At the time of the signing of the Convention for the Protection of the World Cultural and Natural Heritage the Oljeitu Mausoleum at Soltaniyeh in Iran was already the subject of an international ...programme of restoration and conservation, in the spirit of collaboration that was to be sanctioned by the same convention. The designer and person in charge of these works was Piero Sanpaolesi. He was already a consultant for the United Nations Organisation and in those same years he directed the Institute of Restoration of Monuments at the Faculty of Architecture in Florence and headed the institution of the same name that he founded at the University of Tehran. The mausoleum commissioned in the early 14th century by Oljeitu, the eighth ruler of the Ilkhān dynasty, in Soltani- yeh, is covered by a dome, made of masonry with a double calotte, which bears similarities to Brunelleschi's dome in Santa Maria del Fiore, and is the third largest in the world. In July 2005 in Durban, the Mausoleum of Oljeitu in Soltaniyeh was inscribed on the UNESCO World Heritage List. Fifty years after the first restoration work, it is possible to take stock of the effects that the activities carried out, in the spirit of the Heritage Convention, have had on this particular UNESCO site.
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Crosstalk mechanisms between pericytes, endothelial cells, and astrocytes preserve integrity and function of the blood-brain-barrier (BBB) under physiological conditions. Long intercellular channels ...allowing the transfer of small molecules and organelles between distant cells called tunneling nanotubes (TNT) represent a potential substrate for energy and matter exchanges between the tripartite cellular compartments of the BBB. However, the role of TNT across BBB cells under physiological conditions and in the course of BBB dysfunction is unknown. In this work, we analyzed the TNT's role in the functional dialog between human brain endothelial cells, and brain pericytes co-cultured with human astrocytes under normal conditions or after exposure to ischemia/reperfusion, a condition in which BBB breakdown occurs, and pericytes participate in the BBB repair. Using live time-lapse fluorescence microscopy and laser-scanning confocal microscopy, we found that astrocytes form long TNT with pericytes and endothelial cells and receive functional mitochondria from both cell types through this mechanism. The mitochondrial transfer also occurred in multicellular assembloids of human BBB that reproduce the three-dimensional architecture of the BBB. Under conditions of ischemia/reperfusion, TNT formation is upregulated, and astrocytes exposed to oxygen-glucose deprivation were rescued from apoptosis by healthy pericytes through TNT-mediated transfer of functional mitochondria, an effect that was virtually abolished in the presence of TNT-destroying drugs. The results establish a functional role of TNT in the crosstalk between BBB cells and demonstrate that TNT-mediated mitochondrial transfer from pericytes rescues astrocytes from ischemia/reperfusion-induced apoptosis. Our data confirm that the pericytes might play a pivotal role in preserving the structural and functional integrity of BBB under physiological conditions and participate in BBB repair in brain diseases.
In the majority of optoelectronic devices, emission and absorption of light are considered as perturbative phenomena. Recently, a regime of highly non-perturbative interaction, ultra-strong ...light-matter coupling, has attracted considerable attention, as it has led to changes in the fundamental properties of materials such as electrical conductivity, rate of chemical reactions, topological order, and non-linear susceptibility. Here, we explore a quantum infrared detector operating in the ultra-strong light-matter coupling regime driven by collective electronic excitations, where the renormalized polariton states are strongly detuned from the bare electronic transitions. Our experiments are corroborated by microscopic quantum theory that solves the problem of calculating the fermionic transport in the presence of strong collective electronic effects. These findings open a new way of conceiving optoelectronic devices based on the coherent interaction between electrons and photons allowing, for example, the optimization of quantum cascade detectors operating in the regime of strongly non-perturbative coupling with light.
Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies ...(DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000-2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (
pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Psychiatric disorder comorbidity in patients with epilepsy (PWE) is very frequent with a mean percentage prevalence of up to 50% and even higher. Such a high frequency suggests that epilepsy and ...psychiatric disorders might share common pathological pathways. Various aspects contribute in making the matter very complex from a therapeutic point of view. Some antiseizure medications (ASMs), namely valproic acid, carbamazepine, and lamotrigine, have mood-stabilising effects and are routinely used for the treatment of bipolar disorder in patients who do not have epilepsy. Pregabalin and, to a lesser extent, gabapentin, exerts anxiolytic effects. However, several ASMs, in particular levetiracetam, topiramate, and perampanel, may contribute to psychiatric disorders, including depression, aggressive behaviour, and even psychosis. If these ASMs are prescribed, the patient should be monitored closely. A careful selection should be made also with psychotropic drugs. Although most of these can be safely used at therapeutic doses, bupropion, some tricyclic antidepressants, maprotiline, and clozapine may alter seizure threshold and facilitate epileptic seizures. Interactions between ASMs and psychotropic medication may make it difficult to predict individual response. Pharmacokinetic interactions can be assessed with drug monitoring and are consequently much better documented than pharmacodynamic interactions. Another aspect that needs a careful evaluation is patient adherence to treatment. Prevalence of non-adherence in PWE and psychiatric comorbidities is reported to reach values even higher than 70%. A careful evaluation of all these aspects contributes in optimizing therapy with a positive impact on seizure control, psychiatric wellbeing, and quality of life.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare congenital autosomal recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa ...decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human AADC gene into the putamina has become available. This systematic review on PubMed, Scopus databases, and other sources is aimed at describing the AADC whole phenotypic spectrum in order to facilitate its early diagnosis. Literature reviews, original articles, retrospective and comparative studies, large case series, case reports, and short communications were considered. A database was set up using Microsoft Excel to collect clinical, molecular, biochemical, and therapeutic data. By analysing 261 patients from 41 papers with molecular and/or biochemical diagnosis of AADC deficiency for which individuality could be determined with certainty, we found symptom onset to occur in the first 6 months of life in 93% of cases. Hypotonia and developmental delay are cardinal signs, reported as present in 73.9% and 72% of cases, respectively. Oculogyric crises were seen in 67% of patients while hypokinesia in 42% and ptosis in 26%. Dysautonomic features have been revealed in 53% and gastrointestinal symptoms in 19% of cases. With 37% and 30% of patients reported being affected by sleep and behavioural disorders, it seems to be commoner than previously acknowledged. Although reporting bias cannot be excluded, there is still a need for comprehensive clinical descriptions of symptoms at onset and during follow-up. In fact, our review suggests that most of the neurological and extraneurological symptoms and signs reported, although quite frequent in this condition, are not pathognomonic, and therefore, ADCC deficiency can remain an underdiscovered disorder.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the Rett syndrome spectrum (RSS). ...Our awareness of the considerable overlap with pediatric-onset epilepsies and epileptic/developmental encephalopathies (EE/DE) genes is also growing, and the presence of variable clinical features inside a general frame of commonalities has drawn renewed attention into deep phenotyping.
We decided to review the medical literature on atypical Rett syndrome and "Rett-like" phenotypes, with special emphasis on described cases with pediatric-onset epilepsies and/or EE-DE, evaluating Neul's criteria for Rett syndrome and associated movement disorders and notable stereotypies.
"Rett-like" features were described in syndromic and non-syndromic monogenic epilepsy- and DE/EE-related genes, in "intellectual disability plus epilepsy"-related genes and in neurodegenerative disorders. Additionally, prominent stereotypies can be observed in monogenic complex neurodevelopmental disorders featuring epilepsy with or without autistic features outside of the RSS.
Patients share a complex neurodevelopmental and neurological phenotype (developmental delay, movement disorder) with impaired gait, abnormal tone and hand stereotypies. However, the presence and characteristics of regression and loss of language and functional hand use can differ. Finally, the frequency of additional supportive criteria and their distribution also vary widely.
The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into ...supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton. SIGNIFICANCE: This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.
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