rudyvdbrink/CitationDatabase huggingface dataset:
Neutrophil-Derived Microvesicle Induced Dysfunction of Brain Microvascular Endothelial Cells In Vitro.
International journal of molecular sciences, 2019

The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic levels of neutrophils have been detected in patients with altered BBB function, but the role of neutrophils in BMEC dysfunction is unknown. Neutrophils are key players of the immune response and, when activated, produce neutrophil-derived microvesicles (NMV). NMV have been shown to impact the integrity of endothelial cells throughout the body and we hypothesize that NMV released from circulating neutrophils interact with BMEC and induce endothelial cell dysfunction. Therefore, the current study investigated the interaction of NMV with human BMEC and determined whether they altered gene expression and function in vitro. Using flow cytometry and confocal imaging, NMV were shown to be internalized by the human cerebral microvascular endothelial cell line hCMEC/D3 via a variety of energy-dependent mechanisms, including endocytosis and macropinocytosis. The internalization of NMV significantly altered the transcriptomic profile of hCMEC/D3, specifically inducing the dysregulation of genes associated with TJ, ubiquitin-mediated proteolysis and vesicular transport. Functional studies confirmed NMV significantly increased permeability and decreased the transendothelial electrical resistance (TEER) of a confluent monolayer of hCMEC/D3. These findings indicate that NMV interact with and affect gene expression of BMEC as well as impacting their integrity. We conclude that NMV may play an important role in modulating the permeability of BBB during an infection.
Postprocedural, midterm, and long-term results of cerebral aneurysms treated with flow-diverter devices: 7-year experience at a single center.
Neurosurgical focus, 2017

OBJECTIVE Flow diversion has emerged as a viable treatment option for selected intracranial aneurysms and recently has been gaining traction. The aim of this study was to evaluate the safety and effectiveness of flow-diverter devices (FDDs) over a long-term follow-up period. METHODS The authors retrospectively reviewed all cerebral aneurysm cases that had been admitted to the Division of Neurosurgery of the Università degli Studi di Napoli between November 2008 and November 2015 and treated with an FDD. The records of 60 patients (48 females and 12 males) harboring 69 cerebral aneurysms were analyzed. The study end points were angiographic evidence of complete aneurysm occlusion, recanalization rate, occlusion of the parent artery, and clinical and radiological evidence of brain ischemia. The occlusion rate was evaluated according to the O'Kelly-Marotta (OKM) Scale for flow diversion, based on the degree of filling (A, total filling; B, subtotal filling; C, entry remnant; D, no filling). Postprocedural, midterm, and long-term results were strictly analyzed. RESULTS Complete occlusion (OKM D) was achieved in 63 (91%) of 69 aneurysms, partial occlusion (OKM C) in 4 (6%), occlusion of the parent artery in 2 (3%). Intraprocedural technical complications occurred in 3 patients (5%). Postprocedural complications occurred in 6 patients (10%), without neurological deficits. At the 12-month follow-up, 3 patients (5%) experienced asymptomatic cerebral infarction. No further complications were observed at later follow-up evaluations (> 24 months). There were no reports of any delayed aneurysm rupture, subarachnoid or intraparenchymal hemorrhage, ischemic complications, or procedure- or device-related deaths. CONCLUSIONS Endovascular treatment with an FDD is a safe treatment for unruptured cerebral aneurysms, resulting in a high rate of occlusion. In the present study, the authors observed effective and stable aneurysm occlusion, even at the long-term follow-up. Data in this study also suggest that ischemic complications can occur at a later stage, particularly at 12-18 months. On the other hand, no other ischemic or hemorrhagic complications occurred beyond 24 months.
Homotopic reduction in laser-evoked potential amplitude and laser-pain rating by abdominal acupuncture.
European journal of pain (London, England), 2021

The neural mechanism underlying the analgesic effect of acupuncture is largely unknown. We aimed at investigating the effect of abdominal acupuncture (AA) on the laser-evoked potential (LEP) amplitude and laser-pain rating to stimulation of body parts either homotopic or heterotopic to the treated acupoint.
EHD4 is a novel regulator of urinary water homeostasis.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2017

The Eps15-homology domain-containing (EHD) protein family comprises 4 members that regulate endocytic recycling. Although the kidney expresses all 4 EHD proteins, their physiologic roles are largely unknown. This study focused on EHD4, which we found to be expressed differentially across nephron segments with the highest expression in the inner medullary collecting duct. Under baseline conditions,
The neuronal ceroid lipofuscinoses: the same, but different?
Biochemical Society transactions, 2010

