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The Fibroblast growth factor (FGFs) family consists of at least 22 members that exert their function by binding and activating fibroblast growth factor receptors (FGFRs). The Fgf8/FgfD subfamily member, Fgf17, is located on human chromosome 8p21.3 and mouse chromosome 14 D2. In humans, FGF17 can be alternatively spliced to produce two isoforms (FGF17a and b) whereas three isoforms are present in mice (Fgf17a, b, and c), however, only Fgf17a and Fgf17b produce functional proteins. Fgf17 is a secreted protein with a cleavable N-terminal signal peptide and contains two binding domains, namely a conserved core region and a heparin binding site. Fgf17 mRNA is expressed in a wide range of different tissues during development, including the rostral patterning centre, midbrain-hindbrain boundary, tailbud mesoderm, olfactory placode, mammary glands, and smooth muscle precursors of major arteries. Given its broad expression pattern during development, it is surprising that adult Fgf17 -/- mice displayed a rather mild phenotype; such that mutants only exhibited morphological changes in the frontal cortex and mid/hind brain boundary and changes in certain social behaviours. In humans, FGF17 mutations are implicated in several diseases, including Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome. FGF17 mutations contribute to CHH/KS in 1.1% of affected individuals, often presenting in conjunction with mutations in other FGF pathway genes like FGFR1 and FLRT3. FGF17 mutations were also identified in patients diagnosed with Dandy-Walker malformation and Pituitary Stalk Interruption Syndrome, however, it remains unclear how FGF17 is implicated in these diseases. Altered FGF17 expression has been observed in several cancers, including prostate cancer, hematopoietic cancers (acute myeloid leukemia and acute lymphoblastic leukemia), glioblastomas, perineural invasion in cervical cancer, and renal cell carcinomas. Furthermore, FGF17 has demonstrated neuroprotective effects, particularly during ischemic stroke, and has been shown to improve cognitive function in ageing mice., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996-August 1998) and STICLO Italy (April 1999-October 2000), but data were not fully exploited at the time., Methods: This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes., Results: Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients' mean and median (25%; 75%) age were 9.2 years (range 3.0-20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic-clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group., Conclusion: Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials., (© 2024. The Author(s).)

Background: In juvenile systemic lupus erythematosus (j-SLE) with neuropsychiatric (NP) symptoms, there is a lack of diagnostic biomarkers. Thus, we study whether PET-FDG may identify any metabolic dysfunction in j-NPSLE., Methods: A total of 19 18 FDG-PET exams were consecutively performed using PET-MRI system in 11 non-sedated patients presenting with j-NPSLE (11-18y) for less than 18 months (m) and without any significant lesion at MRI. Psychiatric symptoms were scored from 0 (none) to 3 (severe) at PET time. PET images were visually analyzed and voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (spm) with an age-matched control group, at threshold set > 50 voxels using both p < 0.001 uncorrected (unc.) and p < 0.05 corrected family wise error (FWE)., Results: Patients exhibited mainly psychiatric symptoms, with diffuse inflammatory j-NPSLE. First PET (n = 11) was performed at a mean of 15y of age, second/third PET (n = 7/n = 1) 6 to 19 m later. PET individual analysis detected focal bilateral anomalies in 13/19 exams visually but 19/19 using spm (unc.), mostly hypermetabolic areas (18/19). A total of 15% of hypermetabolic areas identified by spm had been missed visually. PET group analysis (n = 19) did not identify any hypometabolic area, but a large bilateral cortico-subcortical hypermetabolic pattern including, by statistical decreasing order (unc.), thalamus, subthalamic brainstem, cerebellum (vermis and cortex), basal ganglia, visual, temporal and frontal cortices. Mostly the subcortical hypermetabolism survived to FWE analysis, being most intense and extensive (51% of total volume) in thalamus and subthalamus brainstem. Hypermetabolism was strictly subcortical in the most severe NP subgroup (n = 8, scores 2-3) whereas it also extended to cerebral cortex, mostly visual, in the less severe subgroup (n = 11, scores 0-1), but difference was not significant. Longitudinal visual analysis was inconclusive due to clinical heterogeneity., Conclusions: j-NPSLE patients showed a robust bilateral cortico-subcortical hypermetabolic network, focused subcortically, particularly in thalamus, proportionally to psychiatric features severity. Further studies with larger, but homogeneous, cohorts are needed to determine the sensitivity and specificity of this dysfunctional pattern as a potential biomarker in diffuse inflammatory j-NPSLE with normal brain MRI., (© 2024. The Author(s).)

