Lhermitte-Duclos disease with concomitant KCNT2 gene mutation: report of an extremely rare combination.

Lhermitte-Duclos disease (LDD) refers to cerebellar dysplastic gangliocytoma, a slow-growing tumor. Pathogenic variants of voltage-gated potassium channels have been associated with epilepsy of variable severity. These include the sodium-activated potassium channel subfamily T member 2 (KCNT2) gene, which encodes for pore-forming alpha subunits. KCNT2 gene mutations have been recently described to cause developmental and epileptic encephalopathies (DEEs). The purpose of the present article is to describe an extremely rare case of a young child who has both LDD and KCNT2 mutation. Our patient is an 11-year-old boy who presented with an absence episode, and his investigations revealed electroencephalography (EEG) abnormalities, LDD, and a heterozygous KCNT2 mutation. Regarding LDD patients, epileptic seizures have been reported in very few cases. Reports of patients with mutated KCNT2 variants are also extremely rare. It is for sure that LDD and KCNT2 mutation is an extremely rare combination. Although further follow-up is mandatory in order to draw safe conclusions for our case, the available data support that our patient is either the first reported case of a subclinical KCNT2 mutation or the first case of its clinical expression in late childhood so far.

Nervous system involvement in Pfeiffer syndrome.

Pfeiffer syndrome (PS) is a rare autosomal dominant craniofacial disorder characterized by primary craniosynostosis, midface hypoplasia, and extremities' abnormalities including syndactyly. The purpose of this article was to review the current knowledge regarding how PS affects the nervous system. Methodologically, we conducted a systematic review of the existing literature concerning involvement of the nervous system in PS. Multiple-suture synostosis is common, and it is the premature fusion and abnormal growth of the facial skeleton's bones that cause the characteristic facial features of these patients. Brain abnormalities in PS can be primary or secondary. Primary anomalies are specific developmental brain defects including disorders of the white matter. Secondary anomalies are the result of skull deformity and include intracranial hypertension, hydrocephalus, and Chiari type I malformation. Spinal anomalies in PS patients include fusion of vertebrae, "butterfly" vertebra, and sacrococcygeal extension. Different features have been observed in different types of this syndrome. Cloverleaf skull deformity characterizes PS type II. The main neurological abnormalities are mental retardation, learning difficulties, and seizures. The tricky neurological examination in severely affected patients makes difficult the early diagnosis of neurological and neurosurgical complications. Prenatal diagnosis of PS is possible either molecularly or by sonography, and the differential diagnosis includes other craniosynostosis syndromes. Knowing how PS affects the nervous system is important, not only for understanding its pathogenesis and determining its prognosis but also for the guidance of decision-making in the various critical steps of its management. The latter necessitates an experienced multidisciplinary team.

Chyloperitoneum following open myelomeningocele repair: dealing with an extremely rare finding.

PURPOSE: Chyloperitoneum is an extremely rare finding following myelomeningocele (MMC) repair in neonates. We aimed to describe the characteristics of such a case and explore its clinical significance. CASE REPORT: A male baby born at term with open MMC and hydrocephalus underwent MMC repair surgery with rotational flaps on the first postnatal day. The procedure was uneventful. Three days later, he underwent a right ventriculoperitoneal shunt (VPS) insertion. On opening the peritoneum, a remarkable amount of yellowish opaque fluid was observed. Chyloperitoneum was suspected, but the VPS procedure was completed as planned. Biochemical analysis was consistent with that of chyle. DISCUSSION: Neonatal chylous ascites is a rare condition; hence, available data on pathophysiology and therapy in the literature are scarce. It is postulated that the MMC repair in neonates causes abdominal tautness, which leads to rupture of small lymphatics and raised intraportal pressure. The combination of these two processes results in extravasation of chyle from the gastrointestinal tract. Presence of chyloperitoneum is not a contraindication for VPS insertion. CONCLUSION: Chyloperitoneum is an extremely rare sequela of MMC repair in neonates. Pediatric neurosurgeons should be aware of it, especially when a VPS procedure is to follow a repair, in order to know how to deal with it and avoid unnecessary abandonment of the shunt.

