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Prolonged neonatal seizures are often due to severe acute brain injuries and are known to be harmful to the brain. No predictors have yet been identified to distinguish at an early time-point between brief and long seizures. We investigated the duration of seizures in neonates to determine the relationship between the duration of a seizure and that of subsequent seizures. We retrospectively reviewed video-electroencephalogram confirmed seizures of 30 preterm and 36 full-term neonates selected from patients admitted to the neonatal intensive care unit of Parma University Hospital. The duration and relationship between successive seizures were investigated. Statistical models were performed to evaluate the risk of long-lasting ictal events among neonates with seizures. A positive monotonic relationship between the duration of successive seizures was identified. Most seizures were brief. No significant differences in seizure duration were found between preterm and full-term neonates, although a borderline significance emerged. Neonatal seizures are usually brief, and as the seizure duration increases, the duration of the subsequent seizures tends to increase. We also suggest that full-term neonates could be at higher risk of experiencing long seizures compared to preterm neonates. In summary, estimating the seizure duration is critical to evaluating the optimal timing of therapeutic interventions and can help to predict how seizures evolve. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EVs) are membrane-enclosed particles released systemically by all cells, including tumours. Tumour EVs have been shown to manipulate their local environments as well as distal targets to sustain the tumour in a variety of tumours, including glioblastoma (GBM). We have previously demonstrated the dual role of the glial water channel aquaporin-4 (AQP4) protein in glioma progression or suppression depending on its aggregation state. However, its possible role in communication mechanisms in the microenvironment of malignant gliomas remains to be unveiled. Results: Here we show that in GBM cells AQP4 is released via EVs that are able to affect the GBM microenvironment. To explore this role, EVs derived from invasive GBM cells expressing AQP4-tetramers or apoptotic GBM cells expressing orthogonal arrays of particles (AQP4-OAPs) were isolated, using a differential ultracentrifugation method, and were added to pre-seeded GBM cells. Confocal microscopy analysis was used to visualize the interaction and uptake of AQP4-containing EVs by recipient cells. Chemoinvasion and Caspase3/7 activation assay, performed on recipient cells after EVs uptake, revealed that EVs produced by AQP4-tetramers expressing cells were able to drive surrounding tumour cells toward the migratory phenotype, whereas EVs produced by AQP4-OAPs expressing cells drive them toward the apoptosis pathway. Conclusion: This study demonstrates that the different GBM cell phenotypes can be transferred by AQP4-containing EVs able to influence tumour cell fate toward invasiveness or apoptosis. This study opens a new perspective on the role of AQP4 in the brain tumour microenvironment associated with the EV-dependent communication mechanism. [ABSTRACT FROM AUTHOR]

The important role of the EEG in preterm and term babies in investigating brain function and seizures, predicting outcomes, evaluating therapeutic interventions and decision-making is being increasingly acknowledged. Development of the brain in the last trimester of pregnancy results in rapid changes in the EEG patterns in this period. Acquiring and interpreting the EEG of a preterm baby can be challenging. The aim of this study was to develop a proforma titled CARFS7 (Continuity, Amplitude, Reactivity, Frequency, Synchrony, Symmetry, Sleep, Sharps, Shapes, Size and Seizures) to enable neurologists to read EEGs of premature babies with greater confidence, ease and accuracy and produce a report more easily repeatable and homogenous among operators. The CARFS7proforma was developed based on a literature review and the personal experience of the authors. The parameters of the EEG evaluated and scored in the proforma are Continuity, Amplitude, Reactivity/Variability, Frequency, Synchrony, Symmetry, Sleep, Sharps, Shapes/Patterns, Size and Seizures. We also assessed the interrater reliability of the proposed scoring system incorporated in the proforma. CARFS7 proforma incorporates a number of parameters that help evaluate the preterm EEG. The interrater reliability of the proposed scoring system in the CARFS7proforma was high. CARFS7 is a user friendly proforma for reading EEGs in the preterm infant. Interrater reliability using Cohen's k shows high agreement between two child neurologists who independently rated the EEGs of 25 premature babies using this proforma. CARFS7 has the potential to provide, accurate, reproducible and valuable information on brain function in the preterm infant in clinical practice. [ABSTRACT FROM AUTHOR]

A major player in the homeostatic response to hypoxia is the hypoxia-inducible factor (HIF)-1 that transactivates a number of genes involved in neovessel proliferation in response to low oxygen tension. In the retina, hypoxia overstimulates β-adrenoceptors (β-ARs) which play a key role in the formation of pathogenic blood vessels. Among β-ARs, β3-AR expression is increased in proliferating vessels in concomitance with increased levels of HIF-1α and vascular endothelial growth factor (VEGF). Whether, similarly to VEGF, hypoxia-induced β3-AR upregulation is driven by HIF-1 is still unknown. We used the mouse model of oxygen-induced retinopathy (OIR), an acknowledged model of retinal angiogenesis, to verify the hypothesis of β3-AR transcriptional regulation by HIF-1. Investigation of β3-AR regulation over OIR progression revealed that the expression profile of β3-AR depends on oxygen tension, similar to VEGF. The additional evidence that HIF-1α stabilization decouples β3-AR expression from oxygen levels further indicates that HIF-1 regulates the expression of the β3-AR gene in the retina. Bioinformatics predicted the presence of six HIF-1 binding sites (HBS #1-6) upstream and inside the mouse β3-AR gene. Among these, HBS #1 has been identified as the most suitable HBS for HIF-1 binding. Chromatin immunoprecipitation-qPCR demonstrated an effective binding of HIF-1 to HBS #1 indicating the existence of a physical interaction between HIF-1 and the β3-AR gene. The additional finding that β3-AR gene expression is concomitantly activated indicates the possibility that HIF-1 transactivates the β3-AR gene. Our results are indicative of β3-AR involvement in HIF-1-mediated response to hypoxia. [ABSTRACT FROM AUTHOR]

Refractive freeform components are becoming increasingly relevant for generating controlled patterns of light, because of their capability to spatially modulate optical signals with high efficiency and low background. However, the use of these devices is still limited by difficulties in manufacturing macroscopic elements with complex, 3D surface reliefs. Here, 3D‐printed and stretchable magic windows generating light patterns by refraction are introduced. The shape and, consequently, the light texture achieved can be changed through controlled device strain. Cryptographic magic windows are demonstrated through exemplary light patterns, including micro‐QR‐codes, that are correctly projected and recognized upon strain gating while remaining cryptic for as‐produced devices. The light pattern of micro‐QR‐codes can also be projected by two coupled magic windows, with one of them acting as the decryption key. Such novel, freeform elements with 3D shape and tailored functionalities is relevant for applications in illumination design, smart labels, anti‐counterfeiting systems, and cryptographic communication. [ABSTRACT FROM AUTHOR]

