rudyvdbrink/CitationDatabase huggingface dataset:
Progranulin protects against exaggerated axonal injury and astrogliosis following traumatic brain injury.
Glia, 2017

In response to traumatic brain injury (TBI) microglia/macrophages and astrocytes release inflammatory mediators with dual effects on secondary brain damage progression. The neurotrophic and anti-inflammatory glycoprotein progranulin (PGRN) attenuates neuronal damage and microglia/macrophage activation in brain injury but mechanisms are still elusive. Here, we studied histopathology, neurology and gene expression of inflammatory markers in PGRN-deficient mice (Grn
A quantitative imaging-based screen reveals the exocyst as a network hub connecting endocytosis and exocytosis.
Molecular biology of the cell, 2015

The coupling of endocytosis and exocytosis underlies fundamental biological processes ranging from fertilization to neuronal activity and cellular polarity. However, the mechanisms governing the spatial organization of endocytosis and exocytosis require clarification. Using a quantitative imaging-based screen in budding yeast, we identified 89 mutants displaying defects in the localization of either one or both pathways. High-resolution single-vesicle tracking revealed that the endocytic and exocytic mutants she4∆ and bud6∆ alter post-Golgi vesicle dynamics in opposite ways. The endocytic and exocytic pathways display strong interdependence during polarity establishment while being more independent during polarity maintenance. Systems analysis identified the exocyst complex as a key network hub, rich in genetic interactions with endocytic and exocytic components. Exocyst mutants displayed altered endocytic and post-Golgi vesicle dynamics and interspersed endocytic and exocytic domains compared with control cells. These data are consistent with an important role for the exocyst in coordinating endocytosis and exocytosis.
Updated reliability and normative values for the standing heel-rise test in healthy adults.
Physiotherapy, 2017

The heel-rise test is used to assess the strength and endurance of the plantar flexors in everyday clinical practice. However, several factors may affect outcomes, including sex, age, body mass index and activity level. The aims of this study were to revisit the reliability and normative values of this test, and establish normative equations accounting for several factors.
AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease.
Biochimica et biophysica acta, 2014

Huntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdh(Q109)) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdh(Q109) cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdh(Q109) cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh(150Q/+)), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD.
Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014

Growth arrest-specific protein 6 (GAS6) is a soluble agonist of the TYRO3, AXL, MERTK (TAM) family of receptor tyrosine kinases identified to have anti-inflammatory, neuroprotective, and promyelinating properties. During experimental autoimmune encephalomyelitis (EAE), wild-type (WT) mice demonstrate a significant induction of Gas6, Axl, and Mertk but not Pros1 or Tyro3 mRNA. We tested the hypothesis that intracerebroventricular delivery of GAS6 directly into the CNS of WT mice during myelin oligodendrocyte glycoprotein (MOG)-induced EAE would improve the clinical course of disease relative to artificial CSF (ACSF)-treated mice. GAS6 did not delay disease onset, but significantly reduced the clinical scores during peak and chronic EAE. Mice receiving GAS6 for 28 d had preserved SMI31(+) neurofilament immunoreactivity, significantly fewer SMI32(+) axonal swellings and spheroids and less demyelination relative to ACSF-treated mice. Alternate-day subcutaneous IFNβ injection did not enhance GAS6 treatment effectiveness. Gas6(-/-) mice sensitized with MOG35-55 peptide exhibit higher clinical scores during late peak to early chronic disease, with significantly increased SMI32(+) axonal swellings and Iba1(+) microglia/macrophages, enhanced expression of several proinflammatory mRNA molecules, and decreased expression of early oligodendrocyte maturation markers relative to WT mouse spinal cords with scores for 8 consecutive days. During acute EAE, flow cytometry showed significantly more macrophages but not T-cell infiltrates in Gas6(-/-) spinal cords than WT spinal cords. Our data are consistent with GAS6 being protective during EAE by dampening the inflammatory response, thereby preserving axonal integrity and myelination.
Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome.
Genes, brain, and behavior, 2017

Smith-Lemli-Opitz syndrome is an inherited monogenic disorder in which mutations to the 7-dehydrocholesterol (7-DHC) reductase (Dhcr7) gene lead to deficits in cholesterol synthesis. As a result, many patients suffer from gross physiological and neurological deficits. The purpose of this study was to identify a potential abnormal behavioral phenotype in a compound mutant mouse model for Smith-Lemli-Opitz disease (Dhcr7
Nightmares and Suicide in Posttraumatic Stress Disorder: The Mediating Role of Defeat, Entrapment, and Hopelessness.
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2016

Although nightmares appear to be related to suicidal behaviors, the mechanisms which underpin this relationship are unknown. We sought to address this gap by examining a multiple mediation hypothesis whereby nightmares were predicted to have an indirect effect on suicidal behaviors through perceptions of defeat, entrapment, and hopelessness.
The modular organization of brain cortical connectivity across the human lifespan.
NeuroImage, 2020