Contextualized Filtering for Shared Cyber Threat Information.

Cyber threat information sharing is an imperative process towards achieving collaborative security, but it poses several challenges. One crucial challenge is the plethora of shared threat information. Therefore, there is a need to advance filtering of such information. While the state-of-the-art in filtering relies primarily on keyword- and domain-based searching, these approaches require sizable human involvement and rarely available domain expertise. Recent research revealed the need for harvesting of business information to fill the gap in filtering, albeit it resulted in providing coarse-grained filtering based on the utilization of such information. This paper presents a novel contextualized filtering approach that exploits standardized and multi-level contextual information of business processes. The contextual information describes the conditions under which a given threat information is actionable from an organization perspective. Therefore, it can automate filtering by measuring the equivalence between the context of the shared threat information and the context of the consuming organization. The paper directly contributes to filtering challenge and indirectly to automated customized threat information sharing. Moreover, the paper proposes the architecture of a cyber threat information sharing ecosystem that operates according to the proposed filtering approach and defines the characteristics that are advantageous to filtering approaches. Implementation of the proposed approach can support compliance with the Special Publication 800-150 of the National Institute of Standards and Technology.

ARES: Automated Risk Estimation in Smart Sensor Environments.

Industry 4.0 adoption demands integrability, interoperability, composability, and security. Currently, integrability, interoperability and composability are addressed by next-generation approaches for enterprise systems integration such as model-based standards, ontology, business process model life cycle management and the context of business processes. Security is addressed by conducting risk management as a first step. Nevertheless, security risks are very much influenced by the assets that the business processes are supported. To this end, this paper proposes an approach for automated risk estimation in smart sensor environments, called ARES, which integrates with the business process model life cycle management. To do so, ARES utilizes standards for platform, vulnerability, weakness, and attack pattern enumeration in conjunction with a well-known vulnerability scoring system. The applicability of ARES is demonstrated with an application example that concerns a typical case of a microSCADA controller and a prototype tool called Business Process Cataloging and Classification System. Moreover, a computer-aided procedure for mapping attack patterns-to-platforms is proposed, and evaluation results are discussed revealing few limitations.

Exploration of zinc-binding groups for the design of inhibitors for the oxytocinase subfamily of M1 aminopeptidases.

The oxytocinase subfamily of M1 aminopeptidases consists of three members, ERAP1, ERAP2 and IRAP that play several important biological roles, including key functions in the generation of antigenic peptides that drive human immune responses. They represent emerging targets for pharmacological manipulation of the immune system, albeit lack of selective inhibitors is hampering these efforts. Most of the previously explored small-molecule binders target the active site of the enzymes via strong interactions with the catalytic zinc(II) atom and, while achieving increased potency, they suffer in selectivity. Continuing our earlier efforts on weaker zinc(II) binding groups (ZBG), like the 3,4-diaminobenzoic acid derivatives (DABA), we herein synthesized and biochemically evaluated analogues of nine potentially weak ZBGs, based on differential substitutions of functionalized pyridinone- and pyridinethione-scaffolds, nicotinic-, isonicotinic-, aminobenzoic- and hydrazinobenzoic-acids. Crystallographic analysis of two analogues in complex with a metalloprotease (MMP-12) revealed unexpected binding topologies, consistent with the observed affinities. Our results suggest that the potency of the compounds as inhibitors of ERAP1, ERAP2 and IRAP is primarily driven by the occupation of active-site specificity pockets and their proper orientation within the enzymes.

Brain Activation During Singing: "Clef de Sol Activation" Is the "Concert" of the Human Brain.

