62 research outputs found
Cardiac microtissues from human pluripotent stem cells recapitulate the phenotype of long-QT syndrome
Background: Human induced pluripotent stem cells (hiPSCs) and their derivative cardiomyocytes (hiPSCCMs) have been successfully used to study the electrical phenotype of cardiac ion channel diseases. However, strategies to mature CMs and more comprehensive systems recapitulating the heart complexity are required to advance our ability to capture adult phenotypes. Methods: We differentiated wild-type (WT) and long QT syndrome type 1 (LQT1) hiPSCs into CMs, endothelial cells and cardiac fibroblasts. The three cell types were combined to form three-dimensional (3D) spheroids, termed "cardiac microtissues" (cMTs) and the electrophysiological properties were measured using 96-well multi-electrode arrays. Results: LQT1 cMTs displayed prolonged field potential duration compared to WT controls, thus recapitulating the typical feature of LQTS. Isoprenaline caused a positive chronotropic effect on both LQT1 and WT cMTs. The 96-well multi-electrode array format proved suitable to detect electrical changes directly in the 3D tissues. Conclusions: 3D hiPSC cMTs are a scalable tool that can be used to identify LQT electrical hallmarks and drug responses. We anticipate this tool can be adopted by pharmaceutical companies to screen cardioactive compounds. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Stem cells & developmental biolog
The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena
Background: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. Methods: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patientâs organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. Results: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. Conclusion: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 ârelatively new statementsâ that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.</p
The Dutch multidisciplinary guideline osteoporosis and fracture prevention, taking a local guideline to the international arena
Background: In 2018, a grant was provided for an evidence-based guideline on osteoporosis and fracture prevention based on 10 clinically relevant questions. Methods: A multidisciplinary working group was formed with delegates from Dutch scientific and professional societies, including representatives from the patientâs organization and the Dutch Institute for Medical Knowledge. The purpose was to obtain a broad consensus among all participating societies to facilitate the implementation of the updated guideline. Results: Novel recommendations in our guideline are as follows: - In patients with an indication for DXA of the lumbar spine and hips, there is also an indication for VFA. - Directly starting with anabolic drugs (teriparatide or romosozumab) in patients with a very high fracture risk; - Directly starting with zoledronic acid in patients 75 years and over with a hip fracture (independent of DXA); - Directly starting with parenteral drugs (denosumab, teriparatide, zoledronic acid) in glucocorticoid-induced osteoporosis with very high fracture risk; - A lifelong fracture risk management, including lifestyle, is indicated from the start of the first treatment. Conclusion: In our new multidisciplinary guideline osteoporosis and fracture prevention, we developed 5 ârelatively new statementsâ that are all a crucial step forward in the optimization of diagnosis and treatment for fracture prevention. We also developed 5 flowcharts, and we suppose that this may be helpful for individual doctors and their patients in daily practice and may facilitate implementation.</p
Targeting the K(v)11.1 (hERG) channel with allosteric modulators: synthesis and biological evaluation of three novel series of LUF7346 derivatives
We synthesized and evaluated three novel series of substituted benzophenones for their allosteric modulation of the human K(v)11.1 (hERG) channel. We compared their effects with reference compound LUF7346 previously shown to shorten the action potential of cardiomyocytes derived from human stem cells. Most compounds behaved as negative allosteric modulators (NAMs) of [H-3]dofetilide binding to the channel. Compound 9i was the most potent amongst all ligands, remarkably reducing the affinity of dofetilide in competitive displacement assays. One of the other derivatives (6k) tested in a second radioligand binding set-up, displayed unusual displacement characteristics with a pseudo-Hill coefficient significantly distinct from unity, further indicative of its allosteric effects on the channel. Some compounds were evaluated in a more physiologically relevant context in beating cardiomyocytes derived from human induced pluripotent stem cells. Surprisingly, the compounds tested showed effects quite different from the reference NAM LUF7346. For instance, compound 5e prolonged, rather than shortened, the field potential duration, while it did not influence this parameter when the field potential was already prolonged by dofetilide. In subsequent patch clamp studies on HEK293 cells expressing the hERG channel the compounds behaved as channel blockers. In conclusion, we successfully synthesized and identified new allosteric modulators of the hERG channel. Unexpectedly, their effects differed from the reference compound in functional assays on hERG-HEK293 cells and human cardiomyocytes, to the extent that the compounds behaved as stand-alone channel blockers. (C) 2020 The Author(s). Published by Elsevier Masson SAS.Stem cells & developmental biolog
A core outcome set for pre-eclampsia research:an international consensus development study
Objective: To develop a core outcome set for pre-eclampsia. Design: Consensus development study. Setting: International. Population: Two hundred and eight-one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. Methods: Modified Delphi method and Modified Nominal Group Technique. Results: A long-list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre-eclampsia trials with those derived from thematic analysis of 30 in-depth interviews of women with lived experience of pre-eclampsia. Forty-seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small-for-gestational-age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. Conclusions: The core outcome set for pre-eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies. Tweetable abstract: 281 healthcare professionals, 41 researchers and 110 women have developed #preeclampsia core outcomes @HOPEoutcomes @jamesmnduffy. [Correction added on 29 June 2020, after first online publication: the order has been corrected.].</p
Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage
The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells
A core outcome set for preâeclampsia research: an international consensus development study
Objective
To develop a core outcome set for preâeclampsia.
Design
Consensus development study.
Setting
International.
Population
Two hundred and eightâone healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated.
Methods
Modified Delphi method and Modified Nominal Group Technique.
Results
A longâlist of 116 potential core outcomes was developed by combining the outcomes reported in 79 preâeclampsia trials with those derived from thematic analysis of 30 inâdepth interviews of women with lived experience of preâeclampsia. Fortyâseven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, smallâforâgestationalâage, neonatal mortality, seizures, admission to neonatal unit required and respiratory support.
Conclusions
The core outcome set for preâeclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies
De (on)betaalde kracht achter goed vrijwilligerswerk. Een onderzoek naar de inzet van betaalde en niet-betaalde coordinatoren binnen de maatjesprojecten van Humanitas
Erratum Recurrence of hypertensive disorders of pregnancy : an individual patient data metaanalysis (vol 212, 624.e1, 2015)
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