Background and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of... Show moreBackground and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of body composition and not in combination with nutritional intake, while both are components of the nutritional status. We aimed to evaluate the most important risk factors regarding body composition (muscle mass, muscle quality and fat mass) and nutritional intake (energy and protein intake) for waiting list mortality in patients with ESLD awaiting liver transplantation (LTx).Methods: Consecutive patients with ESLD listed for LTx between 2007 and 2014 were investigated. Muscle mass quantity (Skeletal Muscle Mass Index, SMI), and muscle quality (Muscle Attenuation, MA), and various body fat compartments were measured on computed tomography using SliceOmatic. Nutritional intake (e.g. energy and protein intake) was assessed. Multivariable stepwise forward Cox regression analysis was used for statistical analysis.Results: 261 Patients (mean age 54 years, 74.7% male) were included. Low SMI and MA were found to be statistically significant predictors of an increased risk for waiting list mortality in patients with ESLD, with a HR of 2.580 (95%CI 1.055-6.308) and HR of 9.124 (95%CI 2.871-28.970), respectively. No association between percentage adipose tissue, and protein and energy intake with waiting list mortality was found in this study.Conclusion: Both low muscle quantity and quality, and not nutritional intake, were independent risk factors for mortality in patients with ESLD. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. Show less
The aim of this thesis was to develop fast reconstruction and acquisition techniques for MRI that can support clinical applications where time is a limiting factor. In general, fast acquisition... Show moreThe aim of this thesis was to develop fast reconstruction and acquisition techniques for MRI that can support clinical applications where time is a limiting factor. In general, fast acquisition techniques were realized by undersampling k-space, while fast reconstruction techniques were achieved by using efficient numerical algorithms. In particular, undersampled acquisitions were processed in a CS and MRF framework. Preconditioning techniques were used to accelerate CS reconstructions, and a number of challenges encountered in MRF were addressed using appropriate post-processing techniques. Show less
Spoel, E. van der; Vliet, N.A. van; Heemst, D. van 2019
Specific hallmarks are thought to underlie the ageing process and age-related functional decline. In this viewpoint, we put forward the hypothesis that disturbances in the process of tissue... Show moreSpecific hallmarks are thought to underlie the ageing process and age-related functional decline. In this viewpoint, we put forward the hypothesis that disturbances in the process of tissue maintenance are an important common denominator that may lie in between specific hallmarks of ageing (i.e. damage and responses to damage) and their ultimate (patho)physiological consequences (i.e. functional decline and age-related disease). As a first step towards verifying or falsifying this hypothesis, it will be important to measure biomarkers of tissue maintenance in future studies in different study populations. The main aim of the current paper is to discuss potential biomarkers of tissue maintenance that could be used in such future studies. Among the many tissues that could have been chosen to explore our hypothesis, to keep the paper manageable, we chose to focus on a selected number of tissues, namely bone, cartilage, muscle, and the brain, which are important for mobility and cognition and affected in several common age-related diseases, including osteoporosis, osteoarthritis, sarcopenia, and neurodegenerative diseases. Furthermore, we discuss the advantages and limitations of potential biomarkers for use in (pre)clinical studies. The proposed biomarkers should be validated in future research, for example by measuring these in humans with different rates of ageing. Show less
Kolk, A.; Zwaal, P. van der; Thomassen, B.J.W.; Kamp, E.W.C. van de; Stijnen, T.; Groot, J.H. de; Nelissen, R.G.H.H. 2018
Duchenne muscular dystrophy (DMD) is a severe progressive muscle wasting disorder. DMD is caused by reading frame disrupting mutations in the DMD gene resulting is an absence of the dystrophin... Show moreDuchenne muscular dystrophy (DMD) is a severe progressive muscle wasting disorder. DMD is caused by reading frame disrupting mutations in the DMD gene resulting is an absence of the dystrophin protein. Dystrophin is an important muscle protein as it provide stability upon muscle fiber contraction. Currently there is no therapy for the majority of the DMD patients. As part of the standard of care patient receive symptomatic treatment e.g. corticosteroids, respiratory and cardiac support. Various therapeutic approached are currently under development. Most advanced therapeutic approach is aimed to restore dystrophin production by using antisense oligonucleotides (AON): exon skipping. This thesis focusses on delivery of AON to skeletal and cardiac muscle for DMD. With the help of phage display technology combined with next generation sequencing analyses, muscle homing peptides have been identified. In this thesis is described how for the first time these homing peptides upon conjugation to a 2OMePS AON resulted in increased delivery and exon skipping in a mouse model for DMD. In Conclusion, muscle homing peptides have the potential to facilitate delivery of AONs and perhaps other compounds to skeletal and cardiac muscle. Show less
Hooijmans, M.T.; Niks, E.H.; Burakiewicz, J.; Anastasopoulos, C.; Berg, S.I. van den; Zwet, E. van; ... ; Kan, H.E. 2017
The aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low... Show moreThe aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low muscle strength, while high acute pro-inflammatory response is associated with high muscle strength. Show less
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the... Show moreIn modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the central clock in the suprachiasmatic nuclei (SCN) in the brain. In mice, a complete abolishment of central clock-driven rhythms resulted in obesity and severe hepatic insulin resistance. An attenuation of rhythms resulted in decreased muscle strength, osteoporosis-like bone changes and transient changes in the immune system. In humans, short sleeping obese individuals with a preference for evening activities ("evening chronotypes") had increased cardiovascular risk factors. Their neurocognitive function was often impaired and could be improved with sleep extension. Insufficient sleep was also associated with an increased risk for osteopenia and sarcopenia. Taken together, disrupted circadian rhythms and insufficient sleep associate with a spectrum of unfavorable health outcomes. Studies described in the thesis provide insight in potential strategies to improve rhythms and sleep: by appropriately timed behavior (active behavior during the active phase; rest during the rest phase), light exposure (light during the subjective day; darkness at night) as well as caffeine intake. Show less
In this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in... Show moreIn this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in muscle of DMD patients with a semi-quantitative method. Dixon MRI showed to be more sensitive to subtle changes. Implementation of a multipeak model to account for multiple lipid spectrum peaks in this method allowed even more sensitive measurements. We evaluated non-contractile and contractile cross-sectional areas in leg muscles of DMD patients. Combined with strength measurements we could measure muscle quality and showed muscle hypertrophy and fatty infiltration to be two distinct processes. We explored the relation between dystrophin levels and fat in BMD patients and found no such relation, but did find a relation between strength and age in a subgroup, demonstrating the location of the mutation to be a major determinant of disease severity. Using T2 MRI as inflammatory marker in DMD/BMD patients and healthy controls we showed an increased T2 in DMD patients. Finally we investigated the muscle energy metabolism in BMD patients with MRS and showed increased PDE/ATP ratios prior to onset of fatty infiltration, consequently 31P MRS could be another potential outcome parameter. Show less
Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive... Show moreDuchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive to exercise-induced damage, resulting in progressive muscle wasting, loss of ambulation and premature death. There is no cure, but several therapeutic approaches are clinically tested. At best, these clinical interventions result in the expression of low dystrophin levels. Fortunately, expression of wild type levels is not needed, as both humans and mice expressing ~50% of dystrophin do not show pathology. Detailed studies on which dystrophin levels are needed to prevent pathology and improve muscle function have been performed in this thesis. After the set-up of good outcome measures and serum biomarkers to monitor disease progression, two new innovative mouse models expressing low levels of dystrophin based on skewed X-inactivation were generated. In the mdx-Xist__hs model we observed that <15% dystrophin already improved muscle performance, while histopathology was largely with >15% dystrophin. To protect muscles from exercise-induced damage >22% dystrophin was needed. Dystrophin levels between 3-21% prevent the development of dilated cardiomyopathy in 10 months old mice. Mice lacking both dystrophin and its homologue utrophin, mimic the human phenotype and die before the age of 12 weeks. In these mice, <10% dystrophin improved life expectancy and muscle function while >10% dystrophin was needed to improve histopathology. These findings are encouraging for ongoing and future clinical trails. Show less
Injection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were... Show moreInjection of (stem) cells into the damaged heart has a positive effect on cardiac function. In this thesis two strategies for improving myocardial regeneration over classical cell therapy were investigated. The first is to induce cardiomyogenic differentiation by genetically engineering cells to express the transcription factor myocardin (a regulator of cardiomyocyte differentiation). We found that overexpression of myocardin induces a large part of the cardiac muscle gene expression program in various non-muscle cells. Forced expression of myocardin enables cardiac infarction scar fibroblasts to conduct a cardiac action potential, and injection of myocardin-transduced MSCs resulted in greater preservation of cardiac function and reduced detrimental remodeling compared to untreated MSCs in a mouse model of myocardial infarction. Indicating that overexpression of myocardin endows cells with several beneficial properties of cardiomyocytes. We hypothesized that myocardial regeneration might be enhanced by including novel cell types with supportive functions in cell therapy strategies. We found that the mesothelial cells of the human epicardium, like embryonic epicardium-derived cells (EPDCs) can form fibroblasts and smooth muscle cells. Indicating that EPDCs from human adults recapitulate at least part of the differentiation potential of their embryonic counterparts, which form various essential supportive cell types during heart development. Show less
