| 1. |
- Hukkanen, J., et al.
(författare)
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The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Blackwell Publishing. - 0306-5251 .- 1365-2125. ; 80:3, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls.Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change.Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity.Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including theconditions with altered cholesterol concentrations.
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| 4. |
- Bastani, H, et al.
(författare)
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Cryothermal vs. radiofrequency ablation as atrial flutter therapy: a randomized comparison
- 2013
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Ingår i: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. - : Oxford University Press (OUP). - 1532-2092. ; 15:3, s. 420-428
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Jemtren, A, et al.
(författare)
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Risk assessment in patients with symptomatic and asymptomatic pre-excitation
- 2024
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Ingår i: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. - 1532-2092. ; 26:2
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| 12. |
- Matoshvili, Z, et al.
(författare)
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Safety of fluoroscopy-guided transseptal approach for ablation of left-sided arrhythmias
- 2017
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Ingår i: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. - : Oxford University Press (OUP). - 1532-2092. ; 19:12, s. 2023-2026
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Tidskriftsartikel (refereegranskat)
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| 13. |
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| 14. |
- Rubulis, Aigars, 1974, et al.
(författare)
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Ischemia induces aggravation of baseline repolarization abnormalities in left ventricular hypertrophy: a deleterious interaction
- 2006
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Ingår i: J Appl Physiol. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 101:1, s. 102-10
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies show that left ventricular hypertrophy (LVH) and hypertension (HT) in coronary artery disease increases the risk for cardiovascular events including sudden cardiac death (SCD). According to experimental studies, myocardial hypertrophy is associated both with altered electrophysiological properties (including prolonged repolarization) and increased vulnerability to ischemia. However, human data to support a repolarization-related mechanism for the increased SCD risk has not been provided. We therefore studied 187 patients undergoing three-dimensional vectorcardiographic monitoring during coronary angioplasty. Eight parameters reflecting different aspects of ventricular repolarization were used: 1) the ST segment (ST-VM and STC-VM), 2) the T vector (QRS-T angle, Televation, and Tazimuth), and 3) the T vector loop (Tavplan, Teigenv, and Tarea). Data collection was performed at rest and at the time of maximum ischemia during coronary occlusion. The patients were divided into three groups: 33 patients with ECG signs of LVH (18 with HT), 54 with HT but without LVH signs, and 100 patients with neither. Coronary artery disease patients with LVH not only had the most abnormal baseline repolarization (as expected) but also a significantly more pronounced repolarization response during coronary occlusion, whereas HT patients had mean parameter values between LVH patients and those without neither HT nor LVH signs. Because there is a relation between increased SCD risk and repolarization disturbances in various clinical settings, the results of the present study are in agreement with animal data and epidemiological observations, although other factors than disturbed repolarization might be of importance.
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| 15. |
- Rubulis, Aigars, 1974, et al.
(författare)
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T vector and loop characteristics in coronary artery disease and during acute ischemia
- 2004
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Ingår i: Heart Rhythm. - 1547-5271. ; 1:3, s. 317-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Three-dimensional characterization of the ventricular repolarization by the T vector and T vector loop morphology in coronary artery disease (CAD), and their response to short-term (no flow) ischemia induced by coronary occlusion during a percutaneous intervention (PCI). BACKGROUND: The risk for sudden cardiac death is increased in conditions of acute or permanently heterogeneous ventricular repolarization, for which ischemia is a risk factor. METHODS: Fifty-six CAD patients without visible collateral circulation were studied during an elective single-vessel PCI, and 10 healthy controls twice at rest. T vector parameters (Televation, Tazimuth, and QRS-T angle), and T loop parameters (Tarea, Tavplan, and Teigenv) were measured by vectorcardiography. ST vector magnitude (ST-VM) and its change (STC-VM) were used for reference. RESULTS: At rest, T vector loop morphology (Tarea, Teigenv) was significantly different in CAD patients and controls, while T vector angles did not separate the groups. Ischemia induced significant changes in T loop parameters in the entire CAD group, whereas in the LAD subgroup significant changes were seen also in T vector angle. The T loop morphology was significantly different at baseline and a more pronounced response to ischemia (Tarea) was seen in patients with, than in those without, a history of hypertension. CONCLUSION: T loop morphology, rather than the T vector angle, separated CAD patients from healthy controls. Coronary occlusion had significant impact on ventricular repolarization, as assessed by T vector and morphology analysis, and most prominently in the LAD group. Hypertensive patients appeared especially vulnerable to ischemia.
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| 19. |
- Själander, Sara, et al.
(författare)
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Assessment of Use vs Discontinuation of Oral Anticoagulation After Pulmonary Vein Isolation in Patients With Atrial Fibrillation
- 2017
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Ingår i: JAMA cardiology. - : American Medical Association. - 2380-6583 .- 2380-6591. ; 2:2, s. 146-152
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.OBJECTIVES: To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort studywas conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.EXPOSURES: Warfarin treatment.MAIN OUTCOMES AND MEASURES: Ischemic stroke, intracranial hemorrhage, and death.RESULTS: In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA(2)DS(2)-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA(2)DS(2)-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA(2)DS(2)-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).CONCLUSIONS AND RELEVANCE: These findings indicate that discontinuation ofwarfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.
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| 26. |
- Wedenoja, S, et al.
(författare)
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A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 14208-
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Tidskriftsartikel (refereegranskat)abstract
- Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital chloride diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish (P < 0.05) and over 120,000 global alleles (P < 0.0001) (ExAC database). Functional studies showed that while SLC26A3 is a strong activator of CFTR-dependent anion transport, SLC26A3-p.Asp688His mutant retains normal Cl−/HCO3− exchange activity but suppresses CFTR, despite unaffected domain binding and expression. These results suggest a novel mechanism for human male infertility─impaired anion transport by the coupled SLC26A3 and CFTR.