Objectives: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS., Methods: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs., Results: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter., Significance: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS., Plain Language Summary: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial., Methods: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc., Results: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints., Interpretation: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure., (© 2024 UCB Biopharma SRL. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: This study was undertaken to evaluate our treatment algorithm for infantile epileptic spasms syndrome (IESS) used between 2000 and 2018. We initiated vigabatrin (VGB), and steroids were added if the electroclinical response (spasms and electroencephalogram [EEG]) to VGB was not obtained or incomplete., Methods: Individuals with IESS treated with VGB were recruited from our hospital clinical data warehouse based on electronic health records (EHRs) generated since 2009 and containing relevant keywords. We confirmed the diagnosis of IESS. Clinical, EEG, imaging, and biological data were extracted from the EHRs. We analyzed factors associated with short-term response, time to response, relapse, time to relapse of spasms, and the presence of spasms at last follow-up., Results: We collected data from 198 individuals (female: 46.5%, IESS onset: 6 [4.5-10.3] months, follow-up: 4.6 [2.5-7.6] years, median [Q1-Q3]) including 129 (65.2%) with identifiable etiology. VGB was started 17 (5-57.5) days after IESS diagnosis. A total of 113 individuals were responders (57.1% of the cohort), 64 with VGB alone and 38 with VGB further combined with steroids (56.6% and 33.6% of responders, respectively). Among responders, 33 (29%) experienced relapses of spasms, mostly those with later onset of spasms (p = .002) and those who received VGB for <24 months after spasms cessation compared to a longer duration on VGB (45% vs. 12.8%, p = .003). At follow-up, 92 individuals were seizure-free (46.5% of the whole cohort), including 26 free of therapy (13.1%). One hundred twelve individuals (56.6%) were still receiving VGB, with a duration of 3.2 (1.75-5.7) years., Significance: Our sequential protocol introducing VGB then adding steroids is an effective alternative to a combined VGB-steroids approach in IESS. It avoids steroid-related adverse events, as well as those from VGB-steroid combination. According to our data, a period of 7 days seems sufficient to assess VGB response and enables the addition of steroids rapidly if needed. Continuing VGB for 2 years may balance the risk of relapse and treatment-induced adverse events., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Aim: To evaluate the safety and efficacy of stiripentol initiated before 2 years of age in patients with Dravet syndrome., Method: This was a 30-year, real-world retrospective study. We extracted the data of the 131 patients (59 females, 72 males) who initiated stiripentol before 2 years of age between 1991 and 2021 from the four longitudinal databases of Dravet syndrome available in France., Results: Stiripentol was added to valproate and clobazam (93%) at 13 months and a median dose of 50 mg/kg/day. With short-term therapy (<6 months on stiripentol, median 4 months, median age 16 months), the frequency of tonic-clonic seizures (TCS) lasting longer than 5 minutes decreased (p < 0.01) and status epilepticus (>30 minutes) disappeared in 55% of patients. With long-term therapy (last visit on stiripentol <7 years of age, median stiripentol 28 months, median age 41 months), the frequency of long-lasting TCS continued to decline (p = 0.03). Emergency hospitalizations dropped from 91% to 43% and 12% with short- and long-term therapies respectively (p < 0.001). Three patients died, all from sudden unexpected death in epilepsy. Three patients discontinued stiripentol for adverse events; 55% reported at least one adverse event, mostly loss of appetite/weight (21%) and somnolence (11%). Stiripentol was used earlier, at lower doses, and was better tolerated by patients in the newest database than in the oldest (p < 0.01)., Interpretation: Initiating stiripentol in infants with Dravet syndrome is safe and beneficial, significantly reducing long-lasting seizures including status epilepticus, hospitalizations, and mortality in the critical first years of life., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

In vitro validation of therapeutic and recombinant proteins expressed from transgenic chickens is limited by the co-culture of fibroblasts. Here, we present a protocol for isolating pure epithelial cells derived from the magnum tubular glands of the chicken oviduct. We describe steps for preparing solutions and buffers, tissue collection, processing, dissociation, and Percoll density centrifugation to separate the epithelial cells from co-isolated fibroblasts. We then detail procedures for expressing a recombinant IgG antibody in the Percoll-derived epithelial cell line., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Melanophilin is a myosin adaptor required for transporting the pigment melanin within cells. Loss of melanophilin in fish, birds, and mammals causes pigmentation defects, but little is known about the role of melanophilin in non-avian reptiles. Here we show that a frameshift in the melanophilin gene in ball python ( P. regius ) is associated with loss of pigment from shed skin. This variant is predicted to remove the myosin-binding domain of melanophilin and thereby impair transport of melanin-containing organelles. Our study represents the first description of a melanophilin variant in a non-avian reptile and confirms the role of melanophilin across vertebrates., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2023 by the authors.)