The network architecture of the human brain contributes in shaping neural activity, influencing cognitive and behavioral processes. The availability of neuroimaging data across the lifespan allows us to monitor how this architecture reorganizes, influenced by processes like learning, adaptation, maturation, and senescence. Changing patterns in brain connectivity can be analyzed with the tools of network science, which can be used to reveal organizational principles such as modular network topology. The identification of network modules is fundamental, as they parse the brain into coherent sub-systems and allow for both functional integration and segregation among different brain areas. In this work we examined the brain's modular organization by developing an ensemble-based multilayer network approach, allowing us to link changes of structural connectivity patterns to development and aging. We show that modular structure exhibits both linear and nonlinear age-related trends. In the early and late lifespan, communities are more modular, and we track the origins of this high modularity to two different substrates in brain connectivity, linked to the number and the weights of the intra-clusters edges. We also demonstrate that aging leads to a progressive and increasing reconfiguration of modules and a redistribution across hemispheres. Finally, we identify those brain regions that most contribute to network reconfiguration and those that remain more stable across the lifespan.
A comprehensive meta-analysis of cognitive-behavioral interventions for social anxiety disorder in children and adolescents.
Journal of anxiety disorders, 2016

The effectiveness of different types of CBT for children and adolescents suffering from Social Anxiety Disorder (SAD) is generally supported. However, no systematic efforts have been made to quantitatively summarize and analyse the impact of specific variables on therapeutic outcome. Here, we assessed the magnitude and duration of CBT effectiveness in children and adolescents with SAD. The effectiveness of CBT was supported by the effect sizes of studies that had examined pre-post (g=0.99), between-group (g=0.71), and follow-up responses (follow-up vs. pre-test mean g=1.18, follow-up vs. post-test mean g=0.25). A significant moderating effect was found for the variable "number of treatment sessions". In addition, larger effect sizes were found in studies that included "Social Skills Training" sessions in the intervention package. Data support the effectiveness of CBT interventions and its durability for SAD in children and adolescents. Adding social skills training to the intervention package can further enhance the impact of treatment.
Plasma amyloid-β and risk of Alzheimer's disease in the Framingham Heart Study.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2015

Plasma amyloid-β (Aβ) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date.
The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.
Behavioural brain research, 2014

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.
The asparaginyl endopeptidase legumain after experimental stroke.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2010

Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1(+) microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74(+) cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.
Inhibitory control and spatial working memory in Parkinson's disease.
Movement disorders : official journal of the Movement Disorder Society, 2007

Patients with Parkinson's disease (PD) have difficulty performing tasks relying on inhibitory control and working memory, functions of the prefrontal cortex. Eye movement paradigms can be used to investigate basic sensorimotor functions and higher order cognitive aspects of motor control. This study investigated inhibitory control and spatial working memory in the saccadic system of 13 individuals with mild-moderate PD and 13 age-matched controls. Tasks explored suppression of reflexive saccades during qualitatively different tasks, generation of express and anticipatory saccades, and the ability to respond to occasional, unpredictable ("oddball") targets that occurred during a sequence of well-learned, reciprocating saccades between horizontal targets. Spatial working memory was assessed using single and two-step (involving a visually guided saccade during the delay period) memory-guided tasks. Results for the PD group indicated an increased percentage of response selection errors during an oddball task, reduced suppression of inappropriate reflexive saccades during memory-guided tasks (but not during fixation or saccade-engagement tasks), and an increased percentage of express and anticipatory saccades. Spatial working memory was preserved in the PD group during single and two-step memory-guided tasks. These findings are consistent with dysfunction within fronto-striatal and prefrontal-collicular pathways influencing suppression and selection of eye movements.
The role of nicotinic acetylcholine receptors in the medial prefrontal cortex and hippocampus in trace fear conditioning.
Neurobiology of learning and memory, 2010

Acute nicotine enhances multiple types of learning including trace fear conditioning but the underlying neural substrates of these effects are not well understood. Trace fear conditioning critically involves the medial prefrontal cortex and hippocampus, which both express nicotinic acetylcholine receptors (nAChRs). Therefore, nicotine could act in either or both areas to enhance trace fear conditioning. To identify the underlying neural areas and nAChR subtypes, we examined the effects of infusion of nicotine, or nicotinic antagonists dihydro-beta-erythroidine (DHβE: high-affinity nAChRs) or methyllycaconitine (MLA: low-affinity nAChRs) into the dorsal hippocampus, ventral hippocampus, and medial prefrontal cortex (mPFC) on trace and contextual fear conditioning. We found that the effects of nicotine on trace and contextual fear conditioning vary by brain region and nAChR subtype. The dorsal hippocampus was involved in the effects of nicotine on both trace and contextual fear conditioning but each task was sensitive to different doses of nicotine. Additionally, dorsal hippocampal infusion of the antagonist DHβE produced deficits in trace but not contextual fear conditioning. Nicotine infusion into the ventral hippocampus produced deficits in both trace and contextual fear conditioning. In the mPFC, nicotine enhanced trace but not contextual fear conditioning. Interestingly, infusion of the antagonists MLA or DHβE in the mPFC also enhanced trace fear conditioning. These findings suggest that nicotine acts on different substrates to enhance trace versus contextual fear conditioning, and that nicotine-induced desensitization of nAChRs in the mPFC may contribute to the effects of nicotine on trace fear conditioning.
The Anti-Inflammatory Properties of Mesenchymal Stem Cells in Epilepsy: Possible Treatments and Future Perspectives.
International journal of molecular sciences, 2020

