A homotropic two-state model and auto-antagonism

BACKGROUND: Bell-shaped and terraced dose-response relations have been observed in single ligand application for enzymes, carriers, transporters, G protein-coupled receptors as well as for other receptive units. It seems that there is still a need for new models as analytical tools for such dose-responses, especially in the light of expanding di- and multi-merization of the receptive units for functionality. RESULTS: Self-inhibition by drugs is analyzed in the frame-work of a theoretical homotropic two-state model, HOTSM. The model is a cubic reaction scheme based on a combination of conformational isomerization between two states within a receptive unit and ternary-complexing of two identical agonist molecules with the receptor. Concepts and terms related to self-inhibition are presented. HOTSM has seven independent parameters. Making a few simplifying assumptions narrows its analysis to initially look at four parameters. Some conclusions to be drawn are that a first level of spontaneous activity is solely determined by an isomerization constant, L. As ligand concentration rises, all seven parameters influence a second level of activity. At high ligand concentrations, a third level of activity is determined by only four of the seven constants, viz. the L constant and three intrinsic efficacy related constants, a, b, and d. The third level is given by 1/[1 + 1/(L·a·b·d)]. The third level may be above, at, or below the first and second levels. When the third level is above the first level, dose-responses may be bell-shaped, terraced, or reversed bell-shaped while when it is below the first level, dose-responses can attain forms of bell-shapes, reverse terraces, or reverse bell-shapes. To exemplify its use, the HOTSM is fitted to experimental dose-responses from sources in the literature. Development of the HOTSM is reviewed. CONCLUSIONS: The homotropic two-state model, HOTSM, is a novel model for analyses of dose-responses at equilibrium that are co-operative or show bell-shapes of auto-antagonism

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

BACKGROUND: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. METHODS: Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. RESULTS: In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. CONCLUSION: In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2980-z) contains supplementary material, which is available to authorized users

Colonic epithelial ion transport is not affected in patients with diverticulosis

<p>Abstract</p> <p>Background</p> <p>Colonic diverticular disease is a bothersome condition with an unresolved pathogenesis. It is unknown whether a neuroepithelial dysfunction is present. The aim of the study was two-fold; (1) to investigate colonic epithelial ion transport in patients with diverticulosis and (2) to adapt a miniaturized Modified Ussing Air-Suction (MUAS) chamber for colonic endoscopic biopsies.</p> <p>Methods</p> <p>Biopsies were obtained from the sigmoid part of the colon. 86 patients were included. All patients were referred for colonoscopy on suspicion of neoplasia and they were without pathological findings at colonoscopy (controls) except for diverticulosis in 22 (D-patients). Biopsies were mounted in MUAS chambers with an exposed area of 5 mm². Electrical responses to various stimulators and inhibitors of ion transport were investigated together with histological examination. The MUAS chamber was easy to use and reproducible data were obtained.</p> <p>Results</p> <p>Median basal short circuit current (SCC) was 43.8 μA·cm^-2(0.8 – 199) for controls and 59.3 μA·cm^-2(3.0 – 177.2) for D-patients. Slope conductance was 77.0 mS·cm^-2(18.6 – 204.0) equal to 13 Ω·cm²for controls and 96.6 mS·cm^-2(8.4 – 191.4) equal to 10.3 Ω·cm²for D-patients. Stimulation with serotonin, theophylline, forskolin and carbachol induced increases in SCC in a range of 4.9 – 18.6 μA·cm^-2, while inhibition with indomethacin, bumetanide, ouabain and amiloride decreased SCC in a range of 6.5 – 27.4 μA·cm^-2, and all with no significant differences between controls and D-patients. Histological examinations showed intact epithelium and lamina propria before and after mounting for both types of patients.</p> <p>Conclusion</p> <p>We conclude that epithelial ion transport is not significantly altered in patients with diverticulosis and that the MUAS chamber can be adapted for studies of human colonic endoscopic biopsies.</p

Increase in invasive group A streptococcal infections and emergence of novel, rapidly expanding sub-lineage of the virulent Streptococcus pyogenes M1 clone, Denmark, 2023

Funding Information: We would like to thank Karina Kaae, Lanni Fugl Niebuhr Nielsen and Joan Nevermann Jensen for their laboratory expertise, and acknowledge the great effort by clinicians and laboratory technicians at hospitals across Denmark and at Landspítali, Reykjavik, in securing samples and data essential for WGS-based surveillance efforts, as well as the dedicated technical staff maintaining and developing the registries and epidemiological databases at the core of national surveillance in Denmark. Publisher Copyright: © 2023 European Centre for Disease Prevention and Control (ECDC). All rights reserved.A highly virulent sub-lineage of the Streptococcus pyogenes M1 clone has been rapidly expanding throughout Denmark since late 2022 and now accounts for 30% of the new invasive group A streptococcal infections. We aimed to investigate whether a shift in variant composition can account for the high incidence rates observed over winter 2022/23, or if these are better explained by the impact of COVID-19-related restrictions on population immunity and carriage of group A Streptococcus. An increase in incidence rates of invasive (iGAS) and non-invasive (nGAS) group A Streptococcus infection has been reported by several countries across Europe during the 2022/23 winter season [1-3]. Through analysis of all whole genome sequencing (WGS) data acquired for national surveillance of iGAS in Denmark since 2018, we aimed to investigate current genomic developments and the impact of emerging lineages on iGAS incidence rates in 2023. In Denmark, iGAS is not notifiable except in case of meningitis, however, test results from all 10 Departments of Clinical Microbiology (DCMs) are submitted to the Danish Microbiology Database (MiBa) [4] and can be used to monitor incidence rates. Iceland also experienced a higher iGAS incidence in early 2023, and we also present Icelandic WGS data on iGAS isolates from 2022 and 2023.Peer reviewe

ARIA 2016 : Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.Peer reviewe