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| 30. |
- Ollila, MM, et al.
(författare)
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Effect of polycystic ovary syndrome on cardiac autonomic function at a late fertile age: a prospective Northern Finland Birth Cohort 1966 study
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:12, s. e033780-
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies of women in their 20s and 30s have reported impaired autonomic function in women with polycystic ovary syndrome (PCOS). We aimed to study, for the first time, whether PCOS is associated with impaired cardiac autonomic function independent of metabolic and hormonal status in their late reproductive years.DesignA prospective Northern Finland Birth Cohort 1966 (NFBC1966) study including 5889 women born in 1966 and followed through the age of 46. At that age, n=3706/5123 women (72%) answered the postal questionnaires and n=3280/5123 women (64%) participated in the clinical examination.SettingGeneral community.ParticipantsThe sample included women presenting both irregular menses (oligomenorrhoea or amenorrhoea) and hirsutism at age 31 (n=125) or with formally diagnosed PCOS by age 46 (n=181) and women without PCOS symptoms or diagnosis (n=1577).Primary and secondary outcome measuresHeart rate variability parameters: the root mean square of successive R-R differences (rMSSD), spectral power densities (LF: low frequency and HF: high frequency) and baroreflex sensitivity (BRS).ResultsWe found that parasympathetic activity (assessed by rMSSD: 19.5 (12.4; 31.9) vs 24.3 (16.1; 34.8) ms, p=0.004 and HF: 172 (75; 399) vs 261 (112; 565) ms2, p=0.002) and BRS (6.13±3.12 vs 6.99±3.52 ms/mm Hg, p=0.036) were lower in women with PCOS compared with the controls. However, in the multivariate regression analysis, PCOS, body mass index and the free androgen index did not significantly associate with rMSSD, whereas blood pressure, insulin resistance and triglycerides did.ConclusionsWe report here for the first time that late reproductive-aged women with PCOS display impaired cardiac autonomic function manifested as decreased vagal activity. Metabolic status, rather than hyperandrogenaemia and PCOS per se, was the strongest contributing factor. Given the link between cardiac morbidity and impaired autonomic function, the findings underline the importance of screening and treating metabolic abnormalities early on in women with PCOS.
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| 31. |
- Paloviita, P, et al.
(författare)
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Small RNA expression and miRNA modification dynamics in human oocytes and early embryos
- 2021
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 31:8, s. 1474-
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Tidskriftsartikel (refereegranskat)abstract
- Small noncoding RNAs (sRNAs) play important roles during the oocyte-to-embryo transition (OET), when the maternal phenotype is reprogrammed and the embryo genome is gradually activated. The transcriptional program driving early human development has been studied with the focus mainly on protein-coding RNAs, and expression dynamics of sRNAs remain largely unexplored. We profiled sRNAs in human oocytes and early embryos using an RNA-sequencing (RNA-seq) method suitable for low inputs of material. We show that OET in humans is temporally coupled with the transition from predominant expression of oocyte short piRNAs (os-piRNAs) in oocytes, to activation of microRNA (miRNA) expression in cleavage stage embryos. Additionally, 3′ mono- and oligoadenylation of miRNAs is markedly increased in zygotes. We hypothesize that this may modulate the function or stability of maternal miRNAs, some of which are retained throughout the first cell divisions in embryos. This study is the first of its kind elucidating the dynamics of sRNA expression and miRNA modification along a continuous trajectory of early human development and provides a valuable data set for in-depth interpretative analyses.
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| 32. |
- Pasquali, Renato, et al.
(författare)
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PCOS Forum: Research in Polycystic Ovary Syndrome Today and Tomorrow.
- 2011
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Ingår i: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 74:4, s. 424-33
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Forskningsöversikt (refereegranskat)abstract
- Objective: To summarize promising areas of investigation into polycystic ovary syndrome(PCOS) and to stimulate further research in this area. Summary: Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.
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| 35. |
- Sepponen, K., et al.
(författare)
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Steroidogenic factor 1 (NR5A1) induces multiple transcriptional changes during differentiation of human gonadal-like cells
- 2022
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Ingår i: Differentiation. - : Elsevier BV. - 0301-4681. ; 128:Nov-Dec, s. 83-100
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear receptor subfamily 5 group A member 1 (NR5A1) encodes steroidogenic factor 1 (SF1), a key regulatory factor that determines gonadal development and coordinates endocrine functions. Here, we have established a stem cell-based model of human gonadal development and applied it to evaluate the effects of NR5A1 during the transition from bipotential gonad to testicular cells. We combined directed differentiation of human induced pluripotent stem cells (46,XY) with activation of endogenous NR5A1 expression by conditionally-inducible CRISPR activation. The resulting male gonadal-like cells expressed several Sertoli cell transcripts, secreted anti-Müllerian hormone and responded to follicle-stimulating hormone by producing sex steroid intermediates. These characteristics were not induced without NR5A1 activation. A total of 2691 differentially expressed genetic elements, including both coding and non-coding RNAs, were detected immediately following activation of NR5A1 expression. Of those, we identified novel gonad-related putative NR5A1 targets, such as SCARA5, which we validated also by immunocytochemistry. In addition, NR5A1 activation was associated with dynamic expression of multiple gonad- and infertility-related differentially expressed genes. In conclusion, by combining targeted differentiation and endogenous activation of NR5A1 we have for the first time, been able to examine in detail the effects of NR5A1 in early human gonadal cells. The model and results obtained provide a useful resource for future investigations exploring the causative reasons for gonadal dysgenesis and infertility in humans. © 2022 The Authors
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