American Public Health Association, 1998. The results obtained confirm the microbiological freshness of the product when the analysis was performed, although coliform levels were unacceptable. Listeria sp was not found, but the isolation of Salmonella spp. confirms the fecal contamination of water where the tilapia is grown, aside of the Public Health concern. Also, it was found a high number of Aeromonas sp, as part of its normal flora, so we recommend including this genus in the quality standards for fresh fish. According to the data obtained, there was no significant difference (95% confidence) between the total plate count, fecal and total coliforms, Enterococcus sp. and Aeromonas sp. from the samples coming from the zones of San Carlos and Cañas.


[Psychophysiological optimization of operators' activities].
A concept of complex psychophysiological optimization of human performance, including the models of a relationship between the mechanisms of performance (structure and operational contents) and the ways of its regulation is proposed in the paper. Data on the regularities of separate and combined influences of various labour factors on the quality and functional status of an operator have been experimentally obtained. Rational ways for enhancing performance efficiency of man and for normalizing his status are shown.


Initial arch wires for alignment of crooked teeth with fixed orthodontic braces.
The initial arch wire is the first arch wire to be inserted into the fixed appliance at the beginning of orthodontic treatment and is used mainly for correcting crowding and rotations of teeth. With a number of orthodontic arch wires available for initial tooth alignment, it is important to understand which wire is most efficient, as well as which wires cause the least amount of root resorption and pain during the initial aligning stage of treatment. To identify and assess the evidence for the effects of initial arch wires for alignment of teeth with fixed orthodontic braces in relation to alignment speed, root resorption and pain intensity. We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (30th November 2009), CENTRAL (The Cochrane Library 2009, Issue 4), MEDLINE (1950 to 30th November 2009) and EMBASE (1980 to 30th November 2009). Reference lists of articles were also searched. There was no restriction with regard to publication status or language of publication. We contacted all authors of included studies to identify additional studies. Randomised controlled trials (RCTs) of initial arch wires to align crooked teeth with fixed orthodontic braces were selected. Only studies involving patients with upper and/or lower full arch fixed orthodontic appliances were included. Two review authors were responsible for study selection, validity assessment and data extraction. All disagreements were resolved by discussion amongst the review team. Corresponding authors of included studies were contacted to obtain missing information. Seven RCTs, with 517 participants, provided data for this review. Among them, five trials investigated the speed of initial tooth alignment comparing: 0.016 inch ion-implanted A-NiTi wire versus 0.016 inch A-NiTi versus 0.0175 multistrand stainless steel wire; 0.016x0.022 inch medium force active M-NiTi wire versus 0.016x0.022 inch graded force active M-NiTi wire versus 0.0155 inch multistrand stainless steel wire; 0.016 inch superelastic NiTi wire versus 0.016 inch NiTi wire; 0.014 inch superelastic NiTi wire versus 0.0155 inch multistrand stainless steel wire; 0.016 inch CuNiTi wire versus 0.016 inch NiTi wire. The other two studies investigated pain intensity experienced by patients during the initial stage of treatment comparing: 0.014 inch superelastic NiTi wire versus 0.014 inch NiTi wire; 0.014 inch superelastic NiTi wire versus 0.015 inch multistrand stainless steel wire. Data analyses were often inappropriate within the included studies. There is some evidence to suggest that there is no difference between the speed of tooth alignment or pain experienced by patients when using one initial aligning arch wire over another. However, in view of the general poor quality of the including trials, these results should be viewed with caution. Further RCTs are required.


Evaluating marker-guided treatment selection strategies.
A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements. Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients.


Biological and biochemical characterization of bovine interleukin 2. Studies with cloned bovine T cells.
Bovine peripheral blood lymphocytes stimulated with the T cell mitogen concanavalin A (Con A) secrete a lymphokine with biological properties similar to T cell growth factor (TCGF) or interleukin 2 (IL 2) from other species. The material supports proliferation of Con A-derived T cell blasts, limiting dilution cloning of T cell blasts, and continuous growth of T cell clones for over 6 mo in vitro. A quantitative microassay with the use of TCGF-dependent, Con A-unresponsive cloned T cells was used to determine the biological activity during purification of IL 2. A single peak of activity with an apparent m.w. of 25,000 to 28,000 was recovered after gel filtration. This material eluted from DEAE-Sephacryl between 135 and 165 mM NaCl. After isoelectric focusing, high pressure liquid chromatography, and gel electrophoresis under reducing conditions, peak IL 2 activity was associated with proteins having m.w. of 20,000 and 23,000.


