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.
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.).
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.
To investigate the feasibility of downfield MR spectroscopic imaging (DF-MRSI) in the human brain at 7T.
A 7T DF-MRSI pulse sequence was implemented based on the previously described methodology at ...3T, with 3D phase-encoding,
spectral-spatial excitation, and frequency selective refocusing. Data were pre-processed followed by analysis using the "LCModel" software package, and metabolite maps created from the LCModel results. Total scan time, including brain MRI and a water-reference MRSI, was 24 min. The sequence was tested in 10 normal volunteers. Estimated metabolite levels and uncertainty values (Cramer Rao lower bounds, CRLBs) for nine downfield peaks were compared between seven different brain regions, anterior cingulate cortex (ACC), centrum semiovale (CSO), corpus callosum (CC), cerebellar vermis (CV), dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC), and thalamus (Thal).
DF peaks were relatively uniformly distributed throughout the brain, with only a small number of peaks showing any significant regional variations. Most DF peaks had average CRLB<25% in most brain regions. Average SNR values were higher for the brain regions ACC and DLPFC (˜7 ± 0.95, mean ± SD) while in a range of 3.4-6.0 for other brain regions. Average linewidth (FWHM) values were greater than 35 Hz in the ACC, CV, and Thal, and 22 Hz in CC, CSO, DLPFC, and PCC.
High-field DF-MRSI is able to spatially map exchangeable protons in the human brain at high resolution and with near whole-brain coverage in acceptable scan times, and in the future may be used to study metabolism of brain tumors or other neuropathological disorders.
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