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Stine Mogensen,1 Charlotte Treldal,1 Erik Feldager,2 Sylvia Pulis,1 Jette Jacobsen,3 Ove Andersen,1 Mette Rasmussen,41Clinical Research Centre, Hvidovre University Hospital, Copenhagen, Denmark; 2Department of Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark; 3Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark; 4Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, DenmarkObjective: To evaluate the effect and acceptance of a new lidocaine lozenge compared with a lidocaine viscous oral solution as a pharyngeal anesthetic before upper gastrointestinal endoscopy (UGE), a diagnostic procedure commonly performed worldwide during which many patients experience severe discomfort mostly because of the gag reflex.Participants: The single-blinded, randomized, controlled study involved 110 adult patients undergoing diagnostic UGE at the Department of Gastroenterology, Hvidovre University Hospital, Denmark.Methods: The patients were randomized to receive either 100 mg lidocaine as a lozenge or 5 mL lidocaine viscous oral solution 2%. Intravenous midazolam was administered if needed. The effect of a lidocaine lozenge in reducing patient discomfort, including the gag reflex, during UGE compared with a lidocaine oral solution was assessed.Results: Questionnaires from the patients showed that the gag reflex was acceptable for 64% in the lozenge group compared with 33% in the oral solution group (P = 0.0072). UGE was evaluated as acceptable by 69% in the lozenge group compared with 39% in the oral solution group (P = 0.0092). The taste was evaluated as good by 78% in the lozenge group (P < 0.0001), and 82% found the lozenge to have good texture (P < 0.0001).Conclusion: The lozenge reduced the gag reflex, diminished patients’ discomfort during UGE, and was evaluated as having a good taste and texture. The lozenge improved patients’ acceptance of UGE.Keywords: upper gastrointestinal endoscopy, topical pharyngeal anesthetic, lidocaine lozenge

Background and Purpose Hypoxia causes vasodilatation of coronary arteries, but the underlying mechanisms are poorly understood. We hypothesized that hypoxia reduces intracellular Ca2+ concentration ([ Ca2+]i) by opening of K channels and release of H2S. Experimental Approach Porcine coronary arteries without endothelium were mounted for measurement of isometric tension and [ Ca2+]i, and the expression of voltage-gated K channels KV7 channels (encoded by KCNQ genes) and large-conductance calcium-activated K channels ( KCa1.1) was examined. Voltage clamp assessed the role of KV7 channels in hypoxia. Key Results Gradual reduction of oxygen concentration from 95 to 1% dilated the precontracted coronary arteries and this was associated with reduced [ Ca2+]i in PGF 2α (10 μM)-contracted arteries whereas no fall in [ Ca2+]i was observed in 30 mM K-contracted arteries. Blockers of ATP-sensitive voltage-gated potassium channels and KCa1.1 inhibited hypoxia-induced dilatation in PGF2α-contracted arteries; this inhibition was more marked in the presence of the Kv7 channel blockers, XE991 and linopirdine, while a KV7.1 blocker, failed to change hypoxic vasodilatation. XE991 also inhibited H2S- and adenosine-induced vasodilatation. PCR revealed the expression of KV7.1, KV7.4, KV7.5 and KCa1.1 channels, and KCa1.1, KV7.4 and KV7.5 were also identified by immunoblotting. Voltage clamp studies showed the XE991-sensitive current was more marked in hypoxic conditions. Conclusion The KV7.4 and KV7.5 channels, which we identified in the coronary arteries, appear to have a major role in hypoxia-induced vasodilatation. The voltage clamp results further support the involvement of KV7 channels in this vasodilatation. Activation of these KV7 channels may be induced by H2S and adenosine. [ABSTRACT FROM AUTHOR]

A recent decline in onset of puberty – especially among girls – has been observed, first in the US in the mid-1990s and now also in Europe. The development of breast tissue in girls occurs at a much younger age and the incidence of precocious puberty (PP) is increasing. Genetic factors and increasing prevalence of adiposity may contribute, but environmental factors are also likely to be involved. In particular, the widespread presence of endocrine-disrupting chemicals (EDCs) is suspected to contribute to the trend of earlier pubertal onset. The factors regulating the physiological onset of normal puberty are poorly understood. This hampers investigation of the possible role of environmental influences. There are many types of EDCs. One chemical may have more than one mode of action and the effects may depend on dose and duration of the exposure, as well as the developmental stage of the exposed individual. There may also be a wide range of genetic susceptibility to EDCs. Human exposure scenarios are complex and our knowledge about effects of mixtures of EDCs is limited. Importantly, the consequences of an exposure may not be apparent at the actual time of exposure, but may manifest later in life. Most known EDCs have oestrogenic and/or anti-androgenic actions and only few have androgenic or anti-oestrogenic effects. Thus, it appears plausible that they interfere with normal onset of puberty. The age at menarche has only declined by a few months whereas the age at breast development has declined by 1 year; thus, the time span from initiation of breast development to menarche has increased. This may indicate an oestrogen-like effect without concomitant central activation of the hypothalamic–pituitary axis. The effects may differ between boys and girls, as there are sex differences in age at onset of puberty, hormonal profiles and prevalence of precocius puberty. [ABSTRACT FROM AUTHOR]