Intrusion detection tools have largely benefitted from the usage of supervised classification methods developed in the field of data mining. However, the data produced by modern system/network logs pose many problems, such as the streaming and non-stationary nature of such data, their volume and velocity, and the presence of imbalanced classes. Classifier ensembles look a valid solution for this scenario, owing to their flexibility and scalability. In particular, data-driven schemes for combining the predictions of multiple classifiers have been shown superior to traditional fixed aggregation criteria (e.g., predictions' averaging and weighted voting). In intrusion detection settings, however, such schemes must be devised in an efficient way, since (part of) the ensemble may need to be re-trained frequently. A novel ensemble-based framework is proposed here for the online intrusion detection, where the ensemble is updated through an incremental stream-oriented learning scheme, correspondingly to the detection of concept drifts. Differently from mainstream ensemble-based approaches in the field, our proposal relies on deriving, though an efficient genetic programming (GP) method, an expressive kind of combiner function defined in terms of (non-trainable) aggregation functions. This approach is supported by a system architecture, which integrates different kinds of functionalities, ranging from the drift detection, to the induction and replacement of base classifiers, up to the distributed computation of GP-based combiners. Experiments on both artificial and real-life datasets confirmed the validity of the approach. [ABSTRACT FROM AUTHOR]

The advent of cochlear implants has enormously improved the quality of sensory perception in deaf children. Notwithstanding these advantages, the current literature shows a substantial variability in language proficiency among implanted children. This case series explores the variability of language acquisition in congenitally deaf children with cochlear implants. We report 4 prelingually deaf children (mean age=10.5; SD=1.08), affected by a genetically determined bilateral deafness, due to GJB2 gene mutation Cx26. Each implanted child underwent a systematic assessment of speech perception and production, as well as of lexical, morphologic, and syntactic skills in both comprehension and production. Notwithstanding similar clinical histories and similarly good postimplant pure-tone audiometry, two of the four children fared very poorly in speech audiometry, whereas the other two children gained very good results. We suggest that the language impairment detected in (some) implanted children may not be fully accounted for by pure auditory thresholds and that may be the outcome of concomitant damage to core components of the child's linguistic brain. [ABSTRACT FROM AUTHOR]

Blockchain is receiving considerable attention among practitioners and academics. However, a detailed analysis investigating how the impact of blockchain is going to unfold is still missing. Our article sets out to assess the radicalness of blockchain at an early stage of its development and substantiates the analysis with evidence from the payments industry. We start by distilling five key aspects of radical innovation from extant literature. Our analysis of blockchain then focuses on the payments industry, which represents a major business field of banking and the cradle of this technology. The results of a Delphi study provide 17 statements about the current development of blockchain. The statements deliver insights into the impact of blockchain on the payments industry and reveal the radicalness of the technology. Based on these insights, we investigate how blockchain affects the five key aspects of radical innovation and develop contributions from an innovation management's perspective. [ABSTRACT FROM AUTHOR]

Summary: Objective: Information about the incidence of neonatal seizures (NS) is scarce. Previous studies relied primarily on a clinical diagnosis of seizures. This population‐based, retrospective study evaluated the incidence of electroencephalography (EEG)–confirmed seizures in neonates born in the province of Parma and the perinatal risk factors for mortality and epilepsy. Methods: All neonates with suspected seizures or with medical conditions at high risk for seizures from the study area were recorded in the neonatal intensive care unit (NICU) of the Parma University Hospital. NS were EEG confirmed. Perinatal risk factors for mortality and epilepsy after NS were evaluated with Cox’s proportional hazards models. Results: In a 13‐year period, 112 patients presented with NS: 102 newborns had electroclinical seizures (46 full‐term and 56 preterm), whereas 10 presented only electrical seizures. The incidence was 2.29/1000 live births (95% confidence interval [CI] 1.87‐2.72), with higher rates in preterm neonates (14.28/1000 in preterm vs 1.10/1000 in full‐term infants). The incidence increased with decreasing gestational age (31‐36 weeks of gestation: 5.01/1000, 28‐30: 54.9/1000, and <28: 85.6/1000) and with decreasing birth weight (≥2500 g: 1.19/1000, <1000 g: 127.57/1000). Twenty‐eight patients (25%) died, 16 (14.3%) had a diagnosis of epilepsy, 33 (29.5%) had cerebral palsy, and 39 (34.8%) had a developmental delay. Among the perinatal risk factors considered, the multivariate analysis showed an association between a 5‐minute Apgar score of 0‐7 and etiology with increased mortality and between female gender and status epilepticus with epilepsy. Significance: The incidence of NS is inversely associated with gestational age and birth weight. The etiology and a low Apgar score are strongly related to mortality; female gender and status epilepticus are risk factors for the development of epilepsy. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) is the CNS water channel organized into well-ordered protein aggregates called Orthogonal Arrays of Particles (OAPs). Neuromyelitis Optica (NMO) is an autoimmune disease caused by anti-OAP autoantibodies (AQP4-IgG). Molecular Dynamics (MD) simulations have identified an H-bond between L53 and T56 as the key for AQP4 epitope and therefore of potential interest for drug design in NMO field. In the present study, we have experimentally tested this MD-prediction using the classic mutagenesis approach. We substituted T56 with V56 and tested this mutant for AQP4 aggregates and AQP4-IgG binding. gSTED super-resolution microscopy showed that the mutation does not affect AQP4 aggregate dimension; immunofluorescence and cytofluorimetric analysis demonstrated its unaltered AQP4-IgG binding, therefore invalidating the MD-prediction. We later investigated whether AQP4, expressed in Sf9 insect and HEK-293F cells, is able to correctly aggregate before and after the purification steps usually applied to obtain AQP4 crystal. The results demonstrated that AQP4-IgG recognizes AQP4 expressed in Sf9 and HEK-293F cells by immunofluorescence even though BN-PAGE analysis showed that AQP4 forms smaller aggregates when expressed in insect cells compared to mammalian cell lines. Notably, after AQP4 purification, from both insect and HEK-293F cells, no aggregates are detectable by BN-PAGE and AQP4-IgG binding is impaired in sandwich ELISA assays. All together these results indicate that 1) the MD prediction under analysis is not supported by experimental data and 2) the procedure to obtain AQP4 crystals might affect its native architecture and, as a consequence, MD simulations. In conclusion, given the complex nature of the AQP4 epitope, MD might not be the suitable for molecular medicine advances in NMO. [ABSTRACT FROM AUTHOR]

