Severe Central Nervous System Research Articles

Frequency of Meningococcal Meningitis Susceptibility Associated TLR4 +896 A/G (rs4986790) Allele in the Saudi Population

Meningococcal meningitis (MM) is a severe central nervous system (CNS) infection that occurs primarily in children. MM can damage brain areas associated with hearing, learning, reasoning, focus, and memory. Genetic changes, including single nucleotide polymorphisms (SNPs), which compromise pathogen recognition increase the risk and severity of MM. There is little data on how the variation in the frequency of the rs4986790 polymorphism in the Toll-like receptor 4 (TLR4) gene may affect the population of Saudi Arabia. This study sought to determine the allelic frequency and distribution of the TLR4 rs4986790 A/G polymorphism in the Saudi population and compare the data to other global populations. Data from epidemiological studies conducted in various ethnic groups were extracted using PUBMED (Medline) and similar web databases. An estimated 5.88% of the Saudi population harbors the TLR4 rs4986790 G variant allele. This differed significantly from the frequencies in populations in China (p=0.0002), Japan (p=0.0001), Korea (p=0.0001), and Mexico (p=0.01). The TLR4 rs4986790 polymorphism variant allele has a unique pattern in the Saudi population, which may be the result of racial differences. These findings could assist in the risk assessment of people harboring the TLR4 +896 GG genotype susceptible to MM in the Saudi population.

Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.

47 Systemic lupus erythematosus in Tunisian children: a case series

BackgroundChildhood–onset systemic lupus erythematosus (c-SLE) is the prototype of a multisystemic, inflammatory, heterogeneous autoimmune condition, characterized by simultaneous or sequential organ involvement. Compared with the adult onset form, c-SLE is thought to have a worse prognosis.ObjectivesTo review the epidemiological, and bio-clinical, characteristics of a c-SLE case series.MethodsThe files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviations were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test.ResultsFourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 ± 1.4 years, [5–13.8 years] and 10.75 ± 2.3 years [6–14 years], respectively. Only two children had a family history of autoimmune disease.The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting.The physical examination noted various anomalies. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all favorable for lupus. The musculoskeletal manifestations comprised arthralgia (71.4%), arthritis and myositis (14.3% each). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases each, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were dominated by proteinuria in 7 cases, followed by hematuria in 6 cases, and 2 cases of hypertension (associated with renal failure in one case). The renal biopsy was performed in one case showed a stage-2 lupus nephritis. Pleural effusion was observed in 3 cases, 3 cases of pneumonia, 2 cases of pericarditis, one case of myo-pericarditis and one case of central nervous system (CNS) lupus.Relevant results of the laboratory workup are illustrated in the following table:47 Table 1Laboratory testPerformed (%)Abnormal results (%)Erythrocyte sedimentation rate14 (100%)13 (92%)Antinuclear anti-bodies14 (100%)13 (92%)AntiDNA antibodies7 (50%)5 (71%)AntiSm antibodies8 (57%)5 (62%)Antiphospholipid antibodies8 (57%)5 (62%)Complement11 (78%)9 (81%)The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in one case each.The therapeutic management was based on corticosteroids in 11 cases, followed by hydroxychloroquine in 3 cases, while cyclophosphamides and immunoglobulin were used for one case each.The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.ConclusionChildhood–onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early stage diagnosis, and therefore prevent the serious complications of the disease.