Biodiversity of freshwater fish of a protected river in India: comparison with unprotected habitat.
In India, freshwater environments are experiencing serious threats to biodiversity, and there is an urgent priority for the search of alternative techniques to promote fish biodiversity conservation and management. With this aim, the present study was undertaken to assess the fish biodiversity within and outside a river protected area, and to evaluate whether the protected river area provides some benefits to riverine fish biodiversity. To assess this, the pattern of freshwater fish diversity was studied in river Gerua, along with some physicochemical conditions, from April 2000 to March 2004. For this, a comparison was made between a 15km stretch of a protected area (Katerniaghat Wildlife Sanctuary), and an unprotected one 85km downstream. In each site some physicochemical conditions were obtained, and fish were caught by normal gears and the diversity per site described. Our results showed that water temperature resulted warmest during the pre-monsoon season (25 degreeC) and low during the winter (14-15 degreeC); turbidity considerably varied by season. In the protected area, a total of 87 species belonging to eight orders, 22 families and 52 genera were collected; while a maximum of 59 species belonging to six orders, 20 families and 42 genera were recorded from the unprotected areas. Cyprinids were found to be the most dominant genera and Salmostoma bacaila was the most numerous species in the sanctuary area. Other numerous species were Eutropiichthys vacha, Notopterus notopterus, Clupisoma garua and Bagarius bagarius. The results indicated more species, greater abundances, larger individuals, and higher number of endangered fishes within the sanctuary area when compared to the unprotected area. Analysis on the mean abundance of endangered and vulnerable species for the evaluated areas in the sanctuary versus unprotected ones indicated significant differences in fish abundance (p<0.05). These results showed that this riverine protected area could be important for conservation and management of fish diversity in the region, especially for resident and threatened species.


The oxidative fumarase FumC is a key contributor for E. coli fitness under iron-limitation and during UTI.
The energy required for a bacterium to grow and colonize the host is generated by metabolic and respiratory functions of the cell. Proton motive force, produced by these processes, drives cellular mechanisms including redox balance, membrane potential, motility, acid resistance, and the import and export of substrates. Previously, disruption of succinate dehydrogenase (sdhB) and fumarate reductase (frdA) within the oxidative and reductive tricarboxylic acid (TCA) pathways in uropathogenic E. coli (UPEC) CFT073 indicated that the oxidative, but not the reductive TCA pathway, is required for fitness in the urinary tract. Those findings led to the hypothesis that fumA and fumC encoding fumarase enzymes of the oxidative TCA cycle would be required for UPEC colonization, while fumB of the reductive TCA pathway would be dispensable. However, only UPEC strains lacking fumC had a fitness defect during experimental urinary tract infection (UTI). To further characterize the role of respiration in UPEC during UTI, additional mutants disrupting both the oxidative and reductive TCA pathways were constructed. We found that knock-out of frdA in the sdhB mutant strain background ameliorated the fitness defect observed in the bladder and kidneys for the sdhB mutant strain and results in a fitness advantage in the bladder during experimental UTI. The fitness defect was restored in the sdhBfrdA double mutant by complementation with frdABCD. Taken together, we demonstrate that it is not the oxidative or reductive pathway that is important for UPEC fitness per se, but rather only the oxidative TCA enzyme FumC. This fumarase lacks an iron-sulfur cluster and is required for UPEC fitness during UTI, most likely acting as a counter measure against exogenous stressors, especially in the iron-limited bladder niche.


The effects of human activities on natural radiation exposure: health and regulatory implications.
A decade ago, interest in "enhanced" natural radiation was focused primarily on localized industrial activities, e.g., uranium, radium, thorium and phosphate production. Recognition that all human activities influence natural radiation exposure, and that indoor radon exposure is particularly sensitive to such activities (building construction practices, occupant life-styles) has added a new dimension to the problem. Public health assessments must address the problem of high individual risks of lung cancer as well as substantial population risks that are only minimally ameliorated by reduction of high exposures. In the United States, Federal, State, and local government agencies are collaborating with the private sector in developing the information needed for public guidance. Voluntary standards relating to building construction practices are likely to be developed.


Metallic nanostructures with low dimensionality for electrochemical water splitting.
Metallic nanostructures with low dimensionality (one-dimension and two-dimension) possess unique structural characteristics and distinctive electronic and physicochemical properties including high aspect ratio, high specific surface area, high density of surface unsaturated atoms and high electron mobility. These distinctive features have rendered them remarkable advantages over their bulk counterparts for surface-related applications, for example, electrochemical water splitting. In this review article, we highlight the recent research progress in low-dimensional metallic nanostructures for electrochemical water splitting including hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Fundamental understanding of the electrochemistry of water splitting including HER and OER is firstly provided from the aspects of catalytic mechanisms, activity descriptors and property evaluation metrics. Generally, it is challenging to obtain low-dimensional metallic nanostructures with desirable characteristics for HER and OER. We hereby introduce several typical methods for synthesizing one-dimensional and two-dimensional metallic nanostructures including organic ligand-assisted synthesis, hydrothermal/solvothermal synthesis, carbon monoxide confined growth, topotactic reduction, and templated growth. We then put emphasis on the strategies adopted for the design and fabrication of high-performance low-dimensional metallic nanostructures for electrochemical water splitting such as alloying, structure design, surface engineering, interface engineering and strain engineering. The underlying structure-property correlation for each strategy is elucidated aiming to facilitate the design of more advanced electrocatalysts for water splitting. The challenges and perspectives for the development of electrochemical water splitting and low-dimensional metallic nanostructures are also proposed.