Influence of environmental factors on the expression of phenotypic characters by chicken dorsal root ganglion cells in culture.

Primary sensory neurons were grown under four conditions of culture. The influence of nonneuronal cells, horse serum or both was studied on the phenotypic expression of certain neuronal subpopulations. The number of neurons expressing acetylcholinesterase, alpha-bungarotoxin-binding sites or a high uptake capacity for glutamine was enhanced by nonneuronal cells. The horse serum increases the neuronal subpopulation exhibiting a carbonic anhydrase activity. Certain phenotypic changes fit conditions consistent with an epigenetic induction rather than a cell selection.

Improving the prediction of the functional impact of cancer mutations by baseline tolerance transformation

High-throughput prioritization of cancer-causing mutations (drivers) is a key challenge of cancer genome projects, due to the number of somatic variants detected in tumors. One important step in this task is to assess the functional impact of tumor somatic mutations. A number of computational methods have been employed for that purpose, although most were originally developed to distinguish disease-related nonsynonymous single nucleotide variants (nsSNVs) from polymorphisms. Our new method, transformed Functional Impact score for Cancer (transFIC), improves the assessment of the functional impact of tumor nsSNVs by taking into account the baseline tolerance of genes to functional variants.

Combining clinical factors and quantitative ultrasound improves the detection of women both at low and high risk for hip fracture.

We hypothesized that combining clinical risk factors (CRF) with the heel stiffness index (SI) measured via quantitative ultrasound (QUS) would improve the detection of women both at low and high risk for hip fracture. Categorizing women by risk score improved the specificity of detection to 42.4%, versus 33.8% using CRF alone and 38.4% using the SI alone. This combined CRF-SI score could be used wherever and whenever DXA is not readily accessible. INTRODUCTION AND HYPOTHESIS: Several strategies have been proposed to identify women at high risk for osteoporosis-related fractures; we wanted to investigate whether combining clinical risk factors (CRF) and heel QUS parameters could provide a more accurate tool to identify women at both low and high risk for hip fracture than either CRF or QUS alone. METHODS: We pooled two Caucasian cohorts, EPIDOS and SEMOF, into a large database named "EPISEM", in which 12,064 women, 70 to 100 years old, were analyzed. Amongst all the CRF available in EPISEM, we used only the ones which were statistically significant in a Cox multivariate model. Then, we constructed a risk score, by combining the QUS-derived heel stiffness index (SI) and the following seven CRF: patient age, body mass index (BMI), fracture history, fall history, diabetes history, chair-test results, and past estrogen treatment. RESULTS: Using the composite SI-CRF score, 42% of the women who did not report a hip fracture were found to be at low risk at baseline, and 57% of those who subsequently sustained a fracture were at high risk. Using the SI alone, corresponding percentages were 38% and 52%; using CRF alone, 34% and 53%. The number of subjects in the intermediate group was reduced from 5,400 (including 112 hip fractures) and 5,032 (including 111 hip fractures) to 4,549 (including 100 including fractures) for the CRF and QUS alone versus the combination score. CONCLUSIONS: Combining clinical risk factors to heel bone ultrasound appears to correctly identify more women at low risk for hip fracture than either the stiffness index or the CRF alone; it improves the detection of women both at low and high risk.

Traducción comentada de Guidelines Governing the Adoption of Children, 2011 in India

En este trabajo se analiza la variación discursiva y los diferentes criterios de estilo entre textos jurídicos normativos en inglés y español; se establecen fenómenos lingüísticos propios del discurso jurídico que generan problemas de traducción; y se comparan algunas diferencias entre sistemas jurídicos y políticos para analizar su repercusión en la traducción.

Efficacy Of Canakinumab (Acz885), A Fully Human Anti-Interleukin (Il)-1beta Monoclonal Antibody, In The Prevention Of Flares In Gout Patients Initiating Allopurinol Therapy

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by IL-1b. Canakinumab targets and inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 week double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150 mg divided in doses every 4 weeks (50+50+25+25 mg [q4wk]) or colchicine 0.5 mg p.o. daily for 16 weeks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to the number of gout flares occurring during first 16 weeks. Secondary outcomes included number of patients with gout flares and C-reactive protein (CRP) levels during the first 16 weeks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine could not be determined. Based on a negative binomial model, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25 mg 0.60, 50 mg 0.34, 100 mg 0.28, 200 mg 0.37, 300 mg 0.29, q4wk 0.38; p<=0.05). The percentage of patients with flares was lower for all canakinumab groups (25 mg 27.3%, 50 mg 16.7%, 100 mg 14.8%, 200 mg 18.5%, 300 mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p<=0.05 for all). The median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN=3 mg/L) throughout the 16 week period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), and 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg) and 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. One fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusion: In this large randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine (standard of care), and was well tolerated.

Estimation du degré de couverture d'un registre pour les cancers notifiés au décès [Evaluation of the comprehensiveness of a cancer register from death certificates].

