Use of mobile phones in Norway and risk of intracranial tumours.

To test the hypothesis that exposure to radio-frequency electromagnetic fields from mobile phones increases the incidence of gliomas, meningiomas and acoustic neuromas in adults. The incident cases were of patients aged 19-69 years who were diagnosed during 2001-2002 in Southern Norway. Population controls were selected and frequency-matched for age, sex, and residential area. Detailed information about mobile phone use was collected from 289 glioma (response rate 77%), 207 meningioma patients (71%), and 45 acoustic neuroma patients (68%) and from 358 (69%) controls. For regular mobile phone use, defined as use on average at least once a week or more for at least 6 months, the odds ratio was 0.6 (95% confidence interval 0.4-0.9) for gliomas, 0.8 (95% confidence interval 0.5-1.1) for meningiomas and 0.5 (95% confidence interval 0.2-1.0) for acoustic neuromas. Similar results were found with mobile phone use for 6 years or more for gliomas and acoustic neuromas. An exception was meningiomas, where the odds ratio was 1.2 (95% confidence interval 0.6-2.2). Furthermore, no increasing trend was observed for gliomas or acoustic neuromas by increasing duration of regular use, the time since first regular use or cumulative use of mobile phones. The results from the present study indicate that use of mobile phones is not associated with an increased risk of gliomas, meningiomas or acoustic neuromas.     

Translating expression profiling into a clinically feasible test to predict neuroblastoma outcome.

PURPOSE: To assess the feasibility of predicting neuroblastoma outcome using highly parallel quantitative real-time PCR data. EXPERIMENTAL DESIGN: We generated expression profiles of 63 neuroblastoma patients, 47 of which were analyzed by both Affymetrix U95A microarrays and highly parallel real-time PCR on microfluidic cards (MFC; Applied Biosystems). Top-ranked genes discriminating patients with event-free survival or relapse according to high-level analysis of Affymetrix chip data, as well as known neuroblastoma marker genes (MYCN and NTRK1/TrkA), were quantified simultaneously by real-time PCR. Analysis of PCR data was accomplished using high-level bioinformatics methods including prediction analysis of microarray, significance analysis of microarray, and Computerized Affected Sibling Pair Analyzer and Reporter. RESULTS: Internal validation of the MFC method proved it highly reproducible. Correlation of MFC and chip expression data varied markedly for some genes. Outcome prediction using prediction analysis of microarray on real-time PCR data resulted in 80% accuracy, which is comparable to results obtained using the Affymetrix platform. Real-time PCR data were useful for risk assessment of relapsing neuroblastoma (P = 0.0006, log-rank test) when Computerized Affected Sibling Pair Analyzer and Reporter analysis was applied. CONCLUSIONS: These data suggest that multiplex real-time PCR might be a promising approach to reduce the complexity of information obtained from whole-genome array experiments. It could provide a more convenient and less expensive tool for routine application in a clinical setting.     

Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine.

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.     

Potential Mechanisms of Benefit with Thalidomide in Chronic Heart Failure

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.     

Quality by design – Spray drying of insulin intended for inhalation

Quality by design (QBD) refers to a holistic approach towards drug development. Important parts of QBD include definition of final product performance and understanding of formulation and process parameters. Inhalation of proteins for systemic distribution requires specific product characteristics and a manufacturing process which produces the desired product. The objective of this study was to understand the spray drying process of insulin intended for pulmonary administration. In particular, the effects of process and formulation parameters on particle characteristics and insulin integrity were investigated. Design of experiments (DOE) and multivariate data analysis were used to identify important process parameters and correlations between particle characteristics. The independent parameters included the process parameters nozzle, feed, and drying air flow rate and drying air temperature along with the insulin concentration as a formulation parameter. The dependent variables included droplet size, geometric particle size, aerodynamic particle size, yield, density, tap density, moisture content, outlet temperature, morphology, and physical and chemical integrity. Principal component analysis was performed to find correlations between dependent and independent variables. Prediction equations were obtained for all dependent variables including both interaction and quadratic terms. Overall, the insulin concentration was found to be the most important parameter, followed by inlet drying air temperature and the nozzle gas flow rate. The insulin concentration mainly affected the particle size, yield and tap density, while the inlet drying air temperature mainly affected the moisture content. No change was observed in physical and chemical integrity of the insulin molecule.     

Early sexual maturation,central adiposity and subsequent overweight in late adolescence. A four-year follow-up of 1605 adolescent Norwegian boys and girls: the Young HUNT study

Background  

Early sexual maturation has been associated with overweight that may persist after the completion of biological growth and development. We have prospectively examined the influence of early sexual maturation on subsequent overweight in late adolescence and assessed if this association was modified by central adiposity in early adolescence.     

Who is maintaining weight in a middle-aged population in Sweden? A longitudinal analysis over 10 years

Background  

Obesity has primarily been addressed with interventions to promote weight loss and these have been largely unsuccessful. Primary prevention of obesity through support of weight maintenance may be a preferable strategy although to date this has not been the main focus of public health interventions. The aim of this study is to characterize who is not gaining weight during a 10 year period in Sweden.     

Psychological and behavioral factors unpredictive of disordered eating: a prospective study of the general adolescent population in Norway

OBJECTIVE: To investigate if cross-sectionally identified correlates of disordered eating among adolescents could also predict disordered eating prospectively over and beyond the initial level of disordered eating. METHOD: Two-wave longitudinal questionnaire study of a representative and nationwide sample of 7,751 Norwegian adolescents aged 12-19 at initial testing (t1). A 12-item version of the Eating Attitudes Test (EAT) was included. RESULTS: Forty percent of the girls and 25% of the boys with disordered eating at t1 also scored above the cut-off point 2 years later (t2). Initial disordered eating, gender, depressed mood, body dissatisfaction, unstable self-perceptions, perceived obesity, excessive exercise, and having idols with perfect bodies all predicted change in disordered eating. However, when the initial symptom load was controlled, these variables - except gender - only contributed marginally to the prediction of disordered eating. These negative results are in line with other longitudinal studies of changes in disordered eating in unselected adolescent populations. DISCUSSION: It cannot be established that psychological factors play a major etiological role in the development of disordered eating. The results are discussed with reference to a potential discontinuity between eating problems and eating disorders.     

Determination of Cause of Death Among Breast Cancer Cases in the Swedish Randomized Mammography Screening Trials: A comparison between official statistics and validation by an endpoint committee

Between 1976 and 1982, four randomized mammography screening trials started in five screening centres in Sweden, involving 282 777 women (156 911 invited and 125 866 controls) with the aim to study if invitation to screening reduced the breast cancer mortality. An overview of the trials was performed to reduce the confidence intervals for the relative risk estimates. All 1 296 deaths occurring in women with breast cancer detected after randomization were evaluated by an independent endpoint committee (EPC), consisting of four physicians who reviewed collected medical information that was blinded regarding mammography screening. If there was disagreement between the EPC members at the initial individual evaluation the final classification was made at concensus meetings. In only 6.9% (n = 89) of the cases was there disagreement as to whether breast cancer was or was not the underlying cause of death. It was also found that 'breast cancer as underlying cause of death' and 'breast cancer as underlying or contributory cause of death' according to Statistics Sweden resulted in relative risk estimates very similar to those based on the classification by the EPC. The study thus supports the use of official health statistics in the evaluation of randomized breast screening trials in Sweden.