85 Systemic lupus erythematosus in Tunisian children: a case series

BackgroundChildhood–onset systemic lupus erythematosus (c-SLE) is the prototype of a multisystem, inflammatory, heterogeneous autoimmune condition, characterized by simultaneous or sequential organ involvement. Compared with the adult-onset form, c-SLE have a worse prognosis.ObjectivesTo review the epidemiological, and bio-clinical, characteristics of a c-SLE case series.MethodsThe files of patients diagnosed as c-SLE in the pediatrics department of Monastir, Tunisia from January 2004 to March 2022 were reviewed. Mean and standard-deviation were used to express normally-distributed variables, as verified by the Kolmogorov-Smirnov statistical test.ResultsFourteen patients were collected. Female to male ratio was 6:1. Mean ages at lupus onset and diagnosis were 9.9 ± 1.4 years, [5–13.8 years] and 10.75 ± 2.3 years [6–14 years], respectively. Only two children had a family history of autoimmune disease.The initial admission was motivated primarily by skin and musculoskeletal manifestations, in 64.3% and 51.7% of cases, respectively. General signs (fever, asthenia) were observed in 35.7% of cases, hematological and gastrointestinal manifestations in 28.6% of cases each. In 3 cases, upper gastric endoscopy was performed prior to admission, in view of abdominal pain and vomiting.The physical examination noted various abnormalities. Malar rash (50%) and discoid lupus (28.6%) were the most frequent cutaneous manifestations, while skin biopsy was performed in three cases, all in keeping with lupus. The musculoskeletal manifestations were arthralgia (71.4%), arthritis and myositis (14.3%). Hematological manifestations included thrombocytopenia and leukopenia in 4 cases, as well as 3 cases of auto-immune hemolytic anaemia and splenomegaly. Renal manifestations were proteinuria in 7, haematuria in 6, and hypertension in 2 (with renal failure in one of the patients). The renal biopsy that was performed in one subject showed a class 2 lupus nephritis. Pleural effusion was observed in 3, pneumonia in 3, pericarditis in 2, myo-pericarditis in 1 and central nervous system (CNS) lupus in 1.Relevant results of the laboratory workup are illustrated in the following table:85 Table 1Laboratory testPerformed (%)Abnormal results (%)Erythrocyte sedimentation rate14 (100%)13 (92%)Antinuclear anti-bodies14 (100%)13 (92%)AntiDNA antibodies7 (50%)5 (71%)AntiSm antibodies8 (57%)5 (62%)Antiphospholipid antibodies8 (57%)5 (62%)Complement11 (78%)9 (81%)The formal diagnosis of SLE was established according to the ACR-1997 criteria in 7 cases (50%), the SLICC-2012 in 4 cases (28.6%) and EULAR/ACR-2019 in 3 cases (21.4%). The c-SLE diagnosis was associated with coeliac disease and Hashimoto thyroiditis in two of the subjects respectively.The therapeutic management was based on corticosteroids in 11 cases, hydroxychloroquine in 3, while cyclophosphamides and immunoglobulin were used for two subjects respectively.The outcomes were heterogeneous. Among 11 patients with sufficient follow-up, 6 cases of remission and 2 cases of relapse were noted. Major adverse events were not infrequent: one case each of cardiac tamponade, macrophage activation syndrome and severe CNS lupus were observed, all fatal.ConclusionChildhood–onset systemic lupus is a challenging disease, both to diagnose and to treat. The development of new criteria of higher specificity and sensitivity has greatly helped identify the incomplete types of lupus and allow for early-stage diagnosis, therefore preventing the serious complications of the disease.

Novel mutation in SMPD1 gene found by whole-exome sequencing in Niemann-Pick disease patient

Niemann-Pick diseases (NPD) are heterogeneous and autosomal recessive disorders and are classified into four types: type A, type B, type C1, and type C2 that type A and B Niemann–Pick is induced via SMPD1 gene mutations. Accumulation of sphingomyelin in the central nervous system is the first and prominent cause of the classical infantile type (type A) of NPD which is the most extreme form of NPD and causes severe central nervous system decay, hepatosplenomegaly, and fatal disorder. Our aim with this study was to propose that the novel likely pathogenic variant, c.1586G>C (p.529Trp>Ser) can cause Niemann-Pick disease type A. Present study involves a 2 years-old child as a result of a consanguineous marriage that has been diagnosed with clumsiness and gait disturbance at the beginning, and include hypotonia, microcephaly, severe hepatosplenomegaly in infancy, speech and developmental delay, dysphagia during the disease course. Considering the symptoms of Niemann-Pick disease, the patient's DNA was extracted and used for molecular studying and sequencing. Performing WES on proband identified a novel likely pathogenic, c.1586G>C (p.529Trp>Ser) mutation of the SMPD1 gene. This gene has an autosomal recessive inheritance pattern. To date, c.1586G>C (p.529Trp>Ser) likely pathogenic variant has not been observed or reported in the world. This mutation locates in the 6415659 positions and disrupts the function of the SMPD1 gene, causing symptoms of Niemann-Pick disease type A. The mutation reported in this article is associated with the NPD type A, disease phenotype, molecular findings and clinical observations underscore it.

