Aminoglycoside resistance in clinical Escherichia coli and Klebsiella pneumoniae isolates from Western Norway

Resistance to gentamicin in Escherichia coli from blood culture has shown an increase over the past decade in Norway. This study was done to investigate aminoglycoside resistance in Escherichia coli and Klebsiella pneumoniae in Western Norway. The material included 49 blood culture isolates which had shown aminoglycoside resistance collected during 2000-2009. To investigate co-resistance to alternative antibiotics and dynamics involved in aminoglycoside resistance 67 isolates (mostly from urine) exhibiting resistance to both aminoglycosides and extended spectrum beta-lactam antibiotics were also included. MIC values were obtained for amikacin, gentamicin, kanamycin, netilmicin, streptomycin and tobramycin and all isolates were screened using PCR for aac(3)-II and aac(6')-Ib, encoding aminoglycoside modifying enzymes. Resistance to ≥3 aminoglycosides was found in 92% of the isolates and 60.3% showed resistance to gentamicin, netilmicin, tobramycin and kanamycin. Amikacin resistance was low. Co-resistance to ciprofloxacin was found in 88% of the isolates with gentamicin resistance. aac(3)-IIa/c was found in 79.3% and aac(6')-Ib in 37.9% of the isolates and 28.4% harboured both genes. aac(6')-Ib-cr, possibly contributing to ciprofloxacin resistance was found mostly in extended spectrum beta-lactamase producers. The aminoglycoside resistance patterns indicate co-existence of multiple resistance mechanisms. The use of ciprofloxacin and third generation cephalosporins is likely to have contributed to the increase in aminoglycoside resistance in Norway.     

Location of gliomas in relation to mobile telephone use: a case-case and case-specular analysis

The energy absorbed from the radio-frequency fields of mobile telephones depends strongly on distance from the source. The authors' objective in this study was to evaluate whether gliomas occur preferentially in the areas of the brain having the highest radio-frequency exposure. The authors used 2 approaches: In a case-case analysis, tumor locations were compared with varying exposure levels; in a case-specular analysis, a hypothetical reference location was assigned for each glioma, and the distances from the actual and specular locations to the handset were compared. The study included 888 gliomas from 7 European countries (2000-2004), with tumor midpoints defined on a 3-dimensional grid based on radiologic images. The case-case analyses were carried out using unconditional logistic regression, whereas in the case-specular analysis, conditional logistic regression was used. In the case-case analyses, tumors were located closest to the source of exposure among never-regular and contralateral users, but not statistically significantly. In the case-specular analysis, the mean distances between exposure source and location were similar for cases and speculars. These results do not suggest that gliomas in mobile phone users are preferentially located in the parts of the brain with the highest radio-frequency fields from mobile phones.     

Psychometric properties of brief indexes designed to measure social-cognitive predictors of smoking initiation

BACKGROUND: Constructing indexes which measure factors that may predict smoking initiation is essential for planning prevention programs. Our aim was to examine the criterion-related construct validity of brief psychological indexes of attitude, social influence and self-efficacy to be used in future studies for predicting smoking initiation in adolescents. METHODS: Five indexes were evaluated using cross-sectional data on 4819 adolescents age 13 in a random sample of schools in six Danish counties. Item analyses were performed with the graphical log-linear Rasch model, a modification of the Rasch model that allows for differential item functioning and positive local dependence. RESULTS: The three indexes social influence-norms, social influence-pressure and attitude showed acceptable deviations from the Rasch model, while the two indexes self-efficacy and social influence-behavior were invalidated by negative local dependence. CONCLUSION: Of the five tested indexes, three (social influence-norms, social influence-pressure and attitude) showed acceptable criterion-related construct validity and may be considered unbiased representations of the theory-based factors if statistical analyses are appropriately adjusted. The results of this population-based study show that the graphical log-linear Rasch model is useful for evaluating health-related behavior indexes and identifying problems, which can be dealt with when using the indexes in future studies.     

RAGE signaling sustains inflammation and promotes tumor development

A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer.     

Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain—A comparative PET study with [11C]raclopride and [11C]MNPA

Binding studies in vitro have demonstrated that the dopamine D₂ receptor may exist in two affinity states for agonists. The high affinity state is thought to represent the functional state of the receptor and proportions might alter during disease. In vitro studies further indicate that agonists induce measurable D₂ receptor occupancy at clinically relevant concentrations but only when measured at the high affinity state. Recently developed PET‐radioligands, such as [¹¹C]MNPA, have now made it possible to directly study agonist binding in vivo. The aim of this study was to compare the inhibition by apomorphine of agonist and antagonist radioligand binding to D_2/3 receptors in vivo. A total of 36 PET measurements were performed with the D_2/3 antagonist [¹¹C]raclopride or the D_2/3 agonist [¹¹C]MNPA in two cynomolgus monkeys. On each study day, a baseline measurement was followed by two consecutive pretreatment studies with rising doses of apomorphine (0.01, 0.05, 0.15, 0.5, 1.0, and 3.0 mg/kg). Binding potential (BP_ND) values were calculated for the striatum with cerebellum as reference region. Apomorphine inhibited [¹¹C]raclopride and [¹¹C]MNPA binding in a dose‐dependent manner and to a similar extent. ID₅₀ and K_i values were 0.26 mg/kg and 29 ng/ml for [¹¹C]raclopride and 0.50 mg/kg and 31 ng/ml for [¹¹C]MNPA. The present observations do not support the existence of two affinity states in vivo. It might thus be speculated that all D_2/3 receptors are in the high affinity state at in vivo conditions. Synapse 63:378–389, 2009. © 2009 Wiley‐Liss, Inc.     

