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  • Open access
  • 97 Reads
Exploring inflammatory status in febrile seizures associated with urinary tract infections: a Two-Step cluster approach

Background: Urinary tract infections (UTI) are considered as common facilitating factors along with other infections in triggering febrile seizures (FS). The main purpose of the study is to identify specific patterns of UTIs, using a combination of inflammatory biomarkers, in order to differentiate UTIs from other bacterial diseases associated with FS.

Method: This study included a number of 197 distinct FS events, from patients hospitalized in the Sibiu Pediatric Hospital, among which 10.2% were diagnosed with UTIs. Results: In one third of patients with UTIs symptoms were limited to fever and FS. Using Two-Step cluster analysis, a distinct inflammatory pattern has emerged: higher PDW (median value 9,65 fl), P-LCR (median value 14,45%), VTM (median value 10,40 fl), PCR (median value 74,00 g/L) and neutrophil-lymphocyte ratio (median value 3,64), associated mainly (85,7%) with bacterial respiratory infections. UTIs were highly unlikely in the patients with significantly increased PCR values and normal values of platelet indices.

Conclusion. Considering the nonspecific clinical picture of UTIs at an early age, in order to optimize the management of FS a fast diagnosis of UTI is mandatory. Our study suggests that analyzing the inflammatory biomarkers interlink (rather than individual parameters) could help identify UTI patients, even when oligosymptomatic.

  • Open access
  • 94 Reads
A Novel Retinal Gene Therapy Strategy for Batten Disease and Beyond

Batten Disease is a fatal, lysosomal storage disorder characterized by cognitive and motor deficits, vision impairments, and seizures. Loss of vision is a hallmark of 10 of the 13 Batten Disease subtypes. Our group has pioneered AAV9 gene therapy treatments achieving widespread transduction of the brain and spinal cord. Two clinical trials are currently ongoing at Nationwide Children’s Hospital delivering this vector via cerebrospinal fluid (CSF) to the brain and spinal cord for treatment of the lethal neurodegenerative aspects of Batten Disease. However, AAV9 transduction of the retina after CSF delivery is limited and there is a critical need for a solution that prevents vision loss and further improves quality of life for Batten Disease patients.

Similar to most genetic ocular diseases, photoreceptor degeneration is the most commonly cited pathology in patients. However, recent studies suggest that in some subtypes of Batten Disease, expression must be rescued also within the deeper layers of the retina that are difficult to reach with therapeutic vectors (inner nuclear layer, INL). We performed single cell RNA sequencing of mice and non-human primate retinas in collaboration with Dr. Fischer (OSU) and concluded that Batten Disease vision specific gene therapy needs to target a wide range of cells, including the INL, which is a major challenge for translation of a vision specific therapy to the clinic.

We have recently discovered that administration of neuraminidase (NA), a sialidase enzyme, prior to or in combination with AAV9.GFP, drastically increases transduction throughout the murine C57Bl/6 retina including the INL and all the way through to the photoreceptor layer. Our preliminary data indicates GFP expression in almost all, if not all, retinal cell types using this method. Importantly, we have confirmed successful targeting of INL bipolar cells, a notoriously difficult cell-type to transduce, and up to 40% increase in Müller glia transduction. Preliminary histological examination indicates no damage or alterations in retinal integrity.

While additional testing in large animal models is required and scheduled to occur in a WT pig model in Autumn 2020, this remarkable discovery suggests that it may now be possible to target every cell-type of the retina with a single AAV vector. This is especially important in regard to treatment of Batten Disease but has many additional implications. Current retinal therapies that require a more invasive subretinal delivery to photoreceptors could now opt for the safer intravitreal delivery strategy. In addition, this strategy would be highly useful in the field of optogenetics, where investigators continue to struggle to find an efficient way to express light-sensitive opsins in cells of the INL to restore sight in individuals that have already lost their photoreceptors.

  • Open access
  • 118 Reads
AAV Gene Therapy for noise induced hearing loss using cerebrospinal fluid as route of delivery