Evaluation of anifrolumab safety in systemic lupus erythematosus: A meta-analysis and systematic review.

ObjectivesSystemic lupus erythematosus (SLE) is a chronic autoimmune disease, and type I interferon plays an important role in its pathogenesis. Anifrolumab is a new strategy for the treatment of systemic lupus erythematosus. It could antagonize the activity of all type 1 interferons by binding with type I interferon receptor subunit 1. The aim of our study was to evaluate the safety of anifrolumab in patients with moderate to severe SLE (excluding patients with active severe lupus nephritis or central nervous system lupus).MethodsFour databases (Embase, Cochrane, PubMed, Web of Science) were systematically searched from inception until December 2021 for randomized controlled trials (RCTs) evaluating the safety of anifrolumab versus placebo in SLE patients. Then, the incidence of adverse events in each study was aggregated using meta-analysis.ResultsA total of 1160 SLE patients from four RCTs were included in the analysis. Serious adverse events were less common in the anifrolumab group than in the placebo group (RR: 0.76, 95% CI: 0.59-0.98, p<0.03). The most common adverse events included upper respiratory tract infection (RR: 1.48, 95% CI: 1.13-1.94, P=0.004), nasopharyngitis (RR: 1.66, 95% CI: 1.25-2.20, P=0.0004), bronchitis (RR: 1.96, 95% CI: 1.32-2.92, P=0.0009), and herpes zoster (RR: 3.40, 95% CI: 1.90-6.07, P<0.0001).ConclusionAnifrolumab is considered a well-tolerated option for the treatment of SLE patients with good safety.Systematic Review Registration https://inplasy.com, identifier 202230054.

A Minimal Physiologically Based Pharmacokinetic Model to Characterize CNS Distribution of Metronidazole in Neuro Care ICU Patients

Understanding antibiotic concentration-time profiles in the central nervous system (CNS) is crucial to treat severe life-threatening CNS infections, such as nosocomial ventriculitis or meningitis. Yet CNS distribution is likely to be altered in patients with brain damage and infection/inflammation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model to predict brain concentration-time profiles of antibiotics and to simulate the impact of pathophysiological changes on CNS profiles. A minimal PBPK model consisting of three physiological brain compartments was developed from metronidazole concentrations previously measured in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) of eight brain-injured patients. Volumes and blood flows were fixed to their physiological value obtained from the literature. Diffusion clearances characterizing transport across the blood–brain barrier and blood–CSF barrier were estimated from system- and drug-specific parameters and were confirmed from a Caco-2 model. The model described well unbound metronidazole pharmacokinetic profiles in plasma, ECF and CSF. Simulations showed that with metronidazole, an antibiotic with extensive CNS distribution simply governed by passive diffusion, pathophysiological alterations of membrane permeability, brain ECF volume or cerebral blood flow would have no effect on ECF or CSF pharmacokinetic profiles. This work will serve as a starting point for the development of a new PBPK model to describe the CNS distribution of antibiotics with more limited permeability for which pathophysiological conditions are expected to have a greater effect.

Exploring the nature of interaction between shiga toxin producing Escherichia coli (STEC) and free-living amoeba - Acanthamoeba sp

Free-living amoebae (FLA) are widely distributed protozoa in nature, known to cause severe eye infections and central nervous system disorders. There is growing attention to the potential role that these protozoa could act as reservoirs of pathogenic bacteria and, consequently, to the possibility that, the persistence and spread of the latter may be facilitated, by exploiting internalization into amoebae. Shiga toxin-producing strains of Escherichia coli (STEC) are zoonotic agents capable of causing serious diseases, such as hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Cattle represent the main natural reservoir of STEC, which are frequently found also in other domestic and wild ruminants, often without causing any evident symptoms of disease. The aspects related to the ecology of STEC strains in animal reservoirs and the environment are poorly known, including the persistence of these microorganisms within niches unfavorable to survival, such as soils or waters. In this study we investigated the interaction between STEC strains of serotype O157: H7 with different virulence gene profiles, and a genus of a wild free-living amoeba, Acanthamoeba sp. Our results confirm the ability of STEC strains to survive up to 20 days within a wild Acanthamoeba sp., in a quiescent state persisting in a non-cultivable form, until they reactivate following some stimulus of an unknown nature. Furthermore, our findings show that during their internalization, the E. coli O157 kept the set of the main virulence genes intact, preserving their pathogenetic potential. These observations suggest that the internalization in free-living amoebae may represent a means for STEC to resist in environments with non-permissive growth conditions. Moreover, by staying within the protozoa, STEC could escape their detection in the vehicles of infections and resist to the treatments used for the disinfection of the livestock environment.