Due to the increasing number of surviving preterm newborns and to the recognition of therapeutic hypothermia as the current gold standard in newborns with hypoxic-ischaemic encephalopathy, there has been a growing interest in the implementation of brain monitoring tools in newborns at high risk for neurological disorders. Among the most frequent neurological conditions and presentations in the neonatal period, neonatal seizures and neonatal status epilepticus, paroxysmal non-epileptic motor phenomena, hypoxic-ischaemic encephalopathy, white matter injury of prematurity and stroke require specific approaches to diagnosis. In this review we will describe the characteristics, aims, indications and limitations of routinely available diagnostic techniques such as conventional and amplitude-integrated EEG, evoked potentials, cranial ultrasound and brain MRI. We will conclude by briefly outlining potential future perspectives from research studies. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) is the Central Nervous System water channel highly expressed at the perivascular glial domain. In the retina, two types of AQP4 expressing glial cells take part in the blood-retinal barrier (BRB), astrocytes and Müller cells. The aim of the present study is to investigate the effect of AQP4 deletion on the retinal vasculature by looking at typical pathological hallmark such as BRB dysfunction and gliotic condition. AQP4 dependent BRB properties were evaluated by measuring the number of extravasations in WT and AQP4 KO retinas by Evans blue injection assay. AQP4 deletion did not affect the retinal vasculature, as assessed by Isolectin B 4 staining, but caused BRB impairment to the deep plexus capillaries while the superficial and intermediate capillaries were not compromised. To investigate for gliotic responses caused by AQP4 deletion, Müller cells and astrocytes were analysed by immunofluorescence and western blot, using the Müller cell marker Glutamine Synthetase (GS) and the astrocyte marker GFAP. While GS expression was not altered in AQP4 KO retinas, a strong GFAP upregulation was found at the level of AQP4 KO astrocytes at the superficial plexus and not at Müller cells at the intermediate and deep plexi. These data, together with the upregulation of inflammatory markers (TNF-α, IL-6, IL-1β and ICAM-1) in AQP4 KO retinas indicated AQP4 deletion as responsible for a gliotic phenotype. Interestingly, no GFAP altered expression was found in AQP4 siRNA treated astrocyte primary cultures. All together these results indicate that AQP4 deletion is directly responsible for BRB dysfunction and gliotic condition in the mouse retina. The selective activation of glial cells at the primary plexus suggests that different regulatory elements control the reaction of astrocytes and Müller cells. Finally, GFAP upregulation is strictly linked to gliovascular crosstalk, as it is absent in astrocytes in culture. This study is useful to understand the role of AQP4 in the perivascular domain in the retina and its possible implications in the pathogenesis of retinal vascular diseases and of Neuromyelitis Optica, a human disease characterized by anti-AQP4 auto-antibodies. [ABSTRACT FROM AUTHOR]

Objectives We retrospectively analyze the diagnostic accuracy for paroxysmal abnormal facial movements, comparing one camera versus multi-camera approach. Background Polygraphic video-electroencephalogram (vEEG) recording is the current gold standard for brain monitoring in high-risk newborns, especially when neonatal seizures are suspected. One camera synchronized with the EEG is commonly used. Methods Since mid-June 2012, we have started using multiple cameras, one of which point toward newborns' faces. We evaluated vEEGs recorded in newborns in the study period betweenmid-June 2012 and the end of September 2014 and compared, for each recording, the diagnostic accuracies obtained with one-camera and multi-camera approaches. Results We recorded 147 vEEGs from 87 newborns and found 73 episodes of paroxysmal facial abnormal movements in 18 vEEGs of 11 newborns with the multicamera approach. By using the single-camera approach, only 28.8% of these events were identified (21/73). Ten positive vEEGs with multicamera with 52 paroxysmal facial abnormal movements (52/73, 71.2%) would have been considered as negative with the single-camera approach. Conclusions The use of one additional facial camera can significantly increase the diagnostic accuracy of vEEGs in the detection of paroxysmal abnormal facial movements in the newborns. [ABSTRACT FROM AUTHOR]

Antiepileptic drugs (AEDs) are frequently co-prescribed with new antidepressants (ADs) or new antipsychotics (APs). A PubMed search with no time limit was used to update the review of the clinically significant pharmacokinetic (PK) drug interactions DIs (DIs) between AEDs with new ADs and APs. Our best interpretation of what to expect regarding dosing changes in the average patient after combining AEDs with new ADs or new APs is summarized on updated tables that integrate the information on in vitro metabolism studies, therapeutic drug monitoring (TDM) studies, case report/series and prospective studies. There will be a need to periodically update these dose correction factors as new knowledge becomes available. These tables will provide some orientation to clinicians with no TDM access and may also encourage clinicians to further study TDM. The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone on new ADs and new APs and the inhibitory properties of valproic acid and some new ADs, are relatively well understood. On the other hand, PK DI studies combining new AEDs with weak inductive properties (particularly oxcarbazepine doses ≥ 1200 mg/day), topiramate doses ≥ 400 mg/day, clobazam, eslicarbazepine, and rufinamide), with new ADs and new APs are needed. Valproic acid may be 1) an inhibitor and/or inducer of clozapine and olanzapine with potential for clinically relevant DIs, 2) an inhibitor of paliperidone, and 3) a weak inducer of aripiprazole. Fluoxetine and fluvoxamine are relevant inhibitors of phenytoin and valproic acid and possibly of clobazam, lacosamide, phenobarbital, or primidone. [ABSTRACT FROM AUTHOR]

Themajority of neonatal seizures are of acute symptomatic origin, and their occurrence is associated with higher mortality and morbidity compared with the general population, even if there is conflicting evidence of a detrimental effect per se. Etiology is considered the main determinant of outcome, but other factors, including gestational age, brain damage severity, neonatal neurological examination, and electroencephalographically (EEG) interictal and ictal characteristics are also related to neurodevelopmental outcome or death. Therefore, accuracy in early prognostication since the neonatal period can be improved by conveniently integrating different clinical and instrumental findings. The aim of this review is first to review the outcome of newborns with seizures (mortality, epilepsy, cerebral palsy, and intellectual disability), second to review the risk factors for adverse outcome after seizures in the newborn period, considering clinical, EEG/amplitude-integrated EEG, and neuroimaging findings associated with adverse outcome and lack of response to treatment, and finally to review published scoring systems for predicting neurologic outcome after neonatal seizures. [ABSTRACT FROM AUTHOR]

Serological markers of Nuromyelitis Optica (NMO), an autoimmune disorder of the central nervous system, are autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). We have previously demonstrated that the main epitopes for these autoantibodies (AQP4-IgG) are generated by the supramolecular arrangement of AQP4 tetramers into an Orthogonal Array of Particles (OAPs). Many tests have been developed to detect AQP4-IgG in patient sera but several procedural issues affect OAP assembly and consequently test sensitivity. To date, the protein based ELISA test shows the lowest sensitivity while representing a valid alternative to the more sensitive cell based assay (CBA), which, however, shows economic, technical and interpretation problems. Here we have developed a high perfomance ELISA in which native OAPs are used as the molecular target. To this aim a native size exclusion chromatography method has been developed to isolate integral, highly pure and AQP4-IgG-recognized OAPs from rat brain. These OAPs were immobilized and oriented on a plastic plate by a sandwich approach and 139 human sera were tested, including 67 sera from NMO patients. The OAP-ELISA showed a 99% specificity and a higher sensitivity (91%) compared to the CBA test. A comparative analysis revealed an end-point titer three orders of magnitude higher than the commercial ELISA and six times higher than our in-house CBA test. We show that CNS-extracted OAPs are crucial elements in order to perform an efficient AQP4-IgG test and the OAP-ELISA developed represents a valid alternative to the CBA currently used. [ABSTRACT FROM AUTHOR]

