Assessing asthma in adult clinical trials of inhaled B2-agonists: a search for a standard primary outcome measure

PhDSince the late 1960s the safety of inhaled B2-agonists has been questioned and the longtenn regular use of these drugs has been linked to increasing morbidity and mortality. National and international guidelines recommend that short acting inhaled B2-agonists should only be used on an "as needed" basis and yet the evidence for these recommendations is still unclear, one reason being the lack of common definition for an outcome. The Regular Use of Salbutamol Trial (TRUST) was designed to assess the risks and benefits of regular versus as needed salbutamol in mild to moderate asthma. In order to establish whether a common primary outcome measure could improve the comparability and interpretation of different trials, a systematic rcyiew of randomised controlled trials of long and short acting inhaled B2-agonists in asthmatic subjects was undertaken to identify well designed trials in this field and primary outcome measures used. The systematic review identified five different primary outcome measures from 26 trials of long and short acting inhaled B2-agonists. The TRUST definition of exacerbation was compared with the five primary outcome measures identified using the TRUST diary card data. In addition, the diary card variables (changes in PEF, symptom scores and medication use) were examined to determine the extent to which they predicted exacerbations according to the different definitions. The use of additional corticosteroids and an increase in daytime symptoms of two or more above baseline were the strongest predictors of all four definitions of exacerbation. A fall in morning PEF of 100 lImin was strongly associated with all definitions of exacerbation but was not a sensitive measure. In conclusion, exacerbations of asthma could be identified by use of additional corticosteroids and an increase in two or more of daytime symptoms. The specificity could be improved by including morning PEF but this may reduce patient compliance with study protocol in asthma trials

What Was Really Accomplished Today? Mathematics Content Specialists Observe a Class for Prospective K-8 Teachers

One of the important activities mathematics teacher educators engage in is the development of teachers at both the in-service and pre-service levels. Also of importance is the professional development of these professional developers. In the summer of 2004, a summer institute was held that allowed mathematics teacher educators watch the teaching of a mathematics content course for prospective K-8 teachers. This paper examines the manner in which a specific group of mathematics content specialists experienced this professional development

Neutral genetic variation in adult Chinook salmon (Oncorhynchus tshawytscha) affects brain-to-body trade-off and brain laterality

Low levels of heterozygosity can have detrimental effects on life history and growth characteristics of organisms but more subtle effects such as those on trade-offs of expensive tissues and morphological laterality, especially of the brain, have not been explicitly tested. The objective of the current study was to investigate how estimated differences in heterozygosity may potentially affect brain-to-body trade-offs and to explore how these heterozygosity differences may affect differential brain growth, focusing on directional asymmetry in adult Chinook salmon (Oncorhynchus tshawytscha) using the laterality and absolute laterality indices. Level of inbreeding was estimated as mean microsatellite heterozygosity resulting in four ‘inbreeding level groups’ (Very High, High, Medium, Low). A higher inbreeding level corresponded with a decreased brain-to-body ratio, thus a decrease in investment in brain tissue, and also showed a decrease in the laterality index for the cerebellum, where the left hemisphere was larger than the right across all groups. These results begin to show the role that differences in heterozygosity may play in differential tissue investment and in morphological laterality, and may be useful in two ways. Firstly, the results may be valuable for restocking programmes that wish to emphasize brain or body growth when crossing adults to generate individuals for release, as we show that genetic variation does affect these trade-offs. Secondly, this study is one of the first examinations to test the hypothesized relationship between genetic variation and laterality, finding that in Chinook salmon there is potential for an effect of inbreeding on lateralized morphology, but not in the expected direction

Redefining the Social Geography of Community STI Risk: An Ecological Study of the Association, Mediators, and Moderators of Area-Level Prostitution Arrests

Background: Core groups such as sex workers have been implicated in contributing to higher area STI risk but no studies have analyzed mediators and moderators of this relationship using population data. Objectives: Assess the overall association of area-level prostitution and STI risk, and mediators and moderators of the relationship. Methods: Point-level prostitution and drug arrests were geocoded and aggregated by Census blockgroup. Chlamydia (CT), gonorrhea (GC), syphilis and incident HIV positive test results were aggregated by blockgroup after eliminating same-organism positive tests within 14 days of an initial positive test. Census data also defined moderators: blockgroups with >75% black and >20% Latino (top decile) and >60% below 200% of the federal poverty line (top quartile). Negative binomial and zero-inflated negative binomial regressions were used to estimate incident rate ratios (IRR) of each STI. Results: There was a dose-response relationship between prostitution arrest blockgroup quintiles and IRR of each STI. In models including drug arrest data, this association was completely eliminated. Though % black blockgroup composition had significant interaction with prostitution arrest rates and with respect to its relationship with STI IRR, % Latino did not consistently have this association. Blockgroups with proportions of low minority and low poverty had highest drug arrest IRR for each STI. In these areas, prostitution arrest IRR were only significant for CT and GC and were consistently lower than drug arrest IRRs. Conclusions: Though prostitution arrests are associated with STI risk, this relationship is mediated by drug arrests. Associations of both arrest rates are strongest in low minority, low poverty communities, indicating that high baseline STI prevalence is not moderated by levels of drug and prostitution arrests. Implications for Programs, Policy, and Research: These data suggest that important relationships exist for prostitution and, to a greater degree, drug arrests within communities traditionally defined as ‘low-risk’

Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABA_A Receptor

γ-Aminobutyric acid type A (GABA_A) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain a challenge. Selective targeting of GABA_A receptors could mitigate this problem. Here, we describe the synthesis and functional evaluation of a novel series of pyrroloin-dolines that display significant modulation of the GABA_A receptor, acting as PAMs. We found that halogen incorporation at the C5 position greatly increased the PAM potency relative to the parent ligand, while substitutions at other positions generally decreased potency. Mutagenesis studies suggest that the binding site lies at the top of the transmembrane domain

Synthesis and Biological Evaluation of Pyrroloindolines as Positive Allosteric Modulators of the α1β2γ2 GABA_A Receptor

γ-Aminobutyric acid type A (GABA_A) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain a challenge. Selective targeting of GABA_A receptors could mitigate this problem. Here, we describe the synthesis and functional evaluation of a novel series of pyrroloin-dolines that display significant modulation of the GABA_A receptor, acting as PAMs. We found that halogen incorporation at the C5 position greatly increased the PAM potency relative to the parent ligand, while substitutions at other positions generally decreased potency. Mutagenesis studies suggest that the binding site lies at the top of the transmembrane domain

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker

Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Hubble Space Telescope Images of Stephan's Quintet: Star Cluster Formation in a Compact Group Environment

Analysis of Hubble Space Telescope/Wide Field Planetary Camera 2 images of Stephan's Quintet, Hickson Compact Group 92, yielded 115 candidate star clusters (with V-I < 1.5). Unlike in merger remants, the cluster candidates in Stephan's Quintet are not clustered in the inner regions of the galaxies; they are spread over the debris and surrounding area. Specifically, these sources are located in the long sweeping tail and spiral arms of NGC 7319, in the tidal debris of NGC 7318B/A, and in the intragroup starburst region north of these galaxies. Analysis of the colors of the clusters indicates several distinct epochs of star formation that appear to trace the complex history of dynamical interactions in this compact group.Comment: 24 pages, 21 figures (13 PostScript and 8 JPEG), LaTeX (uses aastexug.sty), accepted for publication in the Astronomical Journal (July 2001). Full-resolution PostScript figures available at http://www.astro.psu.edu/users/gallsc/sq/figs.tar.g