Rikke Søgaard

Regulation of Sodium Channel Function by Bilayer Elasticity: The Importance of Hydrophobic Coupling. Effects of Micelle-forming Amphiphiles and Cholesterol

Membrane proteins are regulated by the lipid bilayer composition. Specific lipid–protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel–bilayer hydrophobic interactions link a “conformational” change (the monomer↔dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (β-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less “stiff”, as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer–protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function.

Long-term benefit and cost-effectiveness analysis of screening for abdominal aortic aneurysms from a randomized controlled trial

The aim was to estimate long‐term mortality benefits and cost‐effectiveness of screening for abdominal aortic aneurysm (AAA) in men aged 64–73 years.

GABAA Receptor Function is Regulated by Lipid Bilayer Elasticity

Docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) promote GABA(A) receptor [(3)H]-muscimol binding, and DHA increases the rate of GABA(A) receptor desensitization. Triton X-100, a structurally unrelated amphiphile, similarly promotes [(3)H]-muscimol binding. The mechanism(s) underlying these effects are poorly understood. DHA and Triton X-100, at concentrations that affect GABA(A) receptor function, increase the elasticity of lipid bilayers measured as decreased bilayer stiffness using gramicidin channels as molecular force transducers. We have previously shown that membrane protein function can be regulated by amphiphile-induced changes in bilayer elasticity and hypothesized that GABA(A) receptors could be similarly regulated. We therefore studied the effects of four structurally unrelated amphiphiles that decrease bilayer stiffness (Triton X-100, octyl-beta-glucoside, capsaicin, and DHA) on GABA(A) receptor function in mammalian cells. All the compounds promoted GABA(A) receptor [(3)H]-muscimol binding by increasing the binding capacity of high-affinity binding without affecting the associated equilibrium binding constant. A semiquantitative analysis found a similar quantitative relation between the effects on bilayer stiffness and [(3)H]-muscimol binding. Membrane cholesterol depletion, which also decreases bilayer stiffness, similarly promoted [(3)H]-muscimol binding. In whole-cell voltage-clamp experiments, Triton X-100, octyl-beta-glucoside, capsaicin, and DHA all reduced the peak amplitude of the GABA-induced currents and increased the rate of receptor desensitization. The effects of the amphiphiles did not correlate with the expected changes in monolayer spontaneous curvature. We conclude that GABA(A) receptor function is regulated by lipid bilayer elasticity. PUFAs may generally regulate membrane protein function by affecting the elasticity of the host lipid bilayer.

Cost effectiveness of abdominal aortic aneurysm screening and rescreening in men in a modern context: evaluation of a hypothetical cohort using a decision analytical model

Objective To assess the cost effectiveness of different screening strategies for abdominal aortic aneurysm in men, from the perspective of a national health service. Setting Screening units at regional hospitals. Participants Hypothetical cohort of 65 year old men from the general population. Main outcome measures Costs (£ in 2010) and effect on health outcomes (quality adjusted life years (QALYs)). Results Screening seems to be highly cost effective compared with not screening. The model estimated a 92% probability that some form of screening would be cost effective at a threshold of £20 000 (€24 790;

The Viborg vascular (VIVA) screening trial of 65-74 year old men in the central region of Denmark: study protocol

31 460). If men with an aortic diameter of 25-29 mm at the initial screening were rescreened once after five years, 452 men per 100 000 initially screened would benefit from early detection, whereas lifetime rescreening every five years would detect 794 men per 100 000. We estimated the associated incremental cost effectiveness ratios for rescreening once and lifetime rescreening to be £10 013 and £29 680 per QALY, respectively. The individual probability of being the most cost effective strategy was higher for each rescreening strategy than for the screening once strategy (in view of the £20 000 threshold). Conclusions This study confirms the cost effectiveness of screening versus no screening and lends further support to considerations of rescreening men at least once for abdominal aortic aneurysm.

Designing a stated choice experiment: The value of a qualitative process

BackgroundScreening for abdominal aortic aneurysm (AAA) of men aged 65-74 years reduces the AAA-related mortality and is generally considered cost effective. Despite of this only a few national health care services have implemented permanent programs.Around 10% of men in this group have peripheral arterial disease (PAD) defined by an ankle brachial systolic blood pressure index (ABI) below 0.9 resulting in an increased mortality-rate of 25-30%. In addition well-documented health benefits may be achieved through primary prophylaxis by initiating systematic cholesterol-lowering, smoking cessation, low-dose acetylsalicylic acid (aspirins), exercise, a healthy diet and blood-pressure control altogether reducing the increased risks for cardiovascular disease by at least 20-25%.The benefits of combining screening for AAA and PAD seem evident; yet they remain to be established. The objective of this study is to assess the efficacy and the cost-effectiveness of a combined screening program for AAA, PAD and hypertension.MethodsThe Viborg Vascular (VIVA) screening trial is a randomized, clinically controlled study designed to evaluate the benefits of vascular screening and modern vascular prophylaxis in a population of 50,000 men aged 65-74 years. Enrolment started October 2008 and is expected to stop in October 2010. The primary outcome is all-cause mortality. The secondary outcomes are cardiovascular mortality, AAA-related mortality, hospital services related to cardiovascular conditions, prevalence of AAA, PAD and potentially undiagnosed hypertension, health-related quality of life and cost effectiveness. Data analysis by intention to treat.ResultsMajor follow-up will be performed at 3, 5 and 10 years and final study result after 15 years.Trial registrationClinicalTrials.gov NCT00662480

Interchangeability of the EQ-5D and the SF-6D in long-lasting low back pain.