Nowadays, the speed of the user and application logs is so quick that it is almost impossible to analyse them in real time without using high-performance systems and platforms. In cybersecurity, human behaviour is responsible directly or indirectly for the most common attacks (i.e. ransomware and phishing). To monitor user behaviour, it is necessary to process fast user logs coming from different and heterogeneous sources, having part of the data or some entire sources missing. A framework based on the elastic stack (ELK) to process and store log data in real time from different users and applications is proposed for this aim. This system generates an ensemble of models to classify user behaviour and detect anomalies in real time, exploiting the advantages of the ELK-based software architecture and of the Kubernetes platform. In addition, a distributed evolutionary algorithm is used to classify the users by exploiting their digital footprints derived from many data sources. Experiments conducted on two real-life data sets verify the approach's goodness in detecting anomalies in user behaviour, coping with missing data and lowering the number of false alarms. [ABSTRACT FROM AUTHOR]

Background: In this retrospective study, we investigated the efficacy and safety of radioimmunotherapy with 90Yttrium- ibritumomab tiuxetan (90Y-RIT) in 9 patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete (CR) or partial remission (PR) with Fludarabine, Cyclophosphamide and Rituximab (FCR). Methods: The median age was 63 years (range 46-77). All patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Those who achieved at least a PR with <25 % bone marrow involvement were treated with 90Y-RIT 11.1 or 14.8 MBq/Kg, at 3 months after completing FCR. Patients underwent a further restaging at 12 weeks after 90Y-RIT with a total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. Results: Nine patients completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR, 7 patients obtained CR and 2 PR; after 90Y-RIT 2 patients in PR converted to CR 12 weeks later. With a median follow up of 95 months (range 20-114) since FCR and 88 months (range 13-104) since 90Y-RIT 3 deaths were not related to lymphoma; all 3 deceased patients obtained CR before 90Y-RIT and died still in CR. The median overall (OS) and progression free survival (PFS) have not been reached, in this analysis both OS or PFS are 67 % at 7.5 year. The most common grade 3 or 4 adverse events were hematologic. Conclusions: These results confirm the long term efficacy and safety of 4 cycles of FCR followed by 90Y-RIT in relapsed grades 1 and 2 FL and suggest that this regimen could be a therapeutic option for this setting of patients, specially at age of 60-75 with no unexpected toxicities. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is characterized by the presence of pathogenic autoantibodies (NMO-IgGs) against supra-molecular assemblies of aquaporin-4 (AQP4), known as orthogonal array of particles (OAPs). NMO-IgGs have a polyclonal origin and recognize different conformational epitopes involving extracellular AQP4 loops A, C, and E. Here we hypothesize a pivotal role for AQP4 transmembrane regions (TMs) in epitope assembly. On the basis of multialignment analysis, mutagenesis, NMO-IgG binding, and cytotoxicity assay, we have disclosed the key role of aspartate 69 (Asp69) of TM2 for NMO-IgG epitope assembly. Mutation of Asp69 to histidine severely impairs NMO-IgG binding for 85.7% of the NMO patient sera analyzed here. Although Blue Native-PAGE, total internal reflection fluorescence microscopy, and water transport assays indicate that the OAP Asp69 mutant is similar in structure and function to the wild type, molecular dynamic simulations have revealed that the D69H mutation has the effect of altering the structural rearrangements of extracellular loop A. In conclusion, Asp69 is crucial for the spatial control of loop A, the particular molecular conformation of which enables the assembly of NMO-IgG epitopes. These findings provide additional clues for new strategies for NMO treatment and a wealth of information to better approach NMO pathogenesis. [ABSTRACT FROM AUTHOR]

Objective The aim of this study is to apply a real-time algorithm for clonic neonatal seizures detection, based on a low complexity image processing approach extracting the differential average luminance from videotaped body movements. Methods 23 video-EEGs from 12 patients containing 78 electrographically confirmed neonatal seizures of clonic type were reviewed and all movements were divided into noise, random movements, clonic seizures or other seizure types. Six video-EEGs from 5 newborns without seizures were also reviewed. Videos were then separately analyzed using either single, double or triple windows (these latter with 50% overlap) each of a 10s duration. Results With a decision threshold set at 0.5, we obtained a sensitivity of 71% (corresponding specificity: 69%) with double-window processing for clonic seizures diagnosis. The discriminatory power, indicated by the Area Under the Curve (AUC), is higher with two interlaced windows (AUC=0.796) than with single (AUC=0.788) or triple-window (AUC=0.728). Among subjects without neonatal seizures, our algorithm showed a specificity of 91% with double-window processing. Conclusions Our algorithm reliably detects neonatal clonic seizures and differentiates them from either noise, random movements and other seizure types. Significance It could represent a low-cost, low complexity, real-time automated screening tool for clonic neonatal seizures. [ABSTRACT FROM AUTHOR]

Simple Summary: Obstructive sleep apnea (OSA) is associated with behavioral, cardiovascular, and metabolic dysfunction. Autonomic changes have also been described in patients with OSA. In this study, we measured the heart rate variability (HRV) on electrocardiogram (ECG) tracings of OSA patients as a measure of cardiac autonomic regulation and putative predictor of disturbed breathing during nighttime. Our findings confirm an altered cardiac autonomic regulation in OSA patients during nighttime and identify a possible role of nighttime HRV in predicting sleep breathing disorders. Obstructive sleep apnea (OSA) can have long-term cardiovascular and metabolic effects. The identification of OSA-related impairments would provide diagnostic and prognostic value. Heart rate variability (HRV) as a measure of cardiac autonomic regulation is a promising candidate marker of OSA and OSA-related conditions. We took advantage of the Physionet Apnea-ECG database for two purposes. First, we performed time- and frequency-domain analysis of nocturnal HRV on each recording of this database to evaluate the cardiac autonomic regulation in patients with nighttime sleep breathing disorders. Second, we conducted a logistic regression analysis (backward stepwise) to identify the HRV indices able to predict the apnea–hypopnea index (AHI) categories (i.e., "Severe OSA", AHI ≥ 30; "Moderate-Mild OSA", 5 ≥ AHI < 30; and "Normal", AHI < 5). Compared to the "Normal", the "Severe OSA" group showed lower high-frequency power in normalized units (HFnu) and higher low-frequency power in normalized units (LFnu). The standard deviation of normal R–R intervals (SDNN) and the root mean square of successive R–R interval differences (RMSSD) were independently associated with sleep-disordered breathing. Our findings suggest altered cardiac autonomic regulation with a reduced parasympathetic component in OSA patients and suggest a role of nighttime HRV in the characterization and identification of sleep breathing disorders. [ABSTRACT FROM AUTHOR]

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism. [ABSTRACT FROM AUTHOR]