Imaging cerebral 2-ketoisocaproate metabolism with hyperpolarized (13)C magnetic resonance spectroscopic imaging

The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-¹³C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-¹³C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.     

Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma

Background P53 and ATM are central checkpoint genes involved in the repair of DNA damage after ionising irradiation, which has been associated with risk of brain tumours. Therefore, we tested the hypothesis that polymorphisms and haplotypes in p53 and ATM could be associated with glioma and meningioma risk. Material and Methods Six hundred and eighty glioma cases (298 glioblastoma (GBM)), 503 meningioma cases, and 1555 controls recruited in the Nordic-UK Interphone study, were analysed in association with three polymorphisms in p53 (rs2287499, rs1042533, rs1625895) and five polymorphisms in ATM ( rs228599, rs3092992, rs664143, rs170548, rs3092993). Haplotypes were constructed using the HAPLOSTAT program. Results The global statistical test of glioblastoma and p53 haplotypes was p = 0.02. The haplotype analysis on glioblastoma revealed the 1-2-2 haplotype (promotor-codon72-intron 6) had a frequency of 6.1% in cases compared with 9.8% in controls (p = 0.003).The 1-2-1 haplotype was significantly more frequent in GBM cases, 10.2%, than in controls, 7.3% (p = 0.02). The haplotype analysis in ATM revealed an increased frequency of the 1-1-1-2-1 haplotype in meningioma cases (33.8%) compared with controls (30.3%) (p = 0.03). The 2-1-2-1-1 haplotype had a lower frequency in meningioma cases (36.1%) than controls (40.7%) (p = 0.009). Conclusions This study found both positive and negative associations of haplotypes in p53 for glioblastoma and ATM for meningioma. This study provides new data that could add to our understanding of brain tumour susceptibility.     

Evaluation of minor groove binding probe and Taqman probe PCR assays: Influence of mismatches and template complexity on quantification

Real-time PCR assays using 3'-minor groove binder (MGB) or Taqman probes are widely used for clinical virological testing and mutation/polymorphism detection. We compared a 3'-MGB probe to a conventional Taqman probe for linearity, sensitivity, specificity and dynamic range. The performance of the two assays was compared using plasmids containing different mismatches or using human genomic DNA as a template. Comparable linearity and sensitivity were observed for the MGB and the Taqman probe assays. Using standard conditions, none of the assays were sequence-specific. Up to five mismatches generated a detectable signal in the Taqman probe assay. The performance of the Taqman as well as the MGB probe assay was influenced by the complexity of the template, the latter, however, to a lesser degree. Overall, these results highlight the advantages of the MGB probe over the Taqman probe regarding mismatch discrimination, but suggest that optimization of reaction conditions and verification of the specificity are necessary also for MGB probes.     

Mortality among participants and non-participants in a prospective cohort study

Socioeconomic position and lifestyle often affect participation in scientific studies. The authors investigated differences in overall and cause-specific mortality between participants and non-participants in the prospective Danish cohort study “Diet, Cancer and Health” and the association between non-participation and mortality by socioeconomic position. A total of 80,996 men and 79,729 women aged 50–64?years, were invited. The authors obtained register data on education, income, death and cause-specific mortality for participants and non-participants and used survival curves to examine differences in overall mortality. Poisson regression models were used to estimate the mortality rate ratio (MRR) by socioeconomic group and by cause of death of participants and non-participants. After a median follow-up of 13?years (5–95 percentiles, 5–14?years), the MRRs for overall mortality among non-participants were 2.09 (95?% CI 1.99–2.14) and 2.29 (95?% CI 2.19–2.40) among men and women, respectively compared with participants. After adjusting for socioeconomic position, the MRRs changed to 1.73 (95?% CI 1.66–1.79) and 2.10 (95?% CO 2.01–2.20) among men and women, respectively. The MRRs did not level out after up to 15?years of follow-up. The MRRs were all significantly increased and ranged from 1.51 to 4.28 for men, depending on the cause of death, and from 1.60 to 3.99 for women. Clear differences in mortality from all investigated causes of death were found between participants and non-participants, which persisted after up to 15?years of follow-up. Socioeconomic position had little effect on this result.