Thomas Kuhn's Structure of Scientific Revolutions became the most widely read book about science in the twentieth century. His terms 'paradigm' and 'scientific revolution' entered everyday speech, ...but they remain controversial. In the second half of the twentieth century, the new field of cognitive science combined empirical psychology, computer science, and neuroscience. In this book, the theories of concepts developed by cognitive scientists are used to evaluate and extend Kuhn's most influential ideas. Based on case studies of the Copernican revolution, the discovery of nuclear fission, and an elaboration of Kuhn's famous 'ducks and geese' example of concept learning, this volume, first published in 2006, offers accounts of the nature of normal and revolutionary science, the function of anomalies, and the nature of incommensurability.
Purpose
To obtain high‐resolution Cr and PCr maps of mouse skeletal muscle using a polynomial and Lorentzian line‐shape fitting (PLOF) CEST method.
Methods
Wild‐type mice and guanidinoacetate ...N‐methyltransferase–deficient (GAMT‐/‐) mice that have low Cr and PCr concentrations in muscle were used to assign the Cr and PCr peaks in the Z‐spectrum at 11.7 T. A PLOF method was proposed to simultaneously extract and quantify the Cr and PCr by assuming a polynomial function for the background and 2 Lorentzian functions for the CEST peaks at 1.95 ppm and 2.5 ppm.
Results
The Z‐spectra of phantoms revealed that PCr has 2 CEST peaks (2 ppm and 2.5 ppm), whereas Cr only showed 1 peak at 2 ppm. Comparison of the Z‐spectra of wild‐type and GAMT‐/‐ mice indicated that, contrary to brain, there was no visible protein guanidinium peak in the skeletal‐muscle Z‐spectrum, which allowed us to extract clean PCr and Cr CEST signals. High‐resolution PCr and Cr concentration maps of mouse skeletal muscle were obtained by the PLOF CEST method after calibration with in vivo MRS.
Conclusions
The PLOF method provides an efficient way to map Cr and PCr concentrations simultaneously in the skeletal muscle at high MRI field.
Magnetic resonance spectroscopy (MRS) and the related technique of magnetic resonance spectroscopic imaging (MRSI) are widely used in both clinical and preclinical research for the non-invasive ...evaluation of brain metabolism. They are also used in medical practice, although their ultimate clinical value continues to be a source of discussion. This chapter reviews the general information content of brain spectra and commonly used protocols for both MRS and MRSI and also touches on data analysis methods and quantitation. The main focus is on proton MRS for application in humans, but many of the methods are also applicable to other nuclei and studies of animal models as well.
Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, μ-opioid receptor antagonist, for the treatment of ...opioid-induced constipation.
In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements.
Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol.
Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).
Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the ...interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.
In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks with the first three doses administered every 4 weeks) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed.
Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV
), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.
Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV
. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).
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