Neuromyelitis Optica (NMO) is an autoimmune demyelinating disease, characterized by the presence of autoantibody (NMO-IgG) to Aquaporin-4 (AQP4). NMO-IgG identification supports NMO diagnosis and several diagnostic tests have been developed, but their sensitivity is too variable, and some assay show low sensitivity. This impairs correct diagnosis of NMO. By cell based assay (CBA) we here evaluate the efficacy of different strategies to express AQP4 in mammalian cells in terms of: a) AQP4 translation initiation signals; b) AQP4 isoforms (M1 and M23) and fluorescent tag position; c) NMO serum concentration and AQP4 degradation. Our results demonstrate that when using AQP4-M1, the nucleotide in position −3 of the AUG greatly affects the AQP4-M1/M23 protein ratio, NMO-IgG binding, and consequently test sensitivity. Test sensitivity was highest with M23 expressing cells (97.5%) and only 27.5% with AQP4-M1. The fluorescent tag added to the N-terminus of AQP4-M23 considerably affected the NMO-IgG binding, and test sensitivity, due to disruption of AQP4 suprastructures. Furthermore, sera used at high concentration resulted in AQP4 degradation which affected test sensitivity. To further evaluate the reliability of the M23 based CBA test, samples of one NMO patient collected during about 2 years clinical follow-up were tested. The results of serum titer correlated with disease activity and treatment response. In conclusion, we provide a molecular explanation for the contrasting CBA test data reported and suggest the use of M23 with a C-terminus fluorescent tag as the proper test for NMO diagnosis. [ABSTRACT FROM AUTHOR]

The information carried by a light pattern, that is encrypted in the 3D topography of the magic windows, is unveiled by projection of the light pattern on a screen. Cryptographic Strain-Dependent Light Pattern Generators (Adv. Keywords: 3D printing; additive manufacturing; cryptographic systems; freeform components; stretchable devices EN 3D printing additive manufacturing cryptographic systems freeform components stretchable devices 1 1 1 01/11/22 20220101 NES 220101 B Cryptographic Magic Windows b In article number 2101129, Francesco Pisani, Andrea Camposeo, and colleagues introduce stretchable and 3D printed cryptographic magic windows capable of generating complex patterns, including micro-QR-codes, by refraction of light in the visible range. [Extracted from the article]

We analyzed clinical and instrumental data of 403 consecutive newborns with gestational age from 24 to 32 weeks, admitted to the University-Hospital of Parma between January 2000 and December 2007, to evaluate the possible relationship between neonatal mortality and occurrence of neonatal seizures in very preterm newborns. Seventy-four subjects died during hospital stay. Seizures were present in 35 neonates, in whom the mortality rate was 37.1%. Multivariate analysis revealed that birth-weight <1000 g (odds ratio: 4.48; 95% confidence interval: 1.47-13.68; P < .01), cardiopulmonary resuscitation (odds ratio: 5.35; 95% confidence interval: 1.19-23.98; P = .02), and moderately and severely abnormal cerebral ultrasound scan findings (odds ratio: 2.48; 95% confidence interval: 1.02-6.05; P < .04; odds ratio: 9.56; 95% confidence interval: 3.45-26.51; P < .01, respectively) were related to the in-hospital mortality but not the presence of neonatal seizures. Our study suggests that neonatal seizures alone are not an independent risk factor for early death in very preterm newborns. [ABSTRACT FROM PUBLISHER]

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease characterized by the presence of anti-aquaporin-4 (AQP4) antibodies in the patient sera. We recently reported that these autoantibodies are able to bind AQP4 when organized in the supramolecular structure called the orthogonal array of particles (OAP). To map the antigenic determinants, we produced a series of AQP4 mutants based on multiple alignment sequence analysis between AQP4 and other OAP-forming AQPs. Mutations were introduced in the three extracellular loops (A, C, and E), and the binding capacity of NMO sera was tested on AQP4 mutants. Results indicate that one group of sera was able to recognize a limited portion of loop C containing the amino acid sequence 146GVT(T/M)V150. A second group of sera was characterized by a predominant role of loop A. Deletion of four AQP4-specific amino acids (61G(S/T)E(N/K)64) in loop A substantially affected the binding of this group of sera. However, the binding capacity was further reduced when amino acids in loop A were mutated together with those in loop E or when those in loop C were mutated in combination with loop E. Finally, a series of AQP0 mutants were produced in which the extracellular loops were progressively changed to make them identical to AQP4. Results showed that none of the mutants was able to reproduce in AQP0 the NMO-IgG epitopes, indicating that the extracellular loop sequence by itself was not sufficient to determine the rearrangement required to create the epitopes. Although our data highlight the complexity of the disease, this study identifies key immunodominant epitopes and provides direct evidence that the transition from AQP4 tetramers to AQP4-OAPs involves conformational changes of the extracellular loops. [ABSTRACT FROM AUTHOR]

Background: This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR. Methods: The median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m²× 3 days), C (1 gr/m² day 1) and R (375 mg/m² day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. Results: Nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection. Conclusions: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) exists as two major isoforms that differ in the length of the N terminus, the shorter AQP4-M23 and the longer AQP4-M1. Both isoforms form tetramers, which can further aggregate in the plasma membrane to form typical orthogonal arrays of particles (OAPs) whose dimension depends on the ratio of the M1 and M23. In this study, we tested the hypothesis that the M23 isoform can be produced directly by the Ml mRNA. In cells transiently transfected with AQP4-M1 coding sequence we observed besides AQP4-M1 the additional presence of the AQP4-M23 isoform associated with the formation of typical OAPs observable by two-dimensional blue native/SDS-PAGE and total internal reflection microscopy. The mutation of the second in-frame methionine M23 in AQP4-M1 (AQP4- M1M231) prevented the expression of the M23 isoform and the formation of OAPs. We propose "leaky scanning" as a translational mechanism for the expression of AQP4-M23 protein isoform and that the formation of OAPs may occur even in the absence of AQP4-M23 mRNA. This mechanism can have important pathophysiological implications for the cell regulation of the M1/M23 ratio and thus OAP size. In this study we also provide evidence that AQP4-Ml is mobile in the plasma membrane, that it is inserted and not excluded into immobile OAPs, and that it is an important determinant of OAP structure and size. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of neonatal death or neurological handicaps such as cerebral palsy, mental delay, and epilepsy. Moreover, an acute consequence of HIE are neonatal seizures which can cause an additional brain damage. The neurodevelopmental outcome is known in the mild or severe cases of HIE, but in the moderate conditions the predictivity results, to date, unsatisfying. Objective: The purpose of this prospective study was to appraise the development of post-neonatal epilepsy in a cohort of term infants with moderate HIE and neonatal seizures. Methods: This study considered all newborns admitted to Neonatal Intensive Care Unit of the University of Parma between January 2000 and December 2002 for perinatal asphyxia, then followed by Neonatal Neurology Service. In all patients, neonatal variables such as type of delivery, birth weight, gestational age, Apgar scores, the need for resuscitation and assisted ventilation soon after birth, and arterial-blood pH were analyzed. Results: Ninety-two newborns were enrolled in the study because of perinatal asphyxia. Of these, 27 subjects developed mild HIE, 25 moderate, and five severe HIE. Neonatal seizures were present in 13 subjects with moderate HIE and in all newborns with severe HIE. At the last follow-up, only three infants belonging to patients with severe HIE developed epilepsy. Conclusion: Moderate HIE seems not to be related to post-neonatal epilepsy either if associated or not with neonatal seizures. [Copyright &y& Elsevier]

