Neuroplasticity is the capacity of the central nervous system to adapt to external or internal stimuli. It is being increasingly recognized as an important factor which contributes to the... Show moreNeuroplasticity is the capacity of the central nervous system to adapt to external or internal stimuli. It is being increasingly recognized as an important factor which contributes to the successful outcome of nerve transfers. Other much more well-known factors are the number of axons that cross the coaptation site, the interval between trauma and repair, and age. Neuroplasticity is mediated by synaptic and neurotransmitter changes which underlie activation of previously existing but low-active connections in the brain. Dendritic sprouting and axonal elongation might also take place but is likely less prominent. We review different factors that play a role in neuroplasticity and functional regeneration after specific nerve transfers. These factors include, amongst others, the distance between cortical areas of the donor and receptor neurons; the presence versus absence of pre-existing low-active inter-neuronal connections; gross versus fine movement restoration; rehabilitation; brain trauma and very important: the age. The potential for plastic adaptation should be taken into consideration if the surgical strategy and postoperative rehabilitation are planned, as its influence on results cannot be denied. 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
Corticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as... Show moreCorticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as transcription factors. Corticosteroid effects can be highly divergent, depending on the receptor type, but also on brain region, cell type, and physiological context. These differences ultimately depend on differential interactions of MR and GR with other proteins, which determine ligand binding, nuclear translocation, and transcriptional activities. In this review, we discuss established and potential mechanisms that confer receptor and cell type-specific effects of the MR and GR-mediated transcriptional effects in the brain. Show less
Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant... Show morePsychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases. Show less
Aims: To describe the characteristics and outcomes of cancer patients receiving Whole Brain Radiotherapy (WBRT) and delineate poor outcome groups after WBRT.Materials and methods: From 1991 to 2007... Show moreAims: To describe the characteristics and outcomes of cancer patients receiving Whole Brain Radiotherapy (WBRT) and delineate poor outcome groups after WBRT.Materials and methods: From 1991 to 2007, 3459 patients receiving WBRT for brain metastases at three centres (in Australia and the Netherlands) were retrospectively reviewed. The effect of clinicodemographic factors, including age, gender, primary cancer, time to WBRT from primary cancer diagnosis and WBRT timing relative to other radiotherapy courses on overall survival, survival from WBRT commencement (WBRT-SV) and death within 6 weeks were analysed.Results: WBRT was the first radiotherapy course in 2161/3459 (63%) and the last in 2932/3459 (85%). The most common primary cancer sites with brain metastases were lung (n = 1800; 52%), breast (n = 568; 16%), melanoma (n = 350; 10%) and colorectal (n = 209; 6%). The median time to WBRT from primary cancer diagnosis was 34 weeks, overall survival 1.42 years (0.04-28.70) and WBRT-SV 0.33 years (0-8.60). Older age, male gender and a shorter time from the primary cancer diagnosis to WBRT predicted worse overall survival and WBRT-SV. Seventeen per cent survived less than 6 weeks. Older patients with a shorter time from the primary cancer diagnosis to WBRT and a lower WBRT episode number were more likely to die less than 6 weeks after WBRT.Conclusions: Cancer patients with brain metastases have poor overall outcomes. High mortality within 6 weeks of starting WBRT suggests patient selection remains challenging. (C) 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Show less
Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there... Show moreDexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development. (C) 2012 Elsevier B.V. All rights reserved. Show less
There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male... Show moreThere are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders. Show less
Steggerda, S.J.; Bruine, F.T. de; Smits-Wintjens, V.E.H.J.; Walther, F.J.; Wezel-Meijler, G. van 2012