Background and Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function., Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility., Key Results: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D 2 -like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, N G -nitro-l-arginine and a D 1 -like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum., Conclusion and Implications: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In major craniosynostosis surgery with moderate to severe blood loss, patients may be exposed to multiple donors. We have previously reported a method for reducing donor exposure using mixed pediatric units including plasma. To further reduce donor exposure, we used plasma-free divided pediatric units. The study aimed to investigate the feasibility of the new strategy for reducing donor exposure. This prospective observational study recruited children younger than 1 year who were scheduled for nonsyndromic craniosynostosis surgery. One adult red blood cell unit was divided into 4 equal units on the day before the operation for use intra- or postoperatively. Number of donor exposures, estimated blood loss, crystalloid, colloid, and blood product volumes, and coagulation parameters were evaluated. Nineteen infants were included. The mean estimated blood loss was 19 (3) mL/kg and the transfusion volume was 17 (7) mL/kg. The median donor exposure per patient was 1 (range, 1-3). During surgery, all infants received at least one DPU. Two infants received transfusions from more than one donor during the intraoperative period. In the first 24 hours postoperatively, 14 infants received transfusion; 10 received only DPUs, whereas 4 received from multiple donors. In all, multiple donor exposure was prevented in 14 of 19 infants. Postoperative Pk-INR was 1.33 (0.16); no plasma or platelets were transfused. The plasma-free DPU transfusion protocol may be useful to reduce donor exposure in open craniosynostosis surgery in infants., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Background: The aim of the current study was to determine if treatment with senicapoc, improves the PaO 2 /FiO 2 ratio in patients with COVID-19 and severe respiratory insufficiency., Methods: Investigator-initiated, randomized, open-label, phase II trial in four intensive care units (ICU) in Denmark. We included patients aged ≥18 years and admitted to an ICU with severe respiratory insufficiency due to COVID-19. The intervention consisted of 50 mg enteral senicapoc administered as soon as possible after randomization and again after 24 h. Patients in the control group received standard care only. The primary outcome was the PaO 2 /FiO 2 ratio at 72 h., Results: Twenty patients were randomized to senicapoc and 26 patients to standard care. Important differences existed in patient characteristics at baseline, including more patients being on non-invasive/invasive ventilation in the control group (54% vs. 35%). The median senicapoc concentration at 72 h was 62.1 ng/ml (IQR 46.7-71.2). The primary outcome, PaO 2 /FiO 2 ratio at 72 h, was significantly lower in the senicapoc group (mean 19.5 kPa, SD 6.6) than in the control group (mean 24.4 kPa, SD 9.2) (mean difference -5.1 kPa [95% CI -10.2, -0.04] p = .05). The 28-day mortality in the senicapoc group was 2/20 (10%) compared with 6/26 (23%) in the control group (OR 0.36 95% CI 0.06-2.07, p = .26)., Conclusions: Treatment with senicapoc resulted in a significantly lower PaO 2 /FiO 2 ratio at 72 h with no differences for other outcomes., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca 3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS., Experimental Approach: K Ca 3.1 channel knockout (Kccn4 -/- ) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca 3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2 /FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF)., Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2 /FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10-70 mg·kg -1 ) prevented the reduction in PaO 2 /FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg -1 ) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg -1 senicapoc also improved the PaO 2 /FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability., Conclusions and Implications: Genetic deficiency of K Ca 3.1 channels and senicapoc improved the PaO 2 /FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca 3.1 channels is a potential treatment in ARDS-like disease., (© 2021 The British Pharmacological Society.)