Humans are the most complex singers in nature, and the human voice is thought by many to be the most beautiful musical instrument. Aside from spoken language, singing represents a second mode of acoustic communication in humans. The purpose of this review article is to explore the functional anatomy of the "singing" brain. Methodologically, the existing literature regarding activation of the human brain during singing was carefully reviewed, with emphasis on the anatomic localization of such activation. Relevant human studies are mainly neuroimaging studies, namely functional magnetic resonance imaging and positron emission tomography studies. Singing necessitates activation of several cortical, subcortical, cerebellar, and brainstem areas, served and coordinated by multiple neural networks. Functionally vital cortical areas of the frontal, parietal, and temporal lobes bilaterally participate in the brain's activation process during singing, confirming the latter's role in human communication. Perisylvian cortical activity of the right hemisphere seems to be the most crucial component of this activation. This also explains why aphasic patients due to left hemispheric lesions are able to sing but not speak the same words. The term clef de sol activation is proposed for this crucial perisylvian cortical activation due to the clef de sol shape of the topographical distribution of these cortical areas around the sylvian fissure. Further research is needed to explore the connectivity and sequence of how the human brain activates to sing.

Music and the nucleus accumbens.

Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA.

Rigid spiroethers targeting the decoding center of the bacterial ribosome.

Continuing our efforts towards understanding the principles governing ribosomal recognition and function, we have synthesized and evaluated a series of diversely functionalized 5,6-, 6,6- and 7,6-spiroethers. These compounds successfully mimic natural aminoglycosides regarding their binding to the decoding center of the bacterial ribosome. Their potential to inhibit prokaryotic protein production in vitro along with their antibacterial potencies have also been examined.

Emerging patterns of the human superior thyroid artery and review of its clinical anatomy.

PURPOSE: There is wide variability of the location of the superior thyroid artery (STA). Our purpose was to describe variations of the STA origin, with great respect to different anatomical patterns which could be observed in humans. METHODS: The material was 68 formalin-embalmed adult cadavers of both sexes (45-70-year-old). Methodologically, we dissected the neck region bilaterally and focused on studying the external carotid artery (ECA) branches, especially the STA emerging pattern. We also measured the distance of the STA origin from the common carotid artery (CCA) bifurcation (using the latter as a landmark). RESULTS: Based on our results we categorized the STA emerging pattern into three major types A, B and C according to its origin (which was CCA, ECA and CCA bifurcation, respectively). Regarding type B, we found that the left STA arises approximately 2 mm closer to the CCA bifurcation compared to the right STA (p < 0.05). CONCLUSIONS: The STA is a carotid branch with variable origin, which can be CCA, ECA or CCA bifurcation. It is also an artery of great clinical importance in head and neck surgery. The present study provided data of the STA emerging patterns, as well as a review of its clinical anatomy.

Scientific Contributions of Prof. Valentin Felixovich Voyno-Yasenetsky (Saint Luke of Simferopol; 1877-1961) to Surgical Operations of the Nervous System.

Valentin Felixovich Voyno-Yasenetsky (VFVY; also known as Saint Luke of Simferopol) was a famous professor of anatomy and surgery of the previous century. He was a particularly skilled surgeon, proficient in various surgical subspecialties, with main interest in regional anesthesia and pyogenic infections. The primary aim of this article is to explore his scientific contributions to surgical operations of the nervous system. His contributions are in three primary fields, namely, neuroanatomy, neurosurgery, and regional anesthesia. His work is characterized by meticulous descriptions of various anatomical structures of the brain and skull and of the intraoperative findings of his neurosurgical procedures. He clarified neurosurgical terms and described neurosurgical techniques. He also provided advice regarding the safety of neurosurgical procedures. Furthermore, he pioneered in techniques for regional anesthesia of the sciatic and trigeminal nerves. His exceptional talent as a scientist and surgeon, as well as his contributions to the neurosciences, makes him an exemplary doctor for modern neurosurgeons.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

A powerful way of teaching anatomy.