Noise-induced hearing loss (NIHL) is one of the most prevalent disabilities for which effective therapeutic treatment is currently lacking. Auditory injury caused by excessive or constant noise exposure damages the sensory elements of the ear, leading to metabolic or mechanical damage to hair cells and subsequent degeneration of spiral ganglion neurons (SGNs). To improve hearing in the NIHL patient population, maintenance and regeneration of inner hair cell-SGN synapses is critical. Although effective compounds for the treatment of NIHL have been suggested, challenges in delivery of the compounds to the inner hair cells (IHCs) hinder translation of these therapies to a clinical setting. Current routes of administration are ineffective in reaching IHCs or are invasive and may damage the cochlea. In this study, we examined less invasive delivery routes, via intrathecal (cerebrospinal fluid delivery) or intravenous injection, to administer adeno-associated virus serotype 9 (AAV9) expressing green fluorescent protein (GFP) to target IHCs and SGNs. To induce auditory injury, mice were exposed to 100 dB sound pressure level (SPL) octave band noise for 2 hours. Mice were then injected at various time points post noise injury to determine if noise exposure influenced targeting efficiency. Three weeks post injection, cochleae were processed and analyzed for GFP expression using immunofluorescence. Our results demonstrate that intravenous delivery was not successful in targeting of IHCs or SGNs at any time point measured. However, intrathecally injected AAV9 was highly effective in targeting cells in both healthy and noise-damaged cochleae at multiple time points post-noise exposure. We conclude that gene therapy techniques can be utilized to efficiently deliver therapeutic transgenes to the cochlea using cerebrospinal fluid as a delivery route. These findings determine a novel route of delivery and open a new avenue of therapeutic treatment for auditory injury and cochlear disorders.

  • Open access
  • 220 Reads
Rapid reprogramming of ALS patient fibroblasts differentiates CuATSM responders from nonresponders.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for ALS. Moreover, the heterogeneity of the ALS patient population is not reflected in currently available transgenic animal models making direct translation of potential therapeutics difficult. To address this, we utilize direct conversion technology to transform skin biopsies from ALS patients into neuronal progenitor cells (NPC). Using induced astrocytes (iAs) differentiated from these NPCs in co-culture with mouse embryonic motor neurons, we developed an in vitro ALS model to screen potential therapeutics. We have screened numerous compounds on multiple sporadic (sALS) and familial (fALS, mtSOD1 and C9ORF72) iAs and observed a diverse patient response to different therapeutic agents. Here, we utilize the compound, CuATSM, to subgroup therapeutic responsiveness of patient lines and identified shared dysfunctional pathways between responders. Following detailed analysis of ALS disease markers, elevated mitochondrial activity states was present in all CuATSM responders and was nonexistent in nonresponders. Treatment of iAs with CuATSM restored this activity to healthy control levels. Together, these findings suggest that iAs can be used to identify both disease modifiers and pathways dysregulated in an individual. Thus enhanced understanding of cellular profiles could facilitate personalized medicine based treatments.

  • Open access
  • 102 Reads
The role of paraoxonase 1 (PON1) as an oxidation marker, in muscle improvement after increased beta-hydroxybutyrate (BHB) in blood, in patients with multiple sclerosis

Various studies have concluded that in multiple sclerosis (MS) metabolic changes related to energy alterations are generated at the mitochondrial level. These changes produce loss of muscle mass and lead to high levels of oxidative stress related to low levels of the enzyme Paraoxonase 1 (PON1). The ketone bodies, mainly beta-hydroxybutyrate (BHB), restore this energetic alteration by improving muscular activity.

This pilot study was conducted over 4 months with 51 patients diagnosed with MS, randomly divided into: an intervention group that received an isocaloric diet of a Mediterranean origin supplemented with 60 ml of coconut oil; and a control group that received the same base diet but without coconut oil. Before and after treatment, anthropometric measurements and blood samples were taken, measuring serum PON1 and BHB concentrations, to determine the role of PON1 in muscle improvement after increased blood BHB in MS patients.

A significant increase in PON1 was obtained, associated with an increase in lean mass and an increase in BHB, so it was concluded that this enzyme appeared to be a good marker of decreased oxidation status in MS patients showing muscle improvement after increased BHB in blood.

  • Open access
  • 68 Reads
Neural states in tourism travel videos
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In marketing, there are many methods to relate reactions from products to customer preference. Current EEG signal analysis in the neuromarketing field focuses mainly on correlations between selected electrodes and hemisphere-based analysis on single scalp measures. The present study shows microstate analysis of brain EEG signals in goal-oriented videos. We measured 16 channel EEG with an Emotiv EPOC+ device. We used two oriented videos from the Ecuadorian Government to publicize Ecuador as a touristic destination. We used a TAAHC microstate analysis for all the long of the EEG from the participant watching each video. We picked the four predominant, in total time and repeatability, microstates maps that represent more than 50% of the time from all recording. We also show in time how topographies are represented along the video which could be in a later step be correlated with the images observed in the videos. We show the existing relations between the existing microstates. Brain signals behavior along time in a microstate analysis might be a valid methodology and useful tool to analyze videos with marketing purposes.