Background: Activation of endothelial small conductance calcium-activated K+ channels (KCa2.3) and intermediate conductance calcium-activated K+ channels (KCa3.1) leads to vascular relaxation. We found endothelial KCa2.3 down-regulation in the corpus cavernosum diminishes erectile function., Aim: We hypothesized that in type-2 diabetic mice, the function of KCa2.3 and KCa1.1 channels is impaired in erectile tissue., Methods: Erectile function was measured, and corpus cavernosum strips were mounted for functional studies and processed for qPCR and immunoblotting., Outcomes: Effects of type 2 diabetes on erectile function, expression and function of calcium-activated potassium channels., Results: In anesthetized diabetic db/db mice, erectile function was markedly decreased compared to non-diabetic heterozygous db/+ mice, and the impairment was even more pronounced compared to normal C57BL/6 mice. qPCR revealed KCa2.3 and KCa1.1α channel expressions were upregulated in corpus cavernosum from db/db mice. Immunoblotting showed down-regulation of KCa2.3 channels in the corpus cavernosum from db/db mice. Acetylcholine relaxations were impaired while relaxations induced by the nitric oxide, donor SNP were unaltered in corpus cavernosum from db/db compared to C57BL/6 and db/+ mice. Apamin, a blocker of KCa2 channels, inhibited acetylcholine relaxation in corpus cavernosum from all experimental groups. In the presence of apamin, acetylcholine relaxation was markedly decreased in corpus cavernosum from db/db vs C57BL/6 and db/+ mice. An opener of KCa2 and KCa3.1 channels, NS309, potentiated acetylcholine relaxations in corpus cavernosum from db/+ and db/db mice. Iberiotoxin, a blocker of KCa1.1 channels, inhibited acetylcholine relaxation in corpus cavernosum from db/+ mice, while there was no effect in tissue from db/db mice., Clinical Translation: Erectile function in diabetic db/db mice was severely affected compared to heterozygous and control mice, findings suggesting the non-diabetic db/+ and diabetic db/db mice for translational purpose can be used for drug testing on, respectively, moderate and severe erectile dysfunction. The altered expressions and impaired acetylcholine relaxation in the presence of apamin compared to C57BL/6 mice may suggest decreased KCa1.1 channel function may underpin impaired endothelium-dependent relaxation and erectile dysfunction in diabetic db/db mice., Strengths & Limitations: The present study provides a mouse model for type 2 diabetes to test moderate and severe erectile dysfunction drugs. Decreased KCa1.1 channel function contributes to erectile dysfunction, and it is a limitation that it is not supported by electrophysiological measurements., Conclusion: Our results suggest that the contribution of iberiotoxin-sensitive KCa1.1 channels to relaxation is reduced in the corpus cavernosum, while apamin-sensitive KCa2.3 channels appear upregulated. The impaired KCa1.1 channel function may contribute to the impaired erectile function in diabetic db/db mice., Competing Interests: Conflicts of interest: One of the authors is Chief Scientific Officer and owner of shares in a biotech company, outside the submitted work. The other authors declare no conflicts of interest., (© 2022, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Variants in SLC34A2 encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2 variants on transporter expression and phosphate uptake in cellular studies., Methods: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402&#95;1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes. The transport function was investigated with a 32 Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively., Results: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32 Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons., Conclusions: Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM., (© 2022. The Author(s).)

Purpose: The main purpose of this study was to investigate the usefulness of wide band tympanometry (WBT) as a diagnostic tool for Ménière's disease (MD) by comparing differences in absorbance measures between normal hearing ears and patient diagnosed with MD., Methods: We conducted a retrospective case-control study. From a cohort of 116 patients diagnosed with Ménière disease, 52 MD patients and 99 normal hearing adults with no history of otological disease served as subjects. Wideband tympanometry was conducted using at Titan Impedance module and audiometry was performed with a MADSEN Astera 2 . Mean energy absorbance curves with 95% confidence intervals were computed across cases with MD and controls in the frequency range 226-8000 Hz. An overall test for difference between curves of cases and controls was calculated by multivariate analysis of variance., Results: The MD group and the subpopulations of MD patients who fulfilled the International criteria for MD showed a statistically significant lower absorbance at tympanic peak pressure compared to the control group (p < 0.001). No overlap of confidence intervals between mean curves was found within the frequency range of 2000-4000 Hz., Conclusion: Absorbance measures obtained by WBT were able to distinguish between MD ears and normal ears within the frequency range of 2000-4000 Hz. The results indicate that WBT potentially could be a useful and simple non-invasive diagnostic tool for MD. However, more research on the association between absorbance measures and inner ear pathologies is needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Species distribution models (SDMs) are widely used to predict range shifts but could be unreliable under climate change scenarios because they do not account for evolution. The thermal physiology of a species is a key determinant of its range and thus incorporating thermal trait evolution into SDMs might be expected to alter projected ranges. We identified a genetic basis for physiological and behavioural traits that evolve in response to temperature change in natural populations of threespine stickleback (Gasterosteus aculeatus). Using these data, we created geographical range projections using a mechanistic niche area approach under two climate change scenarios. Under both scenarios, trait data were either static ("no evolution" models), allowed to evolve at observed evolutionary rates ("evolution" models) or allowed to evolve at a rate of evolution scaled by the trait variance that is explained by quantitative trait loci (QTL; "scaled evolution" models). We show that incorporating these traits and their evolution substantially altered the projected ranges for a widespread panmictic marine population, with over 7-fold increases in area under climate change projections when traits are allowed to evolve. Evolution-informed SDMs should improve the precision of forecasting range dynamics under climate change, and aid in their application to management and the protection of biodiversity., (© 2022 John Wiley & Sons Ltd.)