I read the article entitled "A plea for the use of drawing in human anatomy teaching", by Clavert et al. with great interest. I was glad to read that, in France, anatomy is initially taught by building each structure or region on a blackboard with colored chalk. I find this method quite efficient for this purpose. I believe that drawing is a powerful way of teaching anatomy and therefore the blackboard deserves its rightful place beside other 'high-tech' media. I agree with the authors that the blackboard and the chalk constitute wonderful and powerful educational media, and that appropriate simplification and transposing (of anatomical information) in daily practice are necessary for a sufficient educational result. Among other 'modern' media, movies of surgical procedures could easily attract the students' attention.

Nucleus accumbens changes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), a representative example of motor neuron disease, is a progressive and fatal neurodegenerative disorder. The nucleus accumbens (NA) is the ventral striatum's main part and is considered as a modulator of the human brain's reward network. The purpose of this article is to review the current knowledge regarding NA changes in ALS patients. The NA involvement in ALS includes volumetric, cellular and molecular changes. There are recent imaging and pathological studies revealing NA atrophy in ALS, a finding which seems to be related to neuronal loss and protein deposition in this area. The clinical significance of NA atrophy in these patients is not currently fully understood. Perhaps it could be correlated with apathy, behavioral disturbances and cognitive impairment that ALS patients sometimes manifest.

Vasospasm in Pediatric Subarachnoid Hemorrhage.

Cerebral vasospasm (CV) is a common severe complication of subarachnoid hemorrhage (SAH), a severe type of intracranial bleeding that is uncommon in children. The purpose of this article is to review the current literature regarding this potentially devastating complication. CV may be asymptomatic and is less common in children compared to adults. Several molecular phenomena, including inflammatory ones, contribute to its pathophysiology. Better collateral circulation and higher cerebral blood flow are protective factors in children. When clinically apparent, CV may manifest as a change in the child's neurologic status or vital signs. CV can be diagnosed using brain vessel imaging, such as computed tomography angiography, magnetic resonance angiography, digital subtraction angiography, transcranial Doppler ultrasonography, and computed tomography perfusion. A reduction of < 50% in the artery's caliber confirms the diagnosis. Besides general supportive measures and causative treatment of SAH, CV management options include the administration of calcium channel blockers and neurointerventional approaches, such as intra-arterial vasodilators and balloon angioplasty. Long-term outcomes in children are usually favorable.

Nucleus accumbens atrophy in Parkinson's disease (Mavridis' atrophy): 10 years later.

Parkinson's disease (PD) is a common neurodegenerative disorder associated with gray matter atrophy. The human nucleus accumbens (NA) is a major part of the ventral striatum and modulator of the reward network of the brain. It plays an important role in several cognitive and emotional functions. In patients with PD, dysfunction of this nucleus is correlated not only with movement disorders but also with various neuropsychological deficits and psychiatric symptoms. The human NA suffers atrophy in PD, which is called Mavridis' atrophy (MA), a well established characteristic of PD that was first described 10 years ago. The purpose of this article is to review the current knowledge regarding the clinical significance of MA. We currently know that it begins in early-stage PD patients, precedes clinical phenotype, and is part of the degeneration of the dopaminergic nigrostriatal system in these patients. MA has several clinical consequences. It is, more specifically, associated with the expression (and severity) of specific neuropsychiatric PD symptoms, namely cognitive impairment, apathy, disinhibition, and impulsive behavior, while its association with motor symptoms remains unclear. MA was recently suggested as a marker of global dysfunction in the mesocorticolimbic network. With new research data, new questions about MA emerge and further research is obviously necessary in order to effectively apply MA, as an imaging finding, to clinical practice.

Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on α-Hydroxy-ß-amino Acid Derivatives of Bestatin.

The oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the α-hydroxy-ß-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that α-hydroxy-ß-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases.

Designed spiro-bicyclic analogues targeting the ribosomal decoding center.

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.