Huntington’s disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse ...models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits.
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•Q175 and R6/2 HD models exhibit reduced PDE10A equivalent to manifest HD patients•PDE10 inhibition restored striatal input and indirect pathway output in HD mice•Both cAMP and cGMP elevation were required for rescue•Chronic dosing of HD models from pre-symptomatic ages confers additional benefit
Beaumont et al. demonstrate that acute PDE10 inhibition boosts diminished corticostriatal input and indirect pathway output in symptomatic HD models, despite loss of PDE10. Their data provide rationale for a PDE10i clinical trial to assess symptom improvement in HD patients.
Objective
Immunosuppressive therapy for cardiac sarcoidosis (CS) still largely consists of corticosteroid monotherapy. However, high relapse rates after tapering and insufficient efficacy are ...significant problems. The objective of this study was to investigate the efficacy and safety of non-biological and biological disease-modifying anti-rheumatic drugs (nb/bDMARDs) considering control of myocardial inflammation assessed by
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F-fluorodeoxyglucose positron emission tomography/computed tomography (
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F-FDG PET/CT) of the heart.
Methods
We conducted a retrospective analysis of treatment response to nb/bDMARDs of all CS patients seen in the sarcoidosis center of the University Hospital Zurich between January 2016 and December 2020.
Results
We identified 50 patients with CS. Forty-five patients with at least one follow-up PET/CT scan were followed up for a mean of 20.5 ± 12.8 months. Most of the patients were treated with prednisone and concomitant nb/bDMARDs. At the first follow-up PET/CT scan after approximately 6.7 ± 3 months, only adalimumab showed a significant reduction in cardiac metabolic activity. Furthermore, comparing all serial follow-up PET/CT scans (143), tumor necrosis factor inhibitor (TNFi)-based therapies showed statistically significant better suppression of myocardial
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F-FDG uptake compared to other treatment regimens. On the last follow-up, most adalimumab-treated patients were inactive (n = 15, 48%) or remitting (n = 11, 35%), and only five patients (16%) were progressive. TNFi was safe even in patients with severely reduced left ventricular ejection fraction (LVEF), and a significant improvement in LVEF under TNFi treatment was observed.
Conclusion
TNFi shows better control of myocardial inflammation compared to nbDMARDs and corticosteroid monotherapies in patients with CS. TNFi was efficient and safe even in patients with severely reduced LVEF.
Colonoscopy is the accepted gold standard for screening of neoplastic colorectal lesions, but the substantial miss rate remains a challenge. Computed virtual chromoendoscopy with the Fujinon ...intelligent colour enhancement (FICE) system is a new dyeless imaging technique that might allow higher rates of adenoma detection.
This is a prospective randomised five tertiary care centre trial of colonoscopy in the FICE mode versus standard colonoscopy with targeted indigocarmine chromoscopy (control group) in consecutive patients attending for routine colonoscopy. Histopathology of detected lesions was confirmed by evaluation of endoscopic resection or biopsy specimens.
871 patients were enrolled, and 764 patients (344 female, mean age 64 years) were subjected to final analysis (368 in the FICE group, 396 in the control group). In total, 236 adenomas (mean of 0.64 per case) were detected in the FICE group and 271 adenomas (mean of 0.68 per case) in the control group (p = 0.92). There was no statistically significant difference in the percentage of patients with >or=1 adenoma between the control group (35.4%) and the FICE group (35.6%) (p = 1.0). For the differential diagnosis of adenomas and non-neoplastic polyps, the sensitivity of FICE (92.7%) was comparable with that of indigocarmine (90.4%) (p = 0.44).
At colonoscopy, adenoma detection rates are not improved by virtual chromoendoscopy with the FICE system compared with white light endoscopy with targeted indigocarmine spraying. However, FICE can effectively substitute for chromoscopy concerning the differentiation of neoplastic and non-neoplastic lesions.
La loi sur le prix unique du livre (« Buchpreisbindungsgesetz ») fête cette année ses vingt ans en Allemagne. En raison de l’harmonisation du droit européen, elle avait remplacé une réglementation ...antérieure de prix unique relevant du droit des associations. Dans quel contexte vous êtes-vous intéressé au prix unique du livre ? Économiste spécialiste de l’organisation industrielle et de la politique de la concurrence, je m’intéresse depuis de nombreuses années aux relations verticales entre le...