We report a noteworthy case of Eubacterium plautii infection after kidney transplantation. Our 33-yr-old transplant recipient received standard care; his post-transplant course was uneventful. However, on day 44 he underwent an emergency laparotomy for perforation of the ileum. He was initially treated with ceftazidime, fluconazole and metronidazole, but his fever persisted, so he was switched to meropenem and vancocin. We could not find any cause for his infection. On day 70, his temperature normalized. On day 75, he developed severe leukopenia (280 cell/mL). His cytomegalovirus-DNA test result was negative, so all immunosuppressants, except for prednisone, were stopped; instead, antibiotic prophylaxis was started, using caspofungin, trimethoprim-sulfamethoxazole and ciprofloxacin. On day 83, he underwent percutaneous drainage of massive left pleural effusion. We repeatedly cultured the pleural liquid, but it was not till three wk later that we were finally able to identify the causative organism. We hypothesize that the microorganism – which normally resides on the surface of the intestinal lumen – entered the bloodstream via bacterial translocation, eventually colonizing the pleurae. This translocation was favored by our patient poor clinical condition, his immunosuppressive treatment and his heavy antibiotherapy. Our experience highlights the need for wiser use of antibiotics in transplant recipients. [ABSTRACT FROM AUTHOR]

Neonatal electroencephalographic background activity has been found to be a predictive factor of the neurodevelopmental outcome. The aim of our study was to identify if the electrical ictal findings present on the first electroencephalography (EEG) recording are related to the outcome of newborns with neonatal seizures. The study is based on the prospective evaluation of newborns consecutively admitted to the Neonatal Intensive Care Unit at the University of Parma between September 2001 and September 2004. Thirty-eight subjects were enrolled in the study on the basis of the following inclusion criteria: presence on the first EEG of at least 1 seizure, neurodevelopmental follow-up until 18 months of corrected age, and performance of several ultrasound brain scans during the neonatal period and of at least I cerebral MRI within the first year of life. For each seizure, the following were considered: onset topography, morphology of the epileptiform discharges, spread of the discharge, number of electrographic regions of seizure onset, number of seizures per hour, duration of the seizures, and the Ictal Fraction (= total duration of the seizures/duration of the EEG recording x hour). At the last follow-up, the unfavorable neurodevelopmental outcome seems significantly related to the moderate/severe background activity abnormalities (p = .006), to the spread of ictal discharge to the contralateral hemisphere (p = .02), and to the Ictal Fraction, when it exceeds 10 minutes (p = .036). In conclusion, the analysis of the propagation of the ictal discharge and of the Ictal Fraction might suggest significant prognostic information since the first hours of life. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Our aim was to identify early predictors of poor neurodevelopmental outcome and of subsequent epilepsy in very early preterm and late preterm newborns with neonatal seizures. Study design: Fifty-one preterm infants with gestational age (GA) ⩽36 weeks were identified among those admitted to the NICU of University Hospital of Parma between January 1999 and December 2003 and prospectively followed-up. They were subdivided in two Groups: early preterm newborns with a GA ⩽29 weeks and those with GA between 30 and 36 weeks. Selection criteria included multiple digital-video-EEG confirmed neonatal seizures and a follow-up of at least 30 months. Independent variables considered for analysis included neonatal risk factors, etiology and type of seizures, EEG activity, and cerebral ultrasound scan examinations. Results: Ten infants had a favorable outcome, 17 died, and 23 had an adverse outcome. One infant was lost on follow-up. Apgar score at 1min (O.R.=15.457, 95% CI: 2.236–106.850, p =0.006) and severely abnormal background EEG activity (O.R.=8.298, 95% CI: 1.316–52.301, p =0.024) were independent predictors of abnormal outcome. Nine infants presented post-neonatal epilepsy. Severely abnormal Cerebral Ultrasound scans were predictive of epilepsy (O.R.=13.72, 95% CI: 1.959–96.149, p =0.008). Conclusions: Neonatal seizures in preterm infants are associated to a high rate of mortality and severe morbidity in survivors but no definitive differences between the two groups of preterm infants were found. Risk-factors for development of subsequent epilepsy are strongly related to the underlying brain damage. [Copyright &y& Elsevier]

Background: Early environmental events may be relevant to the etiology of schizophrenia. Among such events, interest has focused especially on obstetric complications (OCs). Objective: Aims of the study were to compare the incidence of OCs in patients, siblings and normal controls and to examine the relationship between OCs and later schizophrenia. Method: One hundred and thirteen patients with schizophrenia were recruited, as were 140 patients’ siblings and 113 controls without schizophrenia. The OCs history of patients, their sibs and controls was obtained through interviews with patients’ and controls’ mothers. Results: The results highlighted that more patients than sibs had at least one definite OC and a higher mean number of OCs; more patients had premature rupture of membranes, threatened abortion and a labor of more than 36 h. Conclusions: Our data provide some evidence for a link between OCs and later schizophrenia. Furthermore, this study highlights how OCs, which may cause fetal distress through a hypoxic-ischemic mechanism, could increase the risk of schizophrenia interacting with genetic susceptibility. [ABSTRACT FROM AUTHOR]

Abstract: Sensory processing is a crucial underpinning of the development of social cognition, a function which is compromised in variable degree in patients with pervasive developmental disorders (PDD). In this manuscript, we review some of the most recent and relevant contributions, which have looked at auditory sensory processing derangement in PDD. The variability in the clinical characteristics of the samples studied so far, in terms of severity of the associated cognitive deficits and associated limited compliance, underlying aetiology and demographic features makes a univocal interpretation arduous. We hypothesise that, in patients with severe mental deficits, the presence of impaired auditory sensory memory as expressed by the mismatch negativity could be a non-specific indicator of more diffuse cortical deficits rather than causally related to the clinical symptomatology. More consistent findings seem to emerge from studies on less severely impaired patients, in whom increased pitch perception has been interpreted as an indicator of increased local processing, probably as compensatory mechanism for the lack of global processing (central coherence). This latter hypothesis seems extremely attractive and future trials in larger cohorts of patients, possibly standardising the characteristics of the stimuli are a much-needed development. Finally, specificity of the role of the auditory derangement as opposed to other sensory channels needs to be assessed more systematically using multimodal stimuli in the same patient group. [Copyright &y& Elsevier]