The NCLs (neuronal ceroid lipofuscinoses) (also known as Batten disease) are a group of at least ten fatal inherited storage disorders. Despite the identification of many of the disease-causing genes, very little is known about the underlying disease mechanisms. However, now that we have mouse or large-animal models for most forms of NCL, we can investigate pathogenesis and compare what happens in the brain in different types of the disease. Broadly similar neuropathological themes have emerged, including the highly selective nature of neuron loss, early effects upon the presynaptic compartment, together with an early and localized glial activation. These events are especially pronounced within the thalamocortical system, but it is clear that where and when they occur varies markedly between different forms of NCL. It is now becoming apparent that, despite having pathological endpoints that resemble one another, these are reached by a sequence of events that is specific to each subtype of NCL.
Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.
Nucleic acids research, 2020

The transcription factor Six1 is essential for induction of sensory cell fate and formation of auditory sensory epithelium, but how it activates gene expression programs to generate distinct cell-types remains unknown. Here, we perform genome-wide characterization of Six1 binding at different stages of auditory sensory epithelium development and find that Six1-binding to cis-regulatory elements changes dramatically at cell-state transitions. Intriguingly, Six1 pre-occupies enhancers of cell-type-specific regulators and effectors before their expression. We demonstrate in-vivo cell-type-specific activity of Six1-bound novel enhancers of Pbx1, Fgf8, Dusp6, Vangl2, the hair-cell master regulator Atoh1 and a cascade of Atoh1's downstream factors, including Pou4f3 and Gfi1. A subset of Six1-bound sites carry consensus-sequences for its downstream factors, including Atoh1, Gfi1, Pou4f3, Gata3 and Pbx1, all of which physically interact with Six1. Motif analysis identifies RFX/X-box as one of the most significantly enriched motifs in Six1-bound sites, and we demonstrate that Six1-RFX proteins cooperatively regulate gene expression through binding to SIX:RFX-motifs. Six1 targets a wide range of hair-bundle regulators and late Six1 deletion disrupts hair-bundle polarity. This study provides a mechanistic understanding of how Six1 cooperates with distinct cofactors in feedforward loops to control lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.
Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.
Psychoneuroendocrinology, 2015

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention.
Curculigoside A attenuates experimental cerebral ischemia injury in vitro and vivo.
Neuroscience, 2011

Recent studies have demonstrated nuclear factor-κB (NF-κB) and high-mobility group box1 (HMGB1) associated with the pathophysiology of cerebral ischemia. We isolated Curculigoside A, the major bioactive compound present in Curculigo orchioides. The objectives of this study were to determine the effects of Curculigoside A on cultured neuronal cell line, SH-SY5Y in vitro and experimental ischemic stroke in vivo. For oxygen-glucose deprivation and tumor necrosis factor-α (TNF-α) stimulated SH-SY5Y cell line in vitro, SH-SY5Y cells were pre-incubated with Curculigoside A. For in vivo experiment, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h, then followed by reperfusion for 23 h. Treatment of SH-SY5Y cells with Curculigoside A reduced the oxygen-glucose deprivation-induced cytotoxicity and apoptosis, blocked TNF-α-induced NF-κB and IκB-α phosphorylation, and decreased HMGB1 expression. At doses higher than 10 mg/kg, Curculigoside A produced a significant neuroprotective potential in rats with ischemia and reperfusion (I/R). Curculigoside A (20 mg/kg) demonstrated significant neuroprotective activity even after delayed administration at 1 h, 3 h, and 5 h after I/R. Curculigoside A 20 mg/kg attenuated histopathological damage, decreased cerebral Evans Blue extravasation, inhibited NF-κB activation and reduced HMGB1 expression. These data show that Curculigoside A protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and its protective effects may involve HMGB1 and NF-κB signaling pathway.
Review of electroconvulsive therapy practice from a tertiary Child and Adolescent Psychiatry Centre.
Asian journal of psychiatry, 2014

The use of electroconvulsive therapy (ECT) in children and adolescents is a controversial issue. This study was done to examine the pattern and practice as well as the outcome of electroconvulsive therapy administered to children and adolescents admitted to a tertiary care centre.
fISHing with immunohistochemistry for housekeeping gene changes in Alzheimer's disease using an automated quantitative analysis workflow.
Journal of neurochemistry, 2021

In situ hybridization (ISH) is a powerful tool that can be used to localize mRNA expression in tissue samples. Combining ISH with immunohistochemistry (IHC) to determine cell type provides cellular context of mRNA expression, which cannot be achieved with gene microarray or polymerase chain reaction. To study mRNA and protein expression on the same section we investigated the use of RNAscope® ISH in combination with fluorescent IHC on paraffin-embedded human brain tissue. We first developed a high-throughput, automated image analysis workflow for quantifying RNA puncta across the total cell population and within neurons identified by NeuN
Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease.
Proceedings of the National Academy of Sciences of the United States of America, 2017

