| 1. |
- Liin, Sara, et al.
(författare)
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Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors
- 2018
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Ingår i: The Journal of General Physiology. - : ROCKEFELLER UNIV PRESS. - 0022-1295 .- 1540-7748. ; 150:8, s. 1215-1230
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Tidskriftsartikel (refereegranskat)abstract
- Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.
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| 2. |
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| 3. |
- Bandak, Ghassan, et al.
(författare)
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Hyperkalemia After Initiating Renin-Angiotensin System Blockade : The Stockholm Creatinine Measurements (SCREAM) Project
- 2017
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Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980 .- 2047-9980. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score.Methods and Results: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new beta-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new beta-blocker and ACEI/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m(2) were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration.Conclusions: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m(2), but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.
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| 4. |
- Bergenfeldt, Henrik, et al.
(författare)
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Time-dependent prognostic effects of recipient and donor age in adult heart transplantation
- 2019
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Ingår i: Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 38:2, s. 174-183
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recipient age and donor age are well-known prognostic factors in adult heart transplantation. However, the association between donor age and recipient age and their interaction and short- and long-term mortality is unknown. METHODS: We studied 64,354 heart transplants to adult recipients between 1988 and 2013 in the ISHLT Registry. Donor age and recipient age were analyzed as continuous and categorical variables and restricted cubic spline functions to assess non-linear associations and interactions. The end-point was all-cause mortality. RESULTS: In the multivariable analysis, the odds ratio for 30-day mortality per 10-year increase in recipient age was 1.05 (95% confidence interval [CI] 1.01 to 1.08, p = 0.009) compared with 1.19 (95% CI 1.15 to 1.22, p < 0.001) for donor age. In the first year, the hazard ratio for mortality was 1.05 (95% CI 1.02 to 1.07, p < 0.001) for a 10-year increase in recipient age and 1.16 (1.14 to 1.18, p < 0.001) for donor age. In Years 1 to 3, 3 to 5, and 5 to 10 post-transplant, the hazard ratio was 0.89 (95% CI 0.86 to 0.92, p < 0.001), 0.98 (95% CI 0.94 to 1.02, p = 0.266), and 1.14 (95% CI 1.11 to 1.17, p < 0.001) for recipient age, and 1.12 (95% CI 1.08 to 1.14, p < 0.001), 1.07 (95% CI 1.03 to 1.10, p < 0.001), and 1.07 (95% CI 1.05 to 1.10, p < 0.001) for donor age, respectively. There was no interaction of recipient age and donor age with survival at any follow-up time-point. CONCLUSIONS: At 30 days, both higher donor age and recipient age were associated with higher mortality. At 1 to 10 years, older donor age was associated with higher mortality at all follow-up time-points, but the hazard was greater in the short term, and recipient age was associated only with longer term mortality. The risk from donor age appears equal across recipient age groups.
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| 5. |
- Braun, Oscar Ö., et al.
(författare)
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Continuous-flow LVADs in the Nordic countries : complications and mortality and its predictors
- 2019
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 53:1, s. 14-20
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this study was to assess complications and mortality and its predictors, with continuous-flow left ventricular assist devices (CF-LVADs) in the Nordic Countries.Design: This was a retrospective, international, multicenter cohort study.Results: Between 1993 and 2013, 442 surgically implanted long-term mechanical assist devices were used among 8 centers in the Nordic countries. Of those, 238 were CF-LVADs (HVAD or HeartMate II) implanted in patients >18 years with complete data. Postoperative complications and survival were compared and Cox proportion hazard regression analysis was used to identify predictors of mortality. The overall Kaplan-Meier survival rate was 75% at 1 year, 69% at 2 years and 63% at 3 years. A planned strategy of destination therapy had poorer survival compared to a strategy of bridge to transplantation or decision (2-year survival of 41% vs. 76%, p < .001). The most common complications were non-driveline infections (excluding sepsis) (44%), driveline infection (27%), need for continuous renal replacement therapy (25%) and right heart failure (24%). In a multivariate model age and left ventricular diastolic dimension was left as independent risk factors for mortality with a hazard ratio of 1.35 (95% confidence interval (CI) [1.01-1.80], p = .046) per 10 years and 0.88 (95% CI [0.72-0.99], p = .044) per 5 mm, respectively.Conclusion: Outcome with CF LVAD in the Nordic countries was comparable to other cohorts. Higher age and destination therapy require particularly stringent selection.
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| 6. |
- Caldenby, Claes, 1946, et al.
(författare)
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Architecture and Engineering - 10 Years Anniversary Book
- 2016
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A Jubilee Book will tell our story, a common share of moments and activities, thoughts and reflections, from 10 years of Architecture and Engineering, in short AT. A creative mixture of strong professional cultures, a desire and an enthusiasm for searching out and taking on the challanges of the future in architecture and engineering of the built environment.
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| 7. |
- Cermakova, Pavla, et al.
(författare)
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Cardiovascular Diseases in similar to 30,000 Patients in the Swedish Dementia Registry
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:4, s. 949-958
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer's disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16-2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74-5.41 and HR = 3.44; 95% CI = 1.31-9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08-4.14 and HR= 3.15; 95% CI = 1.60-6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders.
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| 8. |
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| 9. |
- Di Angelantonio, Emanuele, et al.
(författare)
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Association of Cardiometabolic Multimorbidity With Mortality : The Emerging Risk Factors Collaboration
- 2015
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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