The possible neuroprotective effects of two GABAergic drugs, tiagabine (TGB) and vigabatrin (VGB), against N-methyl- d-aspartate (NMDA)-induced excitotoxicity have been investigated in the isolated chick embryo retina model. Retina segments were incubated either with NMDA alone (100 μM) or with NMDA and TGB or VGB (10–1,000 μM, added 5 min before NMDA). Retina damage was assessed after 24 h by measuring lactate dehydrogenase (LDH) activity present in the medium and by histological analysis. Both drugs reduced LDH release in a dose-dependent manner with comparable mean maximal values of 56.6–63.7% achieved at concentration of 1 mM. Histological analysis of retina slices was in line with the biochemical assays and showed partial preservation of drug exposed retina structure with reduced edema especially in the inner plexiform layer. The present data provide pharmacological evidence that both TGB and VGB reduce the severity of NMDA-induced excitotoxic damage. Although an increase in GABAergic transmission might play a role, this in itself is insufficient to explain the neuroprotective effect of the two drugs and the exact mechanism remains to be elucidated. [ABSTRACT FROM AUTHOR]

Little is known about the clinical evolution and neurologic sequelae of transient periventricular echodensities in the neonatal period. The aim of our study was to assess the neurodevelopmental outcome in preterm infants with transient periventricular echodensities. Cerebral ultrasonography was performed within the first 72 hours of life on all preterms with a I 37 weeks' gestational age who were admitted consecutively to the Neonatal Intensive Care Unit of the University of Parma from January 2001 to December 2002. Cerebral ultrasonography was performed at least twice within the 14th postnatal day and was repeated weekly until 40 weeks' postconceptional age. Transient aspecific echodensities were defined as areas in the periventricular region brighter than the choroid plexus persisting less than 14 days. One hundred sixty-four preterm infants were selected and divided into three groups: (1) 78 preterm infants without ultrasound abnormalities, (2) 50 preterm infants with transient periventricular echodensities, and (3) 36 preterm infants with persistent echodensities. Developmental outcome was assessed at 44 weeks' postconceptional age, after 1 month from the discharge and at the corrected ages of 3,6,9, and 12 months using the Griffiths Mental Developmental Scale. Group 1 and 2 infants showed normal neurodevelopment in 88.5% and 94% of cases, respectively, whereas the preterm infants belonging to group 3 had a favorable outcome in 22.2% (P < .001) of cases only. In conclusion, our study demonstrates how infants with transient echodensities show a neurodevelopmental outcome that is entirely identical to infants with a steadily negative ultrasound finding. [ABSTRACT FROM AUTHOR]

We describe the electroencephalographic findings in nine pediatric migraineurs during the ictal phase of pain. We observed abnormal patterns on electroencephalography (EEG) in seven patients with migraine with aura and in two patients with basilar migraine. These patients were also evaluated with EEG during headache-free interval, at least 7 days after the ictal event; these interictal findings were unremarkable, confirming the observations reported in the literature. Finally, we review migraine and its EEG characteristics as reported in the literature, and discuss the value of EEG performed during interictal and ictal phases of migraine. [ABSTRACT FROM AUTHOR]

Very few cases of short-lasting headaches have been reported in children and adolescents. The aim of this study is to describe a group of patients in the pediatric age group with short attacks of head pain and to demonstrate that they are not easily classified according to existing criteria for adults. We describe 23 subjects in retrospect, 12 males and 11 females, with brief attacks of headache, stabbing in nature, self-limited, lasting from a few seconds to 15 min. This sample was taken from a total population of 548 children and adolescents referred to our Pediatric Headache Unit during the years 1995–1999. Mean age at onset of symptomatology was 9 years. The localization of the headache was bilateral in 60% of the patients and unilateral in 40%. The pain was either unifocal at the orbit or temple (60%) or multifocal (40%). In 24% of the children, the interictal awake EEG showed infrequent posterior slow-waves. In 12 patients we used paracetamol with a good response. Although these painful episodes shared some aspects with the adult form of idiopathic stabbing headache, they had different durations of attack, and other primary headache syndromes did not accompany them either at the time of presentation or during the following 2 years. Short attacks of headache are present in the pediatric age group and are not easily classified according to the International Headache Society criteria. Their nature and correlation with migraine remains unclear. We propose follow-up of these subjects to obtain a better description of the natural history of these forms of headache in the pediatric age group. [Copyright &y& Elsevier]

Congenital hypotonia with favorable outcome is characterized by an early neonatal onset and a benign clinical course. The old term, proposed by Walton, was benign congenital hypotonia, denoting the presence of muscle weakness and hypotonia, with the exception of Werdnig-Hoffmann disease. It has been clear that this term includes congenital myopathies with definite changes in the muscle fiber. However, many cases remain unclarified. The term congenital hypotonia with favorable outcome includes only these last cases. A long-term follow-up study of children with congenital hypotonia with favorable outcome is presented, and a hypothetical mechanism underlying muscle shortening is discussed. The study was carried out at the Department of Child Neuropsychiatric Sciences, University “La Sapienza” of Rome, during the period 1985-2000, and included 41 patients with congenital hypotonia. Our study confirms the good prognosis of congenital hypotonia with favorable outcome and suggests a correlation with joint hyperlaxity, which is observed in many parents of our children, as if the latter developed from the former. On the basis of experimental changes occurring in the muscles, we believe that in our cohort the main cause of shortening is caused by an increase in joint mobility, which keeps muscles shortened in both the passive and active states for a long time. If this view is confirmed by other studies, we suggest continuous muscle exercise as a preventive treatment. [Copyright &y& Elsevier]

Background Objectives Methods Results Conclusions The GCH1 gene encodes the enzyme guanosine triphosphate cyclohydrolase I (GTPCH), which catalyzes the rate‐limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters. Autosomal dominant GTPCH (adGTPCH) deficiency is the most common cause of dopa‐responsive dystonia (DRD), whereas the recessive form (arGTPCH) is an ultrarare and poorly characterized disorder with earlier and more complex presentation that may disrupt neurodevelopmental processes. Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome.The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature.Clinical, biochemical, and genetic data and treatment response of 45 patients are presented.Three phenotypes were outlined: (1) early‐infantile encephalopathic phenotype with profound disability (24 of 45 patients), (2) dystonia‐parkinsonism phenotype with infantile/early‐childhood onset of developmental stagnation/regression preceding the emergence of movement disorder (7 of 45), and (3) late‐onset DRD phenotype (14 of 45). All 3 phenotypes were responsive to pharmacological treatment, which for the first 2 must be initiated early to prevent disabling neurodevelopmental outcomes. A gradient of BH4 defect and genetic variant severity characterizes the 3 clinical subgroups. Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher likelihood of intellectual disability.The clinical spectrum of arGTPCH deficiency is a continuum from early‐onset encephalopathies to classical DRD. Genotype and biochemical alterations may allow early diagnosis and predict clinical severity. Early treatment remains critical, especially for the most severe patients. [ABSTRACT FROM AUTHOR]