Outpatient Parenteral Antibiotic Treatment vs Hospitalization for Infective Endocarditis: Validation of the OPAT-GAMES Criteria.

BackgroundOutpatient parenteral antibiotic treatment (OPAT) programs are increasingly used to manage infective endocarditis (IE), but current criteria for indicating OPAT are markedly conservative. We aimed to investigate whether more liberal criteria for indicating OPAT in IE can be safely used.MethodsThis was a prospective multicenter nationwide cohort study (2008–2018). Rates of readmission, recurrences, and 1-year mortality were compared between hospital-based antibiotic treatment (HBAT) and OPAT. Risk factors for readmission and mortality in OPAT patients were investigated by logistic regression. Patients did not fulfill OPAT-GAMES (Grupos de Apoyo al Manejo de la Endocarditis en ESpaña) criteria if they had any of the following: cirrhosis, severe central nervous system emboli, undrained abscesses, severe conditions requiring cardiac surgery in nonoperable patients, severe postsurgical complications, highly difficult-to-treat microorganisms, or intravenous drug use.ResultsA total of 2279 HBAT patients and 1268 OPAT patients were included. Among OPAT patients, 307 (24.2%) did not fulfill OPAT-GAMES criteria. Overall, OPAT patients presented higher rates of readmission than HBAT patients (18.2% vs 14.4%; P = .004), but no significant differences were found in the propensity analysis. Patients not fulfilling OPAT-GAMES criteria presented significantly higher rates of readmission than HBAT and OPAT-GAMES (23.8%, 14.4%, 16.4%; P < .001), whereas no significant differences were found in mortality (5.9%, 8%, 7.4%; P = .103) or recurrences (3.9%, 3.1%, 2.5%; P = .546). Not fulfilling OPAT-GAMES criteria was associated with higher risk of readmission (odds ratio [OR], 1.43; 95% CI, 1.03–1.97; P = .03), whereas cardiac surgery was associated with lower risk (OR, 0.72; 95% CI, 0.53–0.98; P = .03).ConclusionsOPAT-GAMES criteria allow identification of IE patients at higher risk of long-term complications to whom OPAT cannot be safely administered.

Understanding global changes of the mouse brain proteome after vaginal infection with HSV-2 using a label-free shotgun approach.

Herpes simplex virus type 2 (HSV-2) is a common human pathogen that establishes lifelong latency in neurons of the nervous system. The number of severe central nervous system infections caused by the virus has increased recently. However, the pathogenesis of HSV-2 infection in the nervous system is not fully understood. Here, we demonstrated global proteomic changes in the brain tissue in BALB/c mice vaginally infected with HSV-2. Data are available via ProteomeXchange with identifier PXD034186. A total of 249 differentially expressed proteins were identified in infected brain tissue. The GO and KEGG enrichment analysis of these proteins indicated that they were mainly involved in the regulation of synapse formation and synaptic excitability. In addition, genes affecting autophagy, the development of other neurodegenerative diseases, and signaling pathways relevant to other neurologic diseases were identified. Additional experiments, comparing the brain tissue of asymptomatic and symptomatic mice showed a differential expression of proteins involved in synapse formation and synaptic transmission. Others were involved in autophagy, addiction, and signaling pathways of other neurologic diseases. These results suggest that changes in synaptic structure and function, as well as autophagy, may be related to the development of neurologic abnormalities that follow HSV-2 infection. We also identified a protein GluN2A encoded by Grin2a was continuously expressed at high levels after infection. We propose that GluN2A may be a key molecule in the pathogenesis of HSV-2-induced neurologic diseases.

Central nervous system manifestations of monogenic autoinflammatory disorders and the neurotropic features of SARS-CoV-2: Drawing the parallels.

