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- Tranebjærg, Lisbeth, et al.
(författare)
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The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management
- 2018
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 137:2, s. 111-127
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Tidskriftsartikel (refereegranskat)abstract
- Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.
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| 4. |
- Cortes, Dina, et al.
(författare)
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A new model of paired clinical teaching of international and Danish medical students
- 2016
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Ingår i: Danish Medical Journal. - 2245-1919. ; 63:7, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Since 2006, one hospital has offered two clinical courses in obstetrics/gynaecology and paediatrics to international (I) students. However, as I-student enrolment increased, the hospital faced cut-backs. As from 2010, I-team course evaluations therefore dropped to unacceptable levels and more I- than Danish (DK) students failed exams. Therefore, in 2012 we started a three-year internationalisation project (I-project) at two hospitals. The primary intervention was to pair training for I- and DK-students at clinical contact, and to offer an exclusive daily lecturer for I-teams.METHODS: We compared the course evaluations and exam grades of I-teams and DK-teams for two years prior to (107 from I-teams - 211 participants from DK-teams) and during the I-project (245 participants from I-teams - 575 from DK-teams).RESULTS: During the I-project, the I-teams' course evaluations increased to acceptable values and to levels comparable to the evaluation scores of DK-teams. Furthermore, I-students now considered that their communication with the patients was acceptable. Before the I-project, I-students had lower exam grades (median = 10 (range: 0-12)) than DK-students (10 (4-12)) (p = 0.03), but during the I-project, exam grades increased to the levels achieved by DK-students (10 (2-12) - 10 (0-12) (p = 0.22), and no more I- than DK-students failed exams (p = 0.51).CONCLUSIONS: Pairing students for clinical training and allocating an exclusive lecturer for I-teams produced improved courses for internationalisation. Allocating an exclusive lecturer was associated with a cost of about 615 EUR per student per course when the team consisted of ten students.FUNDING: The Capital Region of Denmark and the University of Copenhagen.TRIAL REGISTRATION: not relevant.
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| 6. |
- Hansen, Lea B.S., et al.
(författare)
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A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
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| 7. |
- Lauridsen, Susanne Vahr, et al.
(författare)
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Effect of a Smoking and Alcohol Cessation Intervention Initiated Shortly Before Radical Cystectomy—the STOP-OP Study : A Randomised Clinical Trial
- 2022
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Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 8:6, s. 1650-1658
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence concerning the reduction of postoperative complications due to smoking and alcohol drinking in patients undergoing radical cystectomy is incomplete. Objective: To evaluate the efficacy of a 6-wk smoking and/or alcohol cessation intervention, initiated shortly before surgery and continued until 4 wk after, in reducing complications. Design, setting, and participants: Between 2014 and 2018, we enrolled 104 patients with high-risk bladder cancer who were daily smokers or consuming at least 3 units of alcohol daily in a multicentre randomised clinical trial. Intervention: Patients were randomised to a 6-wk intensive smoking and/or alcohol cessation intervention or treatment as usual. Outcome measurements and statistical analysis: The primary endpoint was the number of patients developing any postoperative complication, or death, within 30 d after surgery. The secondary endpoints were successful quitters, health-related quality of life, length of stay, time back to habitual activity, and mortality. An intention-to-treat analysis was applied to evaluate treatment effect. Results and limitations: There were some differences in baseline demographic and lifestyle characteristics. Postoperatively, 64% in the intervention group versus 70% in the control group (risk ratio [RR] 0.91, confidence interval [CI] 0.68–1.21, p = 0.51) developed complications. Significantly fewer patients developed three or more complications after 30 d (RR 0.39; CI 0.18–0.84, p = 0.01). The rates of successful quitting were 51% in the intervention group and 27% in the control group (RR 2, CI 1.14–3.51, p = 0.01). The external validity of this trial may be limited because 53% of eligible patients refused participation. Conclusions: Despite a significant effect on the quit rate at completion of the intervention, this multimodal prehabilitation did not show a significant difference regarding our primary outcome postoperative complications. Patient summary: A 6-wk smoking and alcohol cessation intervention in relation to bladder cancer surgery did not reduce postoperative complications, but it was effective in supporting people to quit in the short term.
