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Fully three-dimensional (3-D) ion trajectory simulations of a Nier-type ion source were performed for mono-energetic ions with a spatial resolution of the potential array of 0.1 mm. Experimentally determined ion beam profiles were fitted with a superposition of simulated ion beam profiles in an effort to determine the initial ion kinetic energy distribution and the extraction efficiency from the ion source for a given product ion. This method allows the analysis of ion beam profiles of highly energetic fragment ions that are affected by a reduced ion extraction efficiency. As an example, ion beam profiles of product ions formed by electron impact ionization of acetylene (C2H2) at an electron energy of 100 eV were analyzed with the present method as well as with a method developed by Poll et al. [Int. J. Mass Spectrom. Ion Process. 112 (1992) 1], which is based essentially on a simplified two-dimensional (2-D) ion trajectory analysis. For highly energetic fragment ions, the results obtained by the two methods differ by as much as 84%. [Copyright &y& Elsevier]

Abstract Background Up to date, no information exists about the intra-articular temperature changes of the knee related to activity and ambient temperature. Methods In 6 healthy males, a probe for intra-articular measurement was inserted into the notch of the right knee. Each subject was jogging on a treadmill in a closed room at 19°C room temperature and skiing in a ski resort at -3°C outside temperature for 60 minutes. In both conditions, temperatures were measured every fifteen minutes intra-articulary and at the skin surface of the knee. A possible influence on joint function and laxity was evaluated before and after activity. Statistical analysis of intra-articular and skin temperatures was done using nonparametric Wilcoxon's sign rank sum test and Mann-Whitney's-U-Test. Results Median intra-articular temperatures increased from 31.4°C before activity by 2.1°C, 4°C, 5.8°C and 6.1°C after 15, 30, 45 and 60 min of jogging (all p ≤ 0.05). Median intra-articular temperatures dropped from 32.2°C before activity by 0.5°C, 1.9°C, 3.6°C and 1.1°C after 15, 30, 45 and 60 min of skiing (all n.s.). After 60 minutes of skiing (jogging), the median intra-articular temperature was 19.6% (8.7%) higher than the skin surface temperature at the knee. Joint function and laxity appeared not to be different before and after activity within both groups. Conclusion This study demonstrates different changes of intra-articular and skin temperatures during sports in jogging and alpine skiing and suggests that changes are related to activity and ambient temperature.

Background: Up to date, no information exists about the intra-articular temperature changes of the knee related to activity and ambient temperature.Methods: In 6 healthy males, a probe for intra-articular measurement was inserted into the notch of the right knee. Each subject was jogging on a treadmill in a closed room at 19 degrees C room temperature and skiing in a ski resort at -3 degrees C outside temperature for 60 minutes. In both conditions, temperatures were measured every fifteen minutes intra-articulary and at the skin surface of the knee. A possible influence on joint function and laxity was evaluated before and after activity. Statistical analysis of intra-articular and skin temperatures was done using nonparametric Wilcoxon's sign rank sum test and Mann-Whitney's-U-Test.Results: Median intra-articular temperatures increased from 31.4 degrees C before activity by 2.1 degrees C, 4 degrees C, 5.8 degrees C and 6.1 degrees C after 15, 30, 45 and 60 min of jogging (all p < or = 0.05). Median intra-articular temperatures dropped from 32.2 degrees C before activity by 0.5 degrees C, 1.9 degrees C, 3.6 degrees C and 1.1 degrees C after 15, 30, 45 and 60 min of skiing (all n.s.). After 60 minutes of skiing (jogging), the median intra-articular temperature was 19.6% (8.7%) higher than the skin surface temperature at the knee. Joint function and laxity appeared not to be different before and after activity within both groups.Conclusion: This study demonstrates different changes of intra-articular and skin temperatures during sports in jogging and alpine skiing and suggests that changes are related to activity and ambient temperature. [ABSTRACT FROM AUTHOR]

Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC). The NO-GC/cGMP pathway in platelets has been extensively studied. However, its role in regulating the biomechanical properties of platelets has not yet been addressed and remains unknown. We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). Stimulation of human and murine platelets with cGMP-modulating drugs decreased cellular stiffness and downregulated P-selectin, a marker for platelet activation. We also quantified changes in platelet shape using deep learning-based platelet morphometry, finding that platelets become more circular upon treatment with cGMP-modulating drugs. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research.

Background: Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform PDE10A might be a target for analgesic therapy., Methods: In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors., Results: PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD; 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (Two-way ANOVA, group, F(1, 18) = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund's adjuvant (F(1, 14) = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920., Conclusion: Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs., Competing Interests: Conflicts of Interest: The authors declare no competing interests., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Recent clinical trials of drugs enhancing cyclic guanosine monophosphate (cGMP) signaling for cardiovascular diseases have renewed interest in cGMP biology within the kidney. However, the role of cGMP signaling in glomerular endothelial cells (GECs) and podocytes remains largely unexplored. Using acute kidney slices from mice expressing the FRET-based cGMP biosensor cGi500 in endothelial cells or podocytes enabled real-time visualization of cGMP. Stimulation with atrial natriuretic peptide (ANP) or SNAP (NO donor) and various phosphodiesterase (PDE) inhibitors elevated intracellular cGMP in both cell types. GECs showed a transient cGMP response upon particulate or soluble guanylyl cyclase activation, while the cGMP response in podocytes reached a plateau following ANP administration. Co-stimulation (ANP + SNAP) led to an additive response in GECs. The administration of PDE inhibitors revealed a broader basal PDE activity in GECs dominated by PDE2a. In podocytes, basal PDE activity was mainly restricted to PDE3 and PDE5 activity. Our data demonstrate the existence of both guanylyl cyclase pathways in GECs and podocytes with cell-specific differences in cGMP synthesis and degradation, potentially suggesting new therapeutic options for kidney diseases., (© 2024. The Author(s).)

Background: Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function., Methods: Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody., Results: We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients ( P =0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice., Conclusions: Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy., Competing Interests: None.