Central nervous system (CNS) involvement in monogenic autoinflammatory disorders (AID) is increasingly recognized and can be life threatening. Therefore, a low threshold to consider CNS disease should be maintained in patients with systemic inflammation. Hyperinflammation is also a key feature of severe acute COVID-19 and post COVID-19 entities such as multisystem inflammatory syndrome in children. Like AID, COVID-19 patients can present with severe CNS involvement. The impact of COVID-19 on AID and CNS involvement in particular is still obscure, nevertheless dreaded. In the current review, we synthesize the spectrum of CNS manifestations in monogenic AID. We explore common pathophysiological and clinical features of AID and COVID-19. Moreover, we assess the impact of immune dysregulation associated with SARS-CoV-2 infections and post COVID-19 hyperinflammation in AID. The striking commonalities found between both disease entities warrant caution in the management of AID patients during the current pandemic.

Isolation and characterization of phage display-derived scFv antibodies against human parechovirus 1 VP0 protein

Human parechoviruses (PeVs) are common viruses that are associated with a variety of diseases from mild gastrointestinal and respiratory symptoms to severe central nervous system infections. Until now there has not been antibodies for visualizing parechovirus infection. We used E. coli recombinant PeV-A1-VP0 protein as a target in phage display single chain variable fragment (scFv) antibody library panning. Three rounds of panning allowed identification and isolation of several candidate scFv clones, which tested positive in enzyme-linked immunosorbent assay (ELISA) against VP0. Three scFv clones (scFv-55, -59 and -71) with different CDR-3 sequences were further purified and tested in ELISA, Western blot and immunofluorescence microscopy (IFA) against a set of PeV-A1 isolates and a few isolates representing PeV types 2–6. In IFA, all three scFv binders recognized twenty PeV-A1 isolates. ScFv-55 and -71 also recognized clinical representatives of PeV types 1–6 both in IFA and in capture ELISA, while scFv-59 only recognized PeV-A1, -A2 and -A6. PeV-A1-VP0 (Harris strain) sequence was used to generate a peptide library, which allowed identification of a putative unique conformational antibody epitope with fully conserved flanking regions and a more variable core VVTYDSKL, shared between the scFv antibodies. Sequencing of the VP0 region of virus samples and sequence comparisons against parechoviral sequences in GenBank revealed 107 PeV-A1, -A3, -A8, -A17, -A (untyped) sequences with this exact epitope core sequence, which was most dominant among PeV-A1 isolates. These data suggest the first-time isolation of broad range phage display antibodies against human parechoviruses that may be used in diagnostic antibody development.

Exosomes as Crucial Players in Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects multiple systems. Its clinical manifestation varies across patients, from skin mucosa to multiorgan damage to severe central nervous system involvement. The exosome has been shown to play an important role in the pathogenesis of autoimmune diseases, including SLE. We review the recent knowledge of exosomes, including their biology, functions, mechanism, and standardized extraction and purification methods in SLE, to highlight potential therapeutic targets for SLE.

Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia.

Pelizaeus–Merzbacher Disease (PMD) is an inherited leukodystrophy affecting the central nervous system (CNS)—a rare disorder that especially concerns males. Its estimated prevalence is 1.45–1.9 per 100,000 individuals in the general population. Patients affected by PMD exhibit a drastic reduction or absence of myelin sheaths in the white matter areas of the CNS. The Proteolipid Protein 1 (PLP1) gene encodes a transmembrane proteolipid protein. PLP1 is the major protein of myelin, and it plays a key role in the compaction, stabilization, and maintenance of myelin sheaths. Its function is predominant in oligodendrocyte development and axonal survival. Mutations in the PLP1 gene cause the development of a wide continuum spectrum of leukopathies from the most severe form of PMD for whom patients exhibit severe CNS hypomyelination to the relatively mild late-onset type 2 spastic paraplegia, leading to the concept of PLP1-related disorders. The genetic diversity and the biochemical complexity, along with other aspects of PMD, are discussed to reveal the obstacles that hinder the development of treatments. This review aims to provide a clinical and mechanistic overview of this spectrum of rare diseases.

