Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (≥3024 families with ≥10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21–p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3–q24 in all families for SPT and three other regions in European families (2q32–q34 for EOS, 5q23–q33 for SPTQ and 17q12–q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11–3q21, whereas between-study heterogeneity was detected for asthma in 2p22–p13 and 6p21, and for atopic asthma in 1q23–q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.     

Biologically inspired approaches to drug delivery for nerve regeneration

As the biological processes governing nerve regeneration have become elucidated over the past decades, interest has developed in manipulating these processes to improve nerve regeneration. Drug delivery to the regenerating nerve has the potential for major clinical applications in neurodegenerative diseases, spinal cord injury and peripheral nerve injury or sacrifice. This article reviews the evolution of the field of drug delivery to the regenerating nerve, from simple local applications of neurotrophic agents in solution and osmotic pump delivery, to the existing approaches involving novel biomaterials and genetically manipulated cell populations. A discussion of the various known nerve growth-promoting agents, and the chemical considerations involved in their delivery, is included. A perspective on the role of tissue engineering approaches for nerve regeneration in the future is offered.     

Application of time-resolved fluorescence for direct and continuous probing of release from polymeric delivery vehicles

Though accurately evaluating the kinetics of release is critical for validating newly designed therapeutic carriers for in vivo applications, few methods yet exist for release measurement in real time and without the need for any sample preparation. Many of the current approaches (e.g. chromatographic methods, absorption spectroscopy, or NMR spectroscopy) rely on isolation of the released material from the loaded vehicles, which require additional sample purification and can lead to loss of accuracy when probing fast kinetics of release. In this study we describe the use of time-resolved fluorescence for in situ monitoring of small molecule release kinetics from biodegradable polymeric drug delivery systems. This method relies on the observation that fluorescent reporters being released from polymeric drug delivery systems possess distinct excited-state lifetime components, reflecting their different environments in the particle suspensions, i.e., confined in the polymer matrices or free in the aqueous environment. These distinct lifetimes enable real-time quantitative mapping of the relative concentrations of dye in each population to obtain precise and accurate temporal information on the release profile of particular carrier/payload combinations. We found that fluorescence lifetime better distinguishes subtle differences in release profiles (e.g. differences associated with dye loading) than conventional steady-state fluorescence measurements, which represent the averaged dye behavior over the entire scan. Given the method's applicability to both hydrophobic and hydrophilic cargo, it could be employed to model the release of any drug-carrier combination.     

Effects of interleukin-12 and interleukin-15 on measles-specific T-cell responses in vaccinated infants

Understanding the infant host response to measles vaccination is important because of their increased mortality from measles and the need to provide effective protection during the first year of life. Measles-specific T and B-cell responses are lower in infants after measles vaccination than in adults. To define potential mechanisms, we investigated age-related differences in measles-specific T-cell proliferation, CD40-L expression, and IFN-gamma production after measles immunization, and the effects of rhIL-12 and rhIL-15 on these responses. Measles-specific T-cell proliferation and mean IFN-gamma release from infant PBMCs were significantly lower when compared with responses of vaccinated children and adults. Infant responses increased to ranges observed in children and adults when both rhIL-12 and rhIL-15 were added to PBMC cultures. Furthermore, a significant rise in T-cell proliferation and IFN-gamma release was observed when infant PBMCs were stimulated with measles antigen in the presence of rhIL-12 and rhIL-15 compared to measles antigen alone. CD40-L expression by infant and adult T cells stimulated with measles antigen was comparable, but fewer infant CD40-L(+) T cells expressed IFN-gamma. These observations suggest that lower measles-specific T-cell immune responses elicited by measles vaccine in infants may be due to diminished levels of key cytokines.     

Sequential and simultaneous dual-isotope brain SPECT: comparison with PET for estimation and discrimination tasks in early Parkinson disease

Parkinson disease (PD) is the second most frequently occurring cerebral degenerative disease, after Alzheimer disease. Treatments are available, but their efficacy is diminished unless they are administered in the early stages. Therefore, early identification of PD is crucial. In addition to providing perfectly registered studies, simultaneous 99mTc/123I imaging makes possible the assessment of pre- and postsynaptic neurotransmission functions under identical physiological conditions, while doubling the number of counts for the same total imaging time. These advantages are limited, however, by cross talk between the two radionuclides due to the close emission energies of 99mTc (140 keV) and 123I (159 keV). PET, on the other hand, provides good temporal and spatial resolution and sensitivity but usually requires the use of a single radionuclide. In the present work, the authors compared brain PET with sequential and simultaneous dual-isotope SPECT for the task of estimating striatal activity concentration and striatal size for a normal brain and two stages of early PD. Realistic Monte Carlo simulations of a time-of-flight PET scanner and gamma cameras were performed while modeling all interactions in the brain, collimator (gamma camera) and crystal (detector block in PET), as well as population biological variability of pre- and postsynaptic uptake. For SPECT imaging, we considered two values of system energy resolution and scanners with two and three camera heads. The authors used the Cramer-Rao bound, as a surrogate for the best theoretical performance, to optimize the SPECT acquisition energy windows and objectively compare PET and SPECT. The authors determined the discrimination performance between 500 simulated subjects in every disease stage as measured by the area under the ROC curve (AUC). The discrimination accuracy between a normal subject and a subject in the prodromal disease stage was AUC = 0.924 with PET, compared to 0.863 and 0.831 with simultaneous and sequential SPECT, respectively. The significant improvement in performance obtained with simultaneous dual-isotope SPECT compared to sequential imaging (p = 0.019) was due primarily to the increased number of counts detected and resulted in comparable performance when performing simultaneous SPECT on a two-head camera with 9.2% energy resolution to that obtained with sequential SPECT on a three-head camera with 6.2% energy resolution.     

Understanding situation awareness in nursing work: a hybrid concept analysis

Eighty percent of medical error are attributed to human factors. Human factors experts suggest the least explored factor in patient errors is attention, specifically, situation awareness. The purpose of this article was to analyze the concept of situation awareness using a hybrid concept analysis. The experience of situation awareness among nurses was elicited during the fieldwork phase through semistructured interviews. Content and relational analyses yielded 9 themes: perception, comprehension, projection, knowledge and expertise, cognitive overload, interruption management, task management, instantaneous learning, and cognitive stacking. A conceptual definition of situation awareness emerged along with recommendations for application in nursing.