  • Open access
  • 391 Reads
Identification of a novel disease mechanism and development of therapeutics for the recently identified neurodevelopmental disease “NEDAMSS”

NEDAMSS is a newly discovered neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures. The disease is caused by heterozygous mutations in the Interferon Regulatory Factor 2 Binding Protein-Like (IRF2BPL) gene. IRF2BPL is a ubiquitously expressed intron-less transcriptional regulator. The function of the protein is currently unknown, but the observed disease phenotype indicates a role in development and maintenance of the nervous system. To study this disease, we used patient skin-derived fibroblasts and reprogrammed them into induced neuronal progenitor cells (iNPCs). The iNPCs were then differentiated into astrocytes. Moreover, we also used a direct conversion method to generate neurons directly from the skin fibroblasts. Using these methods and performing molecular and functional analyses of the different cell types, we identified a novel disease mechanism not previously described. While IRF2BPL is localized in the nucleus in healthy individuals, we found that several patient cell lines displayed mis-localization in the form of aggregates in the cytoplasm. Moreover, the patient astrocytes also showed abnormal mitochondrial ATP-linked respiration levels and caused neuronal death in co-culture assays. Based on these observations, we tested treatment with CuATSM, a small molecule drug currently in clinical trials for ALS. We found that CuATSM successfully rescued neuronal survival and reduced ATP-linked respiration to normal levels in NEDAMSS astrocytes. We also established multiple AAV based gene therapy tools to modulate the expression of the protein and restore its normal function in vitro and potentially in vivo. In summary, we identified a novel disease mechanism involved in NEDAMSS disease and found promising therapeutic strategies that might be able to slow or halt the progression of the disease.

  • Open access
  • 81 Reads
Terpenic compounds in Chilean species of the genus Blechnum (Pteridophyta: Blechnaceae) with neuroprotective potential
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The genus Blechnum L. includes a large variety of species native to central and southern continental Chile: B. arcuatum, B. asperum, B. blechnoides, B. chilense, B. corralense, B hastatum, B. magellanicum, B. microphyllum, B. mochaenum and B. penna-marina containing compounds such as flavonols, hydroxycinnamic acids, lignans, and phytoecdysones. In this examination, terpenic compounds of the phytoecdysone type with pharmacological potential on the central nervous system are detailed. These compounds are characterized by a C27, C28 or C29 structure that possesses a 14-alpha-hydroxy-7-en-6-one chromophore and an A/B-cis (5beta-H) ring fusion that can be extracted from the plant with organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, and ethanol, are concentrated in a reduced pressure rotary evaporator and are identified by gas chromatography coupled to a mass spectrometry detector (GC-MS) or a tandem ionization electrospray network detector UHPLC-DAD-ESI-MS/MS. Phytoecdysones applied in vitro and in vivo models of neurodegenerative diseases such as Parkinson's and Alzheimer's at concentrations between 100 and 500 µg/ml, can modulate the enzymatic inhibition of monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) with zero toxicity effects and satisfactory results in cell viability.

  • Open access
  • 82 Reads
Inflammatory biomarkers in febrile seizure: a comprehensive bibliometric, review and visualization analysis

Background: Inflammatory markers association with many diseases was the subject of many articles and reviews. This study presents a comprehensive bibliometric, review and visualization analysis of inflammatory biomarkers (IB) in the context of febrile seizure (FS) patients.

Methods: The study focused on the IB in FS using (1) bibliometric analysis specific indicators and maps in order to analyze and present the network of authors, journals, universities, and countries, (2) automated literature screening and unsupervised clustering approach for filtering and topic cluster identification.

Results: We conducted a literature mining search on FS research, specifically IB in the context of FS, using automated tools VOSViewer and Adjutant. The presentation and discussions on the resulted bibliometric maps and topic clusters offer a comprehensive overview, status and leading trends on existing research of inflammatory biomarkers in FS.


The analysis using bibliometric and review with graphical presentations can be very useful in investigating and better understanding of the relationship of FS and IB.

  • Open access
  • 94 Reads
Sleep/wake cycle and EEG-based biomarkers during neonate to adult transition in C57BL/6 mice

During the transition from neonate to adulthood, brain maturation establishes coherence between behavioral states—wakefulness, non-rapid eye movement, and rapid eye movement sleep. Few studies have characterized and analyzed cerebral rhythms and the sleep–wake cycle in early ages, in relation to adulthood. Since the analysis of sleep in early ages can be used as a predictive model of brain development and the subsequent emergence of neural disturbances in adults, we performed a study on late neonatal and adult wild-type C57BL/6 mice. We acquired longitudinal 24 h electroencephalogram and electromyogram recordings and performed time and spectral analyses. We compared both age groups and found that late neonates: (i) spent moderately more time in wakefulness and less time in non-rapid eye movement sleep, (ii) showed an increased relative band power in delta, which, however, reduced in theta during each behavioral state, (iii) showed a reduced relative band power in beta during wakefulness and non-rapid eye movement sleep, and (iv) manifested an increased total power over all frequencies. Given the mice–human age equivalence, the data presented here might have implications for the clinical context in the analysis of electroencephalogram for sleep-based early and late diagnosis after injury or neurodegeneration.

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