Background: Focal cortical dysplasias (FCD) are a frequent cause of drug-resistant epilepsy in children but are often undetected on structural magnetic resonance imaging (MRI). We aimed to measure and validate the variation of resting state functional MRI (rs-fMRI) blood oxygenation level dependent (BOLD) metrics in surgically proven FCDs in children, to assess the potential yield for detecting and understanding these lesions., Methods: We prospectively included pediatric patients with surgically proven FCD with inconclusive structural MRI and healthy controls, who underwent a ten-minute rs-fMRI acquired at 3T. Rs-fMRI data was pre-processed and maps of values of regional homogeneity (ReHo), degree centrality (DC), amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) were calculated. The variations of BOLD metrics within the to-be-resected areas were analyzed visually, and quantitatively using lateralization indices. BOLD metrics variations were also analyzed in fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolic areas., Results: We included 7 patients (range: 3-15 years) and 6 aged-matched controls (range: 6-17 years). ReHo lateralization indices were positive in the to-be-resected areas in 4/7 patients, and in 6/7 patients in the additional PET hypometabolic areas. These indices were significantly higher compared to controls in 3/7 and 4/7 patients, respectively. Visual analysis revealed a good spatial correlation between high ReHo areas and MRI structural abnormalities (when present) or PET hypometabolic areas. No consistent variation was seen using DC, ALFF, or fALFF., Conclusion: Resting-state fMRI metrics, noticeably increase in ReHo, may have potential to help detect MRI-negative FCDs in combination with other morphological and functional techniques, used in clinical practice and epilepsy-surgery screening., Competing Interests: V.D.-R. was partially funded by GE Healthcare. Other authors have no relevant conflict of interest to disclose., (Thieme. All rights reserved.)

Background: Focal cortical dysplasia (FCD) causes drug-resistant epilepsy in children that can be cured surgically, but the lesions are often unseen by imaging., Objective: To assess the efficiency of arterial spin labeling (ASL), voxel-based-morphometry (VBM), fMRI electroencephalography (EEG), resting-state regional homogeneity (ReHo), 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their combination in detecting pediatric FCD., Methods: We prospectively included 10 children for whom FCD was localized by surgical resection. They underwent 3T MR acquisition with concurrent EEG, including ASL perfusion, resting-state BOLD fMRI (allowing the processing of EEG-fMRI and ReHo), 3D T1-weighted images processed using VBM, and FDG PET-CT coregistered with MRI. Detection was assessed visually and by comparison with healthy controls (for ASL and VBM)., Results: Eight children had normal MRI, and 2 had asymmetric sulci. Using MR techniques, FCD was accurately detected by ASL for 6/10, VBM for 5/10, EEG-fMRI for 5/8 (excluding 2 with uninterpretable results), and ReHo for 4/10 patients. The combination of ASL, VBM, and ReHo allowed correct FCD detection for 9/10 patients. FDG PET alone showed higher accuracy than the other techniques (7/9), and its combination with VBM allowed correct FCD detection for 8/9 patients. The detection efficiency was better for patients with asymmetric sulci (2/2 for all techniques), but advanced MR techniques and PET were useful for MR-negative patients (7/8)., Conclusion: A combination of multiple imaging techniques, including PET, ASL, and VBM analysis of T1-weighted images, is effective in detecting subtle FCD in children., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass. The relative bioavailability of granules A versus syrup, based on dose-normalized C max and AUC 0-∞ was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed t max of 0.75 h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30 min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable profile for pediatric use, being sugar-free, tasteless, bioequivalent, and well-tolerated while enabling precise adjustment to body weight., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Objective: Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization., Methods: Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1 +/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC., Results: Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1 +/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC., Interpretation: Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission., (© 2022 International League Against Epilepsy.)

Outer membrane protein A (OmpA) is one of the most abundant outer membrane proteins of Gram-negative bacteria and is known to have patterns of sequence variations at certain amino acids-allelic variation-in Escherichia coli. Here we subjected seven exemplar OmpA alleles expressed in a K-12 (MG1655) ΔompA background to further characterization. These alleles were observed to significantly impact cell surface charge (zeta potential), cell surface hydrophobicity, biofilm formation, sensitivity to killing by neutrophil elastase, and specific growth rate at 42°C and in the presence of acetate, demonstrating that OmpA is an attractive target for engineering cell surface properties and industrial phenotypes. It was also observed that cell surface charge and biofilm formation both significantly correlate with cell surface hydrophobicity, a cell property that is increasingly intriguing for bioproduction. While there was poor alignment between the observed experimental values relative to the known sequence variation, differences in hydrophobicity and biofilm formation did correspond to the identity of residue 203 (N vs T), located within the proposed dimerization domain. The relative abundance of the (I, δ) allele was increased in extraintestinal pathogenic E. coli (ExPEC) isolates relative to environmental isolates, with a corresponding decrease in (I, α) alleles in ExPEC relative to environmental isolates. The (I, α) and (I, δ) alleles differ at positions 203 and 251. Variations in distribution were also observed among ExPEC types and phylotypes. Thus, OmpA allelic variation and its influence on OmpA function warrant further investigation., Competing Interests: The authors have declared that no competing interests exist.