Mesenchymal stem cells (MSCs) are multipotent adult cells with self-renewing capacities. MSCs display specific properties, such as the ability to repair damaged tissues, resulting in optimal candidates for cell therapy against degenerative diseases. In addition to the reparative functions of MSCs, growing evidence shows that these cells have potent immunomodulatory and anti-inflammatory properties. Therefore, MSCs are potential tools for treating inflammation-related neurological diseases, including epilepsy. In this regard, over the last decades, epilepsy has no longer been considered a purely neuronal pathology, since inflammatory events underlying the genesis of epilepsy have been demonstrated. This review assessed current knowledge on the use of MSCs in the treatment of epilepsy. Mostly, attention will be focused on the anti-inflammatory and immunological skills of MSCs. Understanding the mechanisms by which MSCs might modulate the severity of the disease will contribute to the development of new potential alternatives for both prophylaxis and treatment against epilepsy.
Differential relationships of mismatch negativity and visual p1 deficits to premorbid characteristics and functional outcome in schizophrenia.
Biological psychiatry, 2012

Mismatch negativity (MMN) and visual P1 are established event-related potential (ERP) markers of impaired auditory and visual sensory function in schizophrenia. Differential relationships of these measures with premorbid and present function and with clinical course have been noted previously in independent cohorts, but measures have not yet been compared within the same patient group.
Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) have been associated with neuroplasticity, but most physiological studies have evaluated only the immediate effects of the stimulation on neurochemical markers. Furthermore, although it is known that baseline excitability state plays a major role in rTMS outcomes, the role of spontaneous neural activity in metaplasticity has not been investigated. The first aim of this study was to evaluate and compare the long-term effects of high- and low-frequency rTMS on the markers of neuroplasticity such as BDNF and GluR1 subunit of AMPA receptor. The second aim was to assess whether these effects depend on spontaneous neural activity, by comparing the neurochemical alterations induced by rTMS in anesthetized and awake rats. Ten daily sessions of high- or low-frequency rTMS were applied over the rat brain, and 3 d later, levels of BDNF, GluR1, and phosphorylated GluR1 were assessed in the hippocampus, prelimbic cortex, and striatum. We found that high-frequency stimulation induced a profound effect on neuroplasticity markers; increasing them in awake animals while decreasing them in anesthetized animals. In contrast, low-frequency stimulation did not induce significant long-term effects on these markers in either state. This study highlights the importance of spontaneous neural activity during rTMS and demonstrates that high-frequency rTMS can induce long-lasting effects on BDNF and GluR1 which may underlie the clinical benefits of this treatment in neuroplasticity-related disorders.
Up-regulation of GLT-1 severely impairs LTD at mossy fibre--CA3 synapses.
The Journal of physiology, 2009

Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. By this action, they maintain low levels of ambient glutamate, thus preventing excitotoxic damage, and contribute to shaping synaptic currents. We show that up-regulation of the glutamate transporter GLT-1 by ceftriaxone severely impaired mGluR-dependent long-term depression (LTD), induced at rat mossy fibre (MF)-CA3 synapses by repetitive stimulation of afferent fibres. This effect involved GLT-1, since LTD was rescued by the selective GLT-1 antagonist dihydrokainate (DHK). DHK per se produced a modest decrease in fEPSP amplitude that rapidly regained control levels after DHK wash out. Moreover, the degree of fEPSP inhibition induced by the low-affinity glutamate receptor antagonist gamma-DGG was similar during basal synaptic transmission but not during LTD, indicating that in ceftriaxone-treated rats LTD induction did not alter synaptic glutamate transient concentration. Furthermore, ceftriaxone-induced GLT-1 up-regulation significantly reduced the magnitude of LTP at MF-CA3 synapses but not at Schaffer collateral-CA1 synapses. Postembedding immunogold studies in rats showed an increased density of gold particles coding for GLT-1a in astrocytic processes and in mossy fibre terminals; in the latter, gold particles were located near and within the active zones. In both CEF-treated and untreated GLT-1 KO mice used for verifying the specificity of immunostaining, the density of gold particles in MF terminals was comparable to background levels. The enhanced expression of GLT-1 at release sites may prevent activation of presynaptic receptors, thus revealing a novel mechanism by which GLT-1 regulates synaptic plasticity in the hippocampus.
Clinical audit effectively bridges the evidence-practice gap in chronic subdural haematoma management.
Acta neurochirurgica, 2017

Placement of a subdural drain after drainage of chronic subdural haematoma (CSDH) has been shown to reduce the rate of recurrence in several randomised controlled trials (RCT). The most recently published RCT was from Cambridge, UK, in 2009. Despite class I evidence for the use of subdural drains, it is unclear whether these results have been translated into clinical practice. In this clinical audit we review the use of subdural drains in our institution before and after the publication of the 2009 RCT results.