S-cysteinylated albumin and methionine-oxidized apolipoprotein A-I (apoA-I) have been posed as candidate markers of diseases associated with oxidative stress. Here, a dilute-and-shoot form of ...LC–electrospray ionization–MS requiring half a microliter of blood plasma was employed to simultaneously quantify the relative abundance of these oxidized proteoforms in samples stored at −80 °C, −20 °C, and room temperature and exposed to multiple freeze–thaw cycles and other adverse conditions in order to assess the possibility that protein oxidation may occur as a result of poor sample storage or handling. Samples from a healthy donor and a participant with poorly controlled type 2 diabetes started at the same low level of protein oxidation and behaved similarly; significant increases in albumin oxidation via S-cysteinylation were found to occur within hours at room temperature and days at −20 °C. Methionine oxidation of apoA-I took place on a longer time scale, setting in after albumin oxidation reached a plateau. Freeze–thaw cycles had a minimal effect on protein oxidation. In matched collections, protein oxidation in serum was the same as that in plasma. Albumin and apoA-I oxidation were not affected by sample headspace or the degree to which vials were sealed. ApoA-I, however, was unexpectedly found to oxidize faster in samples with lower surface-area-to-volume ratios. An initial survey of samples from patients with inflammatory conditions normally associated with elevated oxidative stress—including acute myocardial infarction and prostate cancer—demonstrated a lack of detectable apoA-I oxidation. Albumin S-cysteinylation in these samples was consistent with known but relatively brief exposures to temperatures above −30 °C (the freezing point of blood plasma). Given their properties and ease of analysis, these oxidized proteoforms, once fully validated, may represent the first markers of blood plasma specimen integrity based on direct measurement of oxidative molecular damage that can occur under suboptimal storage conditions.
Abstract
Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Promedica Stiftung and the Iten-Kohaut Foundation in collaboration with the USZ Foundation
...Background/Introduction
The invasive British Cardiovascular Intervention Society Jeopardy Score (iBCIS-JS) is a simple angiographic scoring system, enabling quantification of the extent of jeopardized myocardium related to clinically significant coronary artery disease (CAD). Ranging from 0 (no significant CAD) to 12 (CAD jeopardizing the whole LV- myocardium), the score is used for the entire spectrum of CAD including left main coronary artery and coronary artery bypass graft disease. A score of ≥6 identifies patients with anatomically high-risk CAD. Non-invasive CAD assessment with coronary CTA is hampered by modest specificity, leading potentially to increased utilization of downstream diagnostic tests.
Purpose
To validate coronary CTA-based assessment of the BCIS-JS (CT-BCIS-JS) against the iBCIS-JS and to assess its feasibility and reproducibility.
Methods
A total of 137 patients who underwent clinically indicated coronary CTA and subsequent invasive coronary angiography within 90 days were included in the analysis. Eleven patients were excluded due to suboptimal CTA image quality. CT-BCIS-JS and iBCIS-JS were calculated. Correlations were assessed with the Spearman’s rank correlation coefficient and agreement between scores with Bland-Altman (BA) analysis and with weighted kappa statistics. Inter-observer variability was investigated in a subset of 51 randomly selected patients.
Results
Median and interquartile range (IQR) of CT-BCIS-JS was 4 (IQR=8) and of iBCIS-JS 4 (IQR=8) (Figure 1). A CT-BCIS-JS of ≥6 and was observed in 56 (44%) patients and an iBCIS-JS of ≥6 in 54 patients (43%). An excellent correlation between the iBCIS-JS and the CT-BCIS-JS was observed (rho=0.97, p<0.0001; Figure 2A) with high agreement (BA bias 0.1 and limits of agreement −2.0 to 2.2; Figure 2B). Kappa analysis demonstrated excellent aagreement for identification of a iBCIS-JS of ≥6 (Kappa Weighted= 0.94, 95% CI 0.87–0.99). Inter-observer analysis revealed excellent correlation (rho=0.98, p<0.0001) and agreement (BA bias 0.12 and limits of agreement −1.33 to 1.57).
Conclusions
The CT-BCIS-JC represents a feasible and highly reproducible tool for accurate, non-invasive identification of patients with anatomically high-risk CAD. Hence, the CT-BCIS-JC may serve as reliable gatekeeper for invasive testing in the management of patients with CAD.
The 5‐lipoxygenase‐activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the ...pharmacodynamics, pharmacokinetics, and tolerability of 3‐3‐tert‐butylsulfanyl‐1‐4‐(6‐methoxy‐pyridin‐3‐yl)‐benzyl‐5‐(pyridin‐2‐ylmethoxy)‐1H‐indol‐2‐yl‐2,2‐dimethyl‐propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose‐dependent inhibition of blood LTB4 production and dose‐related inhibition of urinary LTE4. After a single oral dose (50–1,000 mg) of AM103, the maximum concentration (Cmax) and area under the curve (AUC) in plasma increased in a dose‐dependent manner. After multiple‐dose administration (50–1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single‐ and multiple‐dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.
Clinical Pharmacology & Therapeutics (2010) 87 4, 437–444. doi:10.1038/clpt.2009.301
We investigate the effect of chemical doping on the electric and magnetic domain pattern in multiferroic hexagonal ErMnO 3 . Hole- and electron doping are achieved through the growth of Er 1-x Ca x ...MnO 3 and Er 1-x Zr x MnO 3 single crystals, which allows for a controlled introduction of divalent and tetravalent ions, respectively. Using conductance measurements, piezoresponse force microscopy and nonlinear optics we study doping-related variations in the electronic transport and image the corrsponding ferroelectric and antiferromagnetic domains. We find that moderate doping levels allow for adjusting the electronic conduction properties of ErMnO 3 without destroying its characteristic domain patterns. Our findings demonstrate the feasibility of chemical doping for nonperturbative property-engineering of intrinsic domain states in this important class of multiferroics.
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