Abstract Designing a stated or discrete choice experiment (DCE) involves a process of developing, testing and optimizing the experiment questionnaire. This process is important for the success of the experiment and the validity of the results, but it is often not reported thoroughly. In the field of health care, one faces challenges in relation to what makes sense both for the respondent and what has clinical relevance, especially in situations with little evidence and unclear choices, where the decision making process is not clear or informed. This is the case for degenerative spine diseases, where the selection of candidates for surgical rather than non-surgical treatment has been widely discussed and where surgery rates accordingly vary across settings. In the present work, we demonstrated how the qualitative process significantly impacted and guided the design, and it was clear that a less thorough qualitative process would have resulted in a less useable and valid design. To elicit relevant attributes and levels for a DCE, fieldwork in clinical departments in Danish hospitals was performed and has been supplemented by qualitative interviews with patients and doctors. Systematic and thorough qualitative investigation of the decision context relevant attributes and levels and appropriate framing appears valuable in the process of designing a DCE for quantitative pilot testing.

Prognosis of ruptured abdominal aortic aneurysms in Denmark from 1994–2008

OBJECTIVES The objective of this study was to investigate the interchangeability of the EuroQol 5D (EQ-5D) and the Short Form 6D (SF-6D) in individuals with long-lasting low back pain to guide the optimal choice of instrument and to inform decision-makers about any between-measure discrepancy, which require careful interpretation of the results of cost-utility evaluations. METHODS A cross-sectional study was conducted across 275 individuals who had spinal surgery on indication of chronic low back pain. EQ-5D and SF-6D were mailed to respondents for self-completion. Statistical analysis of between-measure agreement (using English weights) was based on Bland and Altmans limits of agreement and a series of linear regressions. RESULTS A moderate mean difference of 0.085 (SD 0.241) was found, but because it masked more severe bidirectional variation, the expected variation between observations of EQ-5D and SF-6D in future studies was estimated at 0.546. The EQ-5Ds N3 term alone explained a factor of 0.79 of the variation in between-measure differences, while the explanatory value of adding variables of age, sex, diagnosis, previous surgery, and occupational status was basically zero. A final model including only dummy variables for the N3 term and five identified framing effects explained a factor of 0.86 of the variation in between-measure differences. CONCLUSIONS Although the EQ-5D and the SF-6D are both psychometrically valid for generic outcome assessment in long-lasting low back pain, it appears that they cannot generally be used interchangeably for measurement of preference values. Sensitivity analysis examining the impact of between-measure discrepancy thus remains a necessary condition for the interpretation of the results of cost-utility evaluations.

A three-year follow-up on the efficacy of psychosocial interventions for patients with mild dementia and their caregivers: the multicentre, rater-blinded, randomised Danish Alzheimer Intervention Study (DAISY)

Introduction Few modern population-based estimates of the prognosis of ruptured abdominal aortic aneurysm (rAAA) exist. Methods and materials From 1994–2008, a total of 6954 rAAA cases were identified in Danish nationwide population-based registries. Results Of 3148 (45%) surgery cases, 1454 (46%) died within 30 days of surgery. The overall mortality risk of rAAA was 76%. The proportion of patients who received surgery increased from 44%, in the first study period, to 47% in the last study period; the 30-day postoperative mortality rate decreased from 51% to 42%; and the overall mortality risk declined significantly from 77% to 74% (odds ratio: 0.86: 95% confidence interval: 0.77–0.97). However, the age-adjusted mortality rate remained unchanged, due to the increased incidence of rAAA.

Population screening and intervention for vascular disease in Danish men (VIVA): a randomised controlled trial

Objectives To examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8–12 months for community-dwelling patients with mild Alzheimers disease and their caregivers. Design Multicentre, randomised, controlled, rater-blinded trial. Setting Primary care and memory clinics in five Danish districts. Participants 330 home-dwelling patients with mild Alzheimers disease and their primary caregivers (dyads). Interventions Dyads were randomised to receive intervention during the first year after diagnosis. Both intervention and control groups had follow-up visits at 3, 6, 12 and 36 months. Main outcome measures Primary outcomes for the patients assessed at 36-month follow-up were changes from baseline in global cognitive function (Mini-Mental State Examination), depressive symptoms (Cornell Depression Scale) and proxy-rated EuroQoL quality of life on visual analogue scale. The primary outcomes for the caregivers were changes from baseline in depressive symptoms (Geriatric Depression Scale) and self-rated EuroQoL quality of life on a visual analogue scale. The secondary outcome measures for the patient were proxy-rated Quality of Life Scale for Alzheimers disease (QoL-AD), Neuropsychiatric Inventory-Questionnaire, Alzheimers disease Cooperative Study Activities of Daily Living Scale, all-cause mortality and nursing home placement. Results At a 36-month follow-up, 2 years after the completion of the Danish Alzheimer Intervention Study (DAISY), the unadjusted positive effects previously detected at the 12-month follow-up in one patient primary outcome (Cornell depression score) and one patient secondary outcome (proxy-rated QoL-AD) disappeared (Cornell depression score, p=0.93; proxy-rated QoL-AD, p=0.81). No long-term effect of DAISY intervention on any other primary and secondary outcomes was found at the 36-month follow-up. Conclusions For patients with very mild Alzheimers disease and their caregivers, an intensive, multi-component, semitailored psychosocial intervention programme with counselling, education and support during the first year after diagnosis did not show any positive long-term effect on primary and secondary outcomes. Trial registration The study was registered in the Clinical Trial Database (http://www.controlled-trials.com/ISRCTN74848736).