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- Leal, NS, et al.
(författare)
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Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:12
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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- Martson, A-G, et al.
(författare)
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How to design a study to evaluate therapeutic drug monitoring in infectious diseases?
- 2020
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 26:8, s. 1008-1016
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Forskningsöversikt (refereegranskat)abstract
- Background: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM.Objectives: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM.Sources: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM.Content: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design.
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- Botticelli, Susanna, et al.
(författare)
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Do Infant Cleft Dimensions Have an Influence on Occlusal Relations? A Subgroup Analysis Within an RCT of Primary Surgery in Patients With Unilateral Cleft Lip and Palate
- 2020
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Ingår i: The Cleft Palate-Craniofacial Journal. - : Sage Publications. - 1055-6656 .- 1545-1569. ; 57:3, s. 378-388
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate whether infant cleft dimensions, in a surgical protocol with early or delayed hard palate closure, influence occlusion before orthodontics.less thanbr /greater thanDesign: Subgroup analysis within a randomized trial of primary surgery (Scandcleft).less thanbr /greater thanSetting: Tertiary health care. One surgical centre.less thanbr /greater thanPatients and Methods: A total of 122 unilateral cleft lip and palate infants received primary cheilo-rhinoplasty and soft palate closure at age 4 months and were randomized for hard palate closure at age 12 versus 36 months. A novel 3D analysis of cleft size and morphology was performed on digitized presurgical models. Occlusion was scored on 8-year models using the modified Huddarth-Bodenham (MHB) Index and the Goslon Yardstick.less thanbr /greater thanMain Outcome Measurements: Differences in MHB and Goslon scores among the 2 surgical groups adjusted for cleft size.less thanbr /greater thanResults: The crude analysis showed no difference between the 2 surgical groups in Goslon scores but a better MHB (P = .006) for the group who received delayed hard palate closure. When adjusting for the ratio between cleft surface and palatal surface (3D Infant Cleft Severity Ratio) and for posterior cleft dimensions at tuberosity level, the delayed hard palate closure group received 3.65 points better for MHB (confidence interval: 1.81; 5.48; P less than .001) and showed a trend for reduced risk of receiving a Goslon of 4 or 5 (P = .052). For posterior clefts larger than 9 mm, the Goslon score was better in the delayed hard palate closure group (P = .033).less thanbr /greater thanConclusions: Seen from an orthodontic perspective, when the soft palate is closed first, and the cleft is large, the timing of hard palate closure should be planned in relation to posterior cleft size.
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