The comparison of cancer prevalence with cancer mortality can lead under some hypotheses to an estimate of registration rate. A method is proposed, where the cases with cancer as a cause of death are divided into 3 categories: (1) cases already known by the registry (2) unknown cases having occured before the registry creation date (3) unknown cases occuring during the registry operates. The estimate is then the number of cases in the first category divided by the total of those in categories 1 and 3 (these only are to be registered). An application is performed on the data of the Canton de Vaud. Survival rates of the Norvegian Cancer Registry are used for computing the number of unknown cases to be included in second and third category, respectively. The discussion focusses on the possible determinants of the obtained comprehensiveness rates for various cancer sites.

Using niche-based models to improve the sampling of rare species

Because data on rare species usually are sparse, it is important to have efficient ways to sample additional data. Traditional sampling approaches are of limited value for rare species because a very large proportion of randomly chosen sampling sites are unlikely to shelter the species. For these species, spatial predictions from niche-based distribution models can be used to stratify the sampling and increase sampling efficiency. New data sampled are then used to improve the initial model. Applying this approach repeatedly is an adaptive process that may allow increasing the number of new occurrences found. We illustrate the approach with a case study of a rare and endangered plant species in Switzerland and a simulation experiment. Our field survey confirmed that the method helps in the discovery of new populations of the target species in remote areas where the predicted habitat suitability is high. In our simulations the model-based approach provided a significant improvement (by a factor of 1.8 to 4 times, depending on the measure) over simple random sampling. In terms of cost this approach may save up to 70% of the time spent in the field.

A novel approach to reducing number of sensing units for wearable gait analysis systems.

Gait analysis methods to estimate spatiotemporal measures, based on two, three or four gyroscopes attached on lower limbs have been discussed in the literature. The most common approach to reduce the number of sensing units is to simplify the underlying biomechanical gait model. In this study, we propose a novel method based on prediction of movements of thighs from movements of shanks. Datasets from three previous studies were used. Data from the first study (ten healthy subjects and ten with Parkinson's disease) were used to develop and calibrate a system with only two gyroscopes attached on shanks. Data from two other studies (36 subjects with hip replacement, seven subjects with coxarthrosis, and eight control subjects) were used for comparison with the other methods and for assessment of error compared to a motion capture system. Results show that the error of estimation of stride length compared to motion capture with the system with four gyroscopes and our new method based on two gyroscopes was close ( -0.8 ±6.6 versus 3.8 ±6.6 cm). An alternative with three sensing units did not show better results (error: -0.2 ±8.4 cm). Finally, a fourth that also used two units but with a simpler gait model had the highest bias compared to the reference (error: -25.6 ±7.6 cm). We concluded that it is feasible to estimate movements of thighs from movements of shanks to reduce number of needed sensing units from 4 to 2 in context of ambulatory gait analysis.

Gene Promoter Evolution Targets the Center of the Human Protein Interaction Network

Assessing the contribution of promoters and coding sequences to gene evolution is an important step toward discovering the major genetic determinants of human evolution. Many specific examples have revealed the evolutionary importance of cis-regulatory regions. However, the relative contribution of regulatory and coding regions to the evolutionary process and whether systemic factors differentially influence their evolution remains unclear. To address these questions, we carried out an analysis at the genome scale to identify signatures of positive selection in human proximal promoters. Next, we examined whether genes with positively selected promoters (Prom+ genes) show systemic differences with respect to a set of genes with positively selected protein-coding regions (Cod+ genes). We found that the number of genes in each set was not significantly different (8.1% and 8.5%, respectively). Furthermore, a functional analysis showed that, in both cases, positive selection affects almost all biological processes and only a few genes of each group are located in enriched categories, indicating that promoters and coding regions are not evolutionarily specialized with respect to gene function. On the other hand, we show that the topology of the human protein network has a different influence on the molecular evolution of proximal promoters and coding regions. Notably, Prom+ genes have an unexpectedly high centrality when compared with a reference distribution (P = 0.008, for Eigenvalue centrality). Moreover, the frequency of Prom+ genes increases from the periphery to the center of the protein network (P = 0.02, for the logistic regression coefficient). This means that gene centrality does not constrain the evolution of proximal promoters, unlike the case with coding regions, and further indicates that the evolution of proximal promoters is more efficient in the center of the protein network than in the periphery. These results show that proximal promoters have had a systemic contribution to human evolution by increasing the participation of central genes in the evolutionary process.

An allele-specific, stochastic gene expression process controls the expression of multiple Ly49 family genes and generates a diverse, MHC-specific NK cell receptor repertoire.

Mouse NK cells express MHC class I-specific inhibitory Ly49 receptors. Since these receptors display distinct ligand specificities and are clonally distributed, their expression generates a diverse NK cell receptor repertoire specific for MHC class I molecules. We have previously found that the Dd (or Dk)-specific Ly49A receptor is usually expressed from a single allele. However, a small fraction of short-term NK cell clones expressed both Ly49A alleles, suggesting that the two Ly49A alleles are independently and randomly expressed. Here we show that the genes for two additional Ly49 receptors (Ly49C and Ly49G2) are also expressed in a (predominantly) mono-allelic fashion. Since single NK cells can co-express multiple Ly49 receptors, we also investigated whether mono-allelic expression from within the tightly linked Ly49 gene cluster is coordinate or independent. Our clonal analysis suggests that the expression of alleles of distinct Ly49 genes is not coordinate. Thus Ly49 alleles are apparently independently and randomly chosen for stable expression, a process that directly restricts the number of Ly49 receptors expressed per single NK cell. We propose that the Ly49 receptor repertoire specific for MHC class I is generated by an allele-specific, stochastic gene expression process that acts on the entire Ly49 gene cluster.

