Detection of vim- and ipm-type metallo-beta-lactamases in Pseudomonas aeruginosa clinical isolates

BACKGROUND: Pseudomonas aeruginosa is the most important bacterium isolated from burn wounds, and its resistance to imipenem due to metallo-beta-lactamases is increasing. This study was designed to detect vim1, vim2, ipm1 and ipm2 metallo-beta-lactamases genes between Pseudomonas aeruginosa isolates isolated from Shahid Motahari Burns Hospital, Iran. METHODS: To that end, we isolated 483 nonduplicate consecutive isolates of P. aeruginosa from burn infections; and after biochemical confirmation, we examined the imipenem susceptibility via the Kirby-Bauer method. All the imipenem-resistant and imipenem-intermediate isolates were screened for vim1, vim2, ipm1 and ipm2 genes through the PCR method. RESULTS: From the 483 isolates, 272 (56) and 63 (13) isolates had resistant and intermediate zones in their imipenem antibiogram pattern, respectively. Fifty-four (16.1), 7 (2.1), 22 (6.6), and 11 (3.3) of the resistant and intermediate isolates had vim1, vim2, ipm1 and ipm2 genes in their PCR results, respectively. CONCLUSION: MBL-mediated imipenem resistance in P. aeruginosa is a cause for concern in the treatment of infective burn patients. The rate of imipenem resistance due to MBL was increased dramatically and newer versions of MBL families were detected for the first time. These results suggest that an effective method should be provided to fight MBL production in clinical isolates

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression

The forward physics facility at the high-luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

Role of strong intramolecular N-H...N hydrogen bonds in determining the conformation of adenosine-receptors antagonists

Over the last few years many efforts have been devoted to the discovery of new adenosine antagonists which can selectively bind to one of the four adenosine receptors, called A(1), A(2A), A(2B) and A(3), in order to develop new drugs with few side effects. The present paper reports the crystal structures of four newly synthesized antagonists belonging to the chemical class of pyrazolo-triazolo-pyrimidine derivatives, which display good affinity and selectivity properties towards the A2A or A(3) receptor subtypes. These molecules assume an overall planar conformation due to the formation of strong intramolecular N-H center dot center dot center dot N hydrogen bonds. A systematic investigation on molecules containing the ureidic-NH-C(=O, S)-NH-C C=N- fragment has shown that the formation of such interactions is a common feature for this class of compounds. The associated energy, evaluated through DFT calculations, is some 50.24 kJ mol(-1), leading to the conclusion that the hydrogen bond, and consequently the planar conformation, is retained not only in the solid state but also in solution during the interaction of the molecule with its receptor

Preparation of fused purine derivatives as adenosine A3 receptor modulators.

Adenosine A3 receptor modulators of formula I [X = CH or N; R1, R2 = (un)substituted alkyl, aralkyl, aryl, etc.; R3 = (un)substituted aryl, alkyl, aralkyl; R4 = H, (un)substituted alkyl, aralkyl, aryl] are prepd. These compds. are useful as therapeutic agents for a no. of diseases and medical conditions that are mediated by the A3 receptor. The compds. of this invention are also useful as diagnostic agents for the A3 receptor. Thus, II was prepd., starting from benzylurea and 2-cyanoacetic acid, and had Ki value of 200 nM for binding to A3 receptors expressed in CHO cells

Preparation of substituted purinylpyrazolylacetamides as adenosine A2B receptor antagonists.

The title compds. I [R1, R2 = (un)substituted alkyl; R3 = H, halo; R4, R5 = H or alkyl; R6 = (un)substituted (hetero)aryl] which are adenosine A2B receptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine A2B receptor activity, were prepd. Such conditions and diseases include, but are not limited to, chronic and acute inflammatory diseases involving degranulation of mast cells, e.g., asthma, allergic rhinitis and allergic dermatitis; impaired sensitivity to insulin, e.g., type 2 diabetes, non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis, e.g., solid tumors and angiogenic retinopathies; apnea of preterm infants; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosus; diseases involving microvascular abnormalities of the retina that are mediated by adenosine A2B receptors, e.g., retinopathy of prematurity, macular degeneration, and diabetic retinopathy; and cardiac diseases including hyperplasia consequent to hypertension, arteriosclerosis, and heart attack. E.g., a multi-step synthesis of II, starting from aniline, was described. Exemplified compds. I were tested in adenosine A2B receptor binding and functional assays (data given). Pharmaceutical compn. comprising the compd. I is disclosed

Public transport risk assessment through fault tree analysis

This study focused on the public transport risk assessment in District one of ​​Tehran through Fault Tree Analysis involving the three criteria of human, vehicle and road in Haddon matrix. In fact, it examined the factors contributing to the occurrence of road accidents at several urban black spots within District 1. Relying on road safety checklists and survey of experts, this study made an effort to help urban managers to assess the risks in the public transport and prevent road accidents. Finally, the risk identification and assessment of public transport in District one yielded several results to answer the research questions. The hypotheses analysis suggested that safety issues involved in public transport are concerned by urban managers. The key reactive measures are investigation of accidents, identification of causes and correction of black spots. In addition to high costs, however, the reactive measures give rise to multiple operational problems such as traffic navigation and guaranteeing user safety in every operation. The case study highlighted the same fact. The macro-level management in the metropolis of Tehran is critical. The urban road casualties and losses can be curtailed by preventive measures such as continuous assessment of road safety

Blockade of globus pallidus adenosine A2A receptors displays antiparkinsonian activity in 6-hydroxydopamine-lesioned rats treated with D1 or D2 dopamine receptor agonists.

We have recently demonstrated how antagonism of adenosine A2A receptors within the globus pallidus (GP) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor L-DOPA in 6-hydroxydopamine-lesioned hemiparkinsonian rats. To further characterize the influence of pallidal A2A receptor blockade on the motor stimulant effects elicited by dopamine receptor activation, hemiparkinsonian rats were infused with the water-sol. A2A antagonist SCH BT2 in the GP, alone or in combination with systemic administration of either SKF 38393 or quinpirole, to stimulate dopamine D1 or D2 receptors, resp. SCH BT2 alone (5 g/1 l) neither altered motor behavior nor produced postural asymmetry. In contrast, the contralateral rotations elicited by SKF 38393 (1.5 mg/kg) as well as quinpirole (0.05 mg/kg) were potentiated by the concomitant intrapallidal infusion of SCH BT2. The results of this study demonstrate that blockade of pallidal A2A receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D1 or D2 dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A2A receptor antagonists