Functional neurological symptom disorders (FNSD) pose a common challenge in clinical practice, particularly in pediatric cases where the clinical phenotypes can be intricate and easily confused with structural disturbances. The frequent coexistence of FNSDs with other medical disorders often results in misdiagnosis. In this review, we highlight the distinctions between FNSD and various psychiatric and neurological conditions. Contrary to the misconception that FNSD is a diagnosis of exclusion, we underscore its nature as a diagnosis of inclusion, contingent upon recognizing specific clinical features. However, our focus is on a critical learning point illustrated by the case of a 14-year-old male initially diagnosed with FNSD, but subsequently found to have a rare primary monogenic movement disorder (paroxysmal kinesigenic dyskinesia, PKD). The crucial takeaway from this case is the importance of avoiding an FNSD diagnosis based solely on psychiatric comorbidity and suppressible symptoms. Instead, clinicians should diligently assess for specific features indicative of FNSD, which were absent in this case. This emphasizes the importance of making a diagnosis of inclusion. Extended follow-up and clinical-oriented genetic testing might help identify comorbidities, prevent misdiagnosis, and guide interventions in complex cases, which cannot be simply classified as "functional" solely because other conditions can be excluded. Plain language summary: Understanding and Avoiding Mistakes in Diagnosing Children with Functional Neurological Symptom Disorders: A Review and Case Report: This article discusses Functional Neurological Symptom Disorders (FNSDs), focusing on misdiagnosis, differential diagnosis, and other diagnostic challenges, particularly in pediatric cases. FNSDs involve motor or sensory symptoms that are inconsistent over time and unexplained by neurological disease, often associated with psychosocial factors. The article highlights the complexity of distinguishing FNSDs from other neurological and psychiatric conditions, emphasizing the importance of careful evaluation. The authors review various conditions that can mimic FNSDs, such as epileptic seizures, syncope, and different motor disorders. They emphasize the need to consider psychiatric conditions in the differential diagnosis, including factitious disorders, and malingering. The article presents a case study of a 14-year-old with involuntary movements, initially diagnosed as having a Functional Movement Disorder. After careful evaluation, the patient was diagnosed with a genetic dystonia (PRRT2 mutation). The case shows the importance of not rely solely on psychological problems, bizarre presentations or suppressible symptoms when diagnosing FNSDs. [ABSTRACT FROM AUTHOR]

The small Rho GTP‐binding proteins are important cell morphology, function, and apoptosis regulators. Unlike other Rho proteins, RhoB can be subjected to either geranylgeranylation (RhoB‐GG) or farnesylation (RhoB‐F), making that the only target of the farnesyltransferase inhibitor (FTI). Fluorescence resonance energy transfer experiments revealed that RhoB is activated by hyperosmolarity. By contrast, hyposmolarity did not affect RhoB activity. Interestingly, treatment with farnesyltransferase inhibitor‐277 (FTI‐277) decreased the cell size. To evaluate whether RhoB plays a role in volume reduction, renal collecting duct MCD4 cells and Human Kidney, HK‐2 were transiently transfected with RhoB‐wildtype‐Enhance Green Fluorescence Protein (RhoB‐wt‐EGFP) and RhoB‐CLLL‐EGFP which cannot undergo farnesylation. A calcein‐based fluorescent assay revealed that hyperosmolarity caused a significant reduction of cell volume in mock and RhoB‐wt‐EGFP‐expressing cells. By contrast, cells treated with FTI‐277 or expressing the RhoB‐CLLL‐EGFP mutant did not properly respond to hyperosmolarity with respect to mock and RhoB‐wt‐EGFP expressing cells. These findings were further confirmed by 3D‐LSCM showing that RhoB‐CLLL‐EGFP cells displayed a significant reduction in cell size compared to cells expressing RhoB‐wt‐EGFP. Moreover, flow cytometry analysis revealed that RhoB‐CLLL‐EGFP expressing cells as well as FTI‐277‐treated cells showed a significant increase in cell apoptosis. Together, these data suggested that: (i) RhoB is sensitive to hyperosmolarity and not to hyposmolarity; (ii) inhibition of RhoB farnesylation associates with an increase in cell apoptosis, likely suggesting that RhoB might be a paramount player controlling apoptosis by interfering with responses to cell volume change. [ABSTRACT FROM AUTHOR]

The expression "twice-exceptionality" has been used to describe conditions in which giftedness and specific disorders coexist. Our study offers a retrospective analysis of clinical reports of gifted children evaluated for suspected specific learning disorders (SLD) or attention-deficit/hyperactivity disorder (ADHD). The initial sample included 456 school-aged children referred to our clinic for suspected SLD and/or ADHD over a two-year interval. The inclusion criteria were: a General Ability Index score above 120 in the cognitive assessment; age 6–18 years; and not satisfying diagnostic criteria for autism spectrum disorder. Forty children were selected for the study. We grouped patients according to the final diagnosis: neurodevelopmental disorder (SLD and/or ADHD) (n = 15), psychopathological disorder (n = 8), mixed neurodevelopmental and psychopathological (n = 13), no emerging disorder (n = 4). The study included 36 (90%) males. Mean age was 9.3 years (SD 1.62). Mean Full-Scale Intelligence Quotient was 121.7 (SD 7.77), mean General Ability Index was 130.2 (SD 6.79). Furthermore, the cognitive assessment of the different groups highlighted a non-homogeneous profile in all groups, with lower scores on working memory and processing speed indexes. Our results support the hypothesis that difficulties in gifted children's adaptation to scholastic and social settings could be misinterpreted as a manifestation of a clear disease. [ABSTRACT FROM AUTHOR]

Neonatal seizures (NS) are the most frequent sign of neurological dysfunction in newborn infants. With increased survival of preterm neonates, the current clinical focus has shifted from preventing death to improving long-term neurological outcome. In the context of acute symptomatic NS, the main negative prognostic factors include etiology, and severity of brain injury, but also prolonged seizures and especially status epilepticus. However, the reasons for the detrimental contribution of seizures to outcome are still unclear, and evidence has been collected both in favor of seizures being an epiphenomenon of brain injury and of independently contributing to further damage. In this narrative focused review, we will discuss both hypotheses, with special emphasis on data relating to preterm infants. We will also identify present controversies and possible future lines of research. • Neonatal seizures are associated with negative outcomes in preterm infants. • The relative role of brain injury versus seizures "per se" is unknown. • We review evidence for seizures as effect modifiers versus as epiphenomenon. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica spectrum disorder (NMOSD) is a severe, inflammatory, immune-mediated astrocytopathy of the central nervous system, characterized by recurrent inflammatory events primarily involving optic nerves and the spinal cord. Recently, a triggering role of infectious events in the development of NMOSD has been suggested. Varicella zoster virus (VZV) is the agent most involved, although the linkage with anti-aquaporin-4 antibodies is so far unknown. A review of the literature on the association between NMOSD and VZV infection was carried out by searching PUBMED and EMBASE from 1975 to July 2020. A total of 13 articles concerning Herpes zoster preceding NMOSD were identified. All patients were female and the median age at NMOSD presentation was 28.5 (range 5–63) years. Four NMOSD cases occurred after chicken pox while the remaining ten after HZ. Full recovery occurred in 5/14 patients. From the review of the literature, we can infer that VZV seems to trigger LETM attacks and not the disease itself. The strict temporal relationship between VZV infection and NMOSD seems to exceed the pure chance and represents an unusual clinical scenario posing several diagnostic and management challenges. [ABSTRACT FROM AUTHOR]