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| 8. |
- Nyblom, Maria, et al.
(författare)
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Crystal Structure of Na+, K+-ATPase in the Na+-Bound State
- 2013
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 342:6154, s. 123-127
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Tidskriftsartikel (refereegranskat)abstract
- The Na+, K+-adenosine triphosphatase (ATPase) maintains the electrochemical gradients of Na+ and K+ across the plasma membrane-a prerequisite for electrical excitability and secondary transport. Hitherto, structural information has been limited to K+-bound or ouabain-blocked forms. We present the crystal structure of a Na+-bound Na+, K+-ATPase as determined at 4.3 angstrom resolution. Compared with the K+-bound form, large conformational changes are observed in the a subunit whereas the beta and gamma subunit structures are maintained. The locations of the three Na+ sites are indicated with the unique site III at the recently suggested IIIb, as further supported by electrophysiological studies on leak currents. Extracellular release of the third Na+ from IIIb through IIIa, followed by exchange of Na+ for K+ at sites I and II, is suggested.
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| 9. |
- Oster, Michael, et al.
(författare)
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Bridging gaps in the agricultural phosphorus cycle from an animal husbandry perspective: The case of pigs and poultry
- 2018
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Ingår i: Sustainability. - Basel, Switzerland : MDPI. - 2071-1050. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Since phosphorus (P) is an essential element for life, its usage and application across agricultural production systems requires great attention. Monogastric species such as pigs and poultry can significantly contribute to global food security but these animals remain highly dependent on the supply of mineral inorganic P in their feeds. Pig and poultry, which represent 70% of the global meat production, are also major P excretors and thus represent important sources of environmental P inputs. Balancing the P cycle within farming systems is crucial to achieve P sustainable and resilient livestock production. Therefore, the interconnection of animal feed, livestock farming, manure, and soil/aquatic ecosystems requires multidisciplinary approaches to improve P management. With regard to a sustainable agricultural P cycle, this study addresses aspects of feeding strategies and animal physiology (e.g., phase feeding, P conditioning, liquid feeding, phytase supplementation, genetics), soil agroecosystems (e.g., P cycling, P losses, P gains), reuse and recycling (e.g., manure, slaughter waste), measures of farmers' economic performance (e.g., bio-economic models), and P governance/policy instruments (e.g., P quota, P tax). To reconcile the economic and ecological sustainability of animal husbandry, the strategic objective of future research will be to provide solutions for a sufficient supply of high-quality animal products from resource-efficient and economically competitive agro-systems which are valued by society and preserve soil and aquatic ecosystems.
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| 10. |
- Paulsen, Peter Aasted, et al.
(författare)
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The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
- 2013
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Ingår i: Molecular membrane biology. - : Informa UK Limited. - 0968-7688 .- 1464-5203. ; 30:2, s. 195-205
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Tidskriftsartikel (refereegranskat)abstract
- The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used pharmaceutically in cardiac treatment for centuries. The inhibitors block the pump by binding on its extracellular side and thereby locking it. To explore the possibilities for designing an alternative way of targeting the pump function, we have examined the structural requirements for binding to a pocket that accommodates the two C-terminal residues, YY, in the crystal structures of the pump. To cover the sample space of two residues, we first performed docking studies with the 400 possible dipeptides. For validation of the in silico predictions, pumps with 13 dipeptide sequences replacing the C-terminal YY were expressed in Xenopus laevis oocytes and examined with electrophysiology. Our data show a significant correlation between the docking scores from two different methods and the experimentally determined sodium affinities, which strengthens the previous hypothesis that sodium binding is coupled to docking of the C-terminus. From the dipeptides that dock the best and better than wild-type YY, it may therefore be possible to develop specific drugs targeting a previously unexplored binding pocket in the sodium pump.
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