The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.
Communicability Characterization of Structural DWI Subcortical Networks in Alzheimer's Disease.
Entropy (Basel, Switzerland), 2019

In this paper, we investigate the connectivity alterations of the subcortical brain network due to Alzheimer's disease (AD). Mostly, the literature investigated AD connectivity abnormalities at the whole brain level or at the cortex level, while very few studies focused on the sub-network composed only by the subcortical regions, especially using diffusion-weighted imaging (DWI) data. In this work, we examine a mixed cohort including 46 healthy controls (HC) and 40 AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. We reconstruct the brain connectome through the use of state of the art tractography algorithms and we propose a method based on graph communicability to enhance the information content of subcortical brain regions in discriminating AD. We develop a classification framework, achieving 77% of area under the receiver operating characteristic (ROC) curve in the binary discrimination AD vs. HC only using a 12 × 12 subcortical features matrix. We find some interesting AD-related connectivity patterns highlighting that subcortical regions tend to increase their communicability through cortical regions to compensate the physical connectivity reduction between them due to AD. This study also suggests that AD connectivity alterations mostly regard the inter-connectivity between subcortical and cortical regions rather than the intra-subcortical connectivity.
Perampanel with concomitant levetiracetam and topiramate: Post hoc analysis of adverse events related to hostility and aggression.
Epilepsy & behavior : E&B, 2017

In 4 Phase III registration trials (3 in patients with partial seizures, N=1480; 1 in patients with PGTCS, N=163), perampanel administered to patients already receiving 1-3 concomitant antiepileptic drugs (AEDs) demonstrated statistically superior efficacy compared to placebo in reducing seizure frequency. However, use of perampanel in these studies was associated with a risk of psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation and threats. The present study is a post hoc analysis of pooled data from these 4 trials to determine if concomitant treatment with levetiracetam and/or topiramate increased the risk of hostility- and aggression-related AEs. Treatment-emergent AEs (TEAEs) were determined using a "Narrow & Broad" search based on the Medical Dictionary for Regulatory Activities (MedDRA) standard MedDRA query (SMQ) for hostility- and aggression-related events. The rate of hostility- and aggression-related TEAEs was observed to be similar among perampanel-treated patients: a) receiving levetiracetam (N=340) compared to those not receiving levetiracetam (N=779); b) receiving topiramate (N=223) compared to those not receiving topiramate (N=896); and c) receiving both levetiracetam and topiramate (N=47) compared to those not receiving levetiracetam and topiramate (N=1072). Severe and serious TEAEs related to hostility and aggression were rare and occurred at a similar rate regardless of concomitant levetiracetam and/or topiramate therapy. Taken together, these results suggest that concomitant treatment with levetiracetam and/or topiramate has no appreciable effect on the occurrence of hostility- or aggression-related TEAEs in patients receiving perampanel.
HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.
Brain, behavior, and immunity, 2018

Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.
Distinct mechanisms of Up state maintenance in the medial entorhinal cortex and neocortex.
Neuropharmacology, 2017

The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here, we compared the mechanisms involved in the maintenance of the Up state in the barrel cortex (BC) and mEC using whole cell recordings in acute mouse brain slices. Bath application of an NMDA receptor antagonist abolished Up states in the BC, and reduced the incidence but not the duration of Up states in the mEC. Conversely, blockade of kainate receptors decreased Up state duration in the mEC, but not in the BC. Voltage clamp recordings demonstrated the presence of a non-NMDA glutamate receptor-mediated slow excitatory postsynaptic current, sensitive to the selective kainate receptor antagonist UBP-302, in layer III neurons of the mEC, which was not observed in the BC. Moreover, we found that kainate receptor-mediated currents assist in recovery back to the Up state membrane potential following a current-induced hyperpolarisation of individual cells in the mEC. Finally, we were able to generate Up state activity in a network model of exponential integrate-and-fire neurons only supported by AMPA and kainate receptor-mediated currents. We propose that synaptic kainate receptors are responsible for the unique properties of mEC Up states.
Neurologic aspects of microcephalic osteodysplastic primordial dwarfism type II.
Pediatric neurology, 2008

Microcephalic osteodysplastic primordial dwarfism type II is a specific disorder characterized by severe intrauterine and postnatal growth retardation, acquired microcephaly, cerebrovascular abnormalities, progressive bone dysplasia, and a characteristic face. Whereas the diagnostic features of this syndrome are well-recognized, the neurologic aspects have not been clearly defined. We report on a detailed neurodevelopmental follow-up study of a new case of microcephalic osteodysplastic primordial dwarfism type II, followed from the first years of life to adolescence, and we discuss the neurocognitive features of our patient. We also review the neurologic aspects of this disorder compared with syndromes with overlapping phenotypes, such as microcephalic osteodysplastic primordial dwarfism types I and III and Seckel syndrome.