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.

NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss.

A loss in the necessary amount of sleep alters expression of genes and proteins implicated in brain plasticity, but key proteins that render neuronal circuits sensitive to sleep disturbance are unknown. We show that mild (4-6 h) sleep deprivation (SD) selectively augmented the number of NR2A subunits of NMDA receptors on postsynaptic densities of adult mouse CA1 synapses. The greater synaptic NR2A content facilitated induction of CA3-CA1 long-term depression in the theta frequency stimulation range and augmented the synaptic modification threshold. NR2A-knock-out mice maintained behavioral response to SD, including compensatory increase in post-deprivation resting time, but hippocampal synaptic plasticity was insensitive to sleep loss. After SD, the balance between synaptically activated and slowly recruited NMDA receptor pools during temporal summation was disrupted. Together, these results indicate that NR2A is obligatory for the consequences of sleep loss on hippocampal synaptic plasticity. These findings could advance pharmacological strategies aiming to sustain hippocampal function during sleep restriction.

The role of imaging in acute ischemic stroke.

Neuroimaging has expanded beyond its traditional diagnostic role and become a critical tool in the evaluation and management of stroke. The objectives of imaging include prompt accurate diagnosis, treatment triage, prognosis prediction, and secondary preventative precautions. While capitalizing on the latest treatment options and expanding upon the "time is brain" doctrine, the ultimate goal of imaging is to maximize the number of treated patients and improve the outcome of one the most costly and morbid disease. A broad overview of comprehensive multimodal stroke imaging is presented here to affirm its utilization.

The Role of Magnesium in Concrete Deterioration, HR-355, Appendix, 1994

In the main report concerning the role that magnesium may have in highway concrete aggregate, over 20,000 electron microprobe data were obtained, primarily from automated scans, or traverses, across dolomite aggregate grains and the adjacent cement paste. Representative traverses were shown in figures and averages of the data were presented in Table II. In this Appendix, detailed representative and selected analyses of carbonate aggregate only are presented. These analyses were not presented in the main report because they would be interesting to only a few specialists in dolomite· rocks. In this Appendix, individual point analyses of mineral compositions in the paste have been omitted along with dolomite compositions at grain boundaries and cracks. Clay minerals and quartz inclusions in the aggregate are also not included. In the analyses, the first three column headings from left to right show line number, x-axis, and y-axis (Line number is an artifact of the computer print-out for each new traverse. Consecutive line numbers indicate a continuous traverse with distances between each point of 1.5 to a few μ-m. X-axis and y-axis are coordinates on the electron microscope stage). The next columns present weight percent oxide content of FeO, K20, CaO, Si02, Al203, MgO, SrO, BaO, MnO, Na20, and C02 (calculated assuming the number of moles of C02 is equal to the sum of moles of oxides, chiefly CaO and MgO), TOTAL (the sum of all oxides), and total (sum of all oxides excluding COi). In many of the analyses total is omitted.

A protocol for a systematic review on the impact of unpublished studies and studies published in the gray literature in meta-analyses.

BACKGROUND: Meta-analyses are particularly vulnerable to the effects of publication bias. Despite methodologists' best efforts to locate all evidence for a given topic the most comprehensive searches are likely to miss unpublished studies and studies that are published in the gray literature only. If the results of the missing studies differ systematically from the published ones, a meta-analysis will be biased with an inaccurate assessment of the intervention's effects.As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:â-ª To assess the impact of studies that are not published or published in the gray literature on pooled effect estimates in meta-analyses (quantitative measure).â-ª To assess whether the inclusion of unpublished studies or studies published in the gray literature leads to different conclusions in meta-analyses (qualitative measure). METHODS/DESIGN: Inclusion criteria: Methodological research projects of a cohort of meta-analyses which compare the effect of the inclusion or exclusion of unpublished studies or studies published in the gray literature.Literature search: To identify relevant research projects we will conduct electronic searches in Medline, Embase and The Cochrane Library; check reference lists; and contact experts.Outcomes: 1) The extent to which the effect estimate in a meta-analyses changes with the inclusion or exclusion of studies that were not published or published in the gray literature; and 2) the extent to which the inclusion of unpublished studies impacts the meta-analyses' conclusions.Data collection: Information will be collected on the area of health care; the number of meta-analyses included in the methodological research project; the number of studies included in the meta-analyses; the number of study participants; the number and type of unpublished studies; studies published in the gray literature and published studies; the sources used to retrieve studies that are unpublished, published in the gray literature, or commercially published; and the validity of the methodological research project.Data synthesis: Data synthesis will involve descriptive and statistical summaries of the findings of the included methodological research projects. DISCUSSION: Results are expected to be publicly available in the middle of 2013.