Insulin-like growth factor 1 (IGF1) is an important biomarker for the management of growth hormone disorders. Recently there has been rising interest in deploying mass spectrometric (MS) methods of ...detection for measuring IGF1. However, widespread clinical adoption of any MS-based IGF1 assay will require increased throughput and speed to justify the costs of analyses, and robust industrial platforms that are reproducible across laboratories. Presented here is an MS-based quantitative IGF1 assay with performance rating of >1,000 samples/day, and a capability of quantifying IGF1 point mutations and posttranslational modifications. The throughput of the IGF1 mass spectrometric immunoassay (MSIA) benefited from a simplified sample preparation step, IGF1 immunocapture in a tip format, and high-throughput MALDI-TOF MS analysis. The Limit of Detection and Limit of Quantification of the resulting assay were 1.5 μg/L and 5 μg/L, respectively, with intra- and inter-assay precision CVs of less than 10%, and good linearity and recovery characteristics. The IGF1 MSIA was benchmarked against commercially available IGF1 ELISA via Bland-Altman method comparison test, resulting in a slight positive bias of 16%. The IGF1 MSIA was employed in an optimized parallel workflow utilizing two pipetting robots and MALDI-TOF-MS instruments synced into one-hour phases of sample preparation, extraction and MSIA pipette tip elution, MS data collection, and data processing. Using this workflow, high-throughput IGF1 quantification of 1,054 human samples was achieved in approximately 9 hours. This rate of assaying is a significant improvement over existing MS-based IGF1 assays, and is on par with that of the enzyme-based immunoassays. Furthermore, a mutation was detected in ∼1% of the samples (SNP: rs17884626, creating an A→T substitution at position 67 of the IGF1), demonstrating the capability of IGF1 MSIA to detect point mutations and posttranslational modifications.
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...
Acceptor and donor doping is a standard for tailoring semiconductors. More recently, doping was adapted to optimize the behavior at ferroelectric domain walls. In contrast to more than a century of ...research on semiconductors, the impact of chemical substitutions on the local electronic response at domain walls is largely unexplored. Here, the hexagonal manganite ErMnO3 is donor doped with Ti4+. Density functional theory calculations show that Ti4+ goes to the B site, replacing Mn3+. Scanning probe microscopy measurements confirm the robustness of the ferroelectric domain template. The electronic transport at both macroscopic and nanoscopic length scales is characterized. The measurements demonstrate the intrinsic nature of emergent domain wall currents and point towards Poole-Frenkel conductance as the dominant transport mechanism. Aside from the new insight into the electronic properties of hexagonal manganites, B-site doping adds an additional degree of freedom for tuning the domain wall functionality.
We report on the structure, magnetization, magnetic anisotropy, and domain morphology of ultrathin yttrium iron garnet (YIG)/Pt films with thickness ranging from 3 to 90 nm. We find that the ...saturation magnetization is close to the bulk value in the thickest films and decreases at low thickness with a strong reduction below 10 nm. We characterize the magnetic anisotropy by measuring the transverse spin Hall magnetoresistance as a function of applied field. Our results reveal strong easy-plane anisotropy fields of the order of 50-100 mT, which add to the demagnetizing field, as well as weaker in-plane uniaxial anisotropy ranging from 10 to 100 mu T. The in-plane easy-axis direction changes with thickness but presents also significant fluctuations among samples with the same thickness grown on the same substrate. X-ray photoelectron emission microscopy reveals the formation of zigzag magnetic domains in YIG films thicker than 10 nm, which have dimensions larger than several 100 mu m and are separated by achiral Neel-type domain walls. Smaller domains characterized by interspersed elongated features are found in YIG films thinner than 10 nm.
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.
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