Human myelin proteolipid protein structure and lipid bilayer stacking

The myelin sheath is an essential, multilayered membrane structure that insulates axons, enabling the rapid transmission of nerve impulses. The tetraspan myelin proteolipid protein (PLP) is the most abundant protein of compact myelin in the central nervous system (CNS). The integral membrane protein PLP adheres myelin membranes together and enhances the compaction of myelin, having a fundamental role in myelin stability and axonal support. PLP is linked to severe CNS neuropathies, including inherited Pelizaeus-Merzbacher disease and spastic paraplegia type 2, as well as multiple sclerosis. Nevertheless, the structure, lipid interaction properties, and membrane organization mechanisms of PLP have remained unidentified. We expressed, purified, and structurally characterized human PLP and its shorter isoform DM20. Synchrotron radiation circular dichroism spectroscopy and small-angle X-ray and neutron scattering revealed a dimeric, α-helical conformation for both PLP and DM20 in detergent complexes, and pinpoint structural variations between the isoforms and their influence on protein function. In phosphatidylcholine membranes, reconstituted PLP and DM20 spontaneously induced formation of multilamellar myelin-like membrane assemblies. Cholesterol and sphingomyelin enhanced the membrane organization but were not crucial for membrane stacking. Electron cryomicroscopy, atomic force microscopy, and X-ray diffraction experiments for membrane-embedded PLP/DM20 illustrated effective membrane stacking and ordered organization of membrane assemblies with a repeat distance in line with CNS myelin. Our results shed light on the 3D structure of myelin PLP and DM20, their structure–function differences, as well as fundamental protein–lipid interplay in CNS compact myelin.

Exome sequencing as first-tier test for fetuses with severe central nervous system structural anomalies.

ABSTRACTObjectivePrenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.MethodsThis was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA‐negative cases were offered ES. CMA‐positive cases were reanalyzed using ES to assess its ability to detect copy‐number variants (CNVs).ResultsCMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty‐six CMA‐negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non‐significantly higher compared with non‐recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA‐positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non‐causative CNVs.ConclusionsIn our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post‐TOP cases from a specialist referral center. These data suggest that ES may be considered as a first‐tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Phosphorylation of ERK-Dependent NF-κB Triggers NLRP3 Inflammasome Mediated by Vimentin in EV71-Infected Glioblastoma Cells.

Enterovirus 71 (EV71) is a dominant pathogenic agent that may cause severe central nervous system (CNS) diseases among infants and young children in the Asia-pacific. The inflammasome is closely implicated in EV71-induced CNS injuries through a series of signaling pathways. However, the activation pathway of NLRP3 inflammasome involved in EV71-mediated CNS injuries remains poorly defined. In the studies, EV71 infection, ERK1/2 phosphorylation, and activation of NLRP3 are abolished in glioblastoma cells with low vimentin expression by CRISPR/Cas9-mediated knockdown. PD098059, an inhibitor of p-ERK, remarkably blocks the vimentin-mediated ERK1/2 phosphorylation in EV71-infected cells. Nuclear translocation of NF-κB p65 is dependent on p-ERK in a time-dependent manner. Moreover, NLRP3 activation and caspase-1 production are limited in EV71-infected cells upon the caffeic acid phenethyl ester (CAPE) administration, an inhibitor of NF-κB, which contributes to the inflammasome regulation. In conclusion, these results suggest that EV71-mediated NLRP3 inflammasome could be activated via the VIM-ERK-NF-κB pathway, and the treatment of the dephosphorylation of ERK and NF-κB inhibitors is beneficial to host defense in EV71-infected CNS.

A two-decade review of butane toxicity as a substance of abuse.

Butane, an aliphatic hydrocarbon with explosive and flammable properties, is widely misused especially by young people. Acting as an asphyxiant gas, butane mainly targets the central nervous and cardiovascular systems. We aimed to review butane-attributed toxicities due to its harmful use or misuse reported in a two-decade period. We searched English-language publications reporting butane toxicities from 2000 up to 2021 and collected data on age, gender, route and source of exposure, country of origin, clinical presentation and outcome. Among 54 butane's harmful use/misuse cases identified in the literature, there were 11 survivors successfully discharged from the hospital. Patients were predominantly males with a mean age ± SD of 23 ± 13 years. The main route of exposure was inhalation. Manifestations were mainly cardiac and neurological. Majority of the cases were reported from Europe and Japan. To conclude, butane exposure is at risk of severe central nervous system and cardiac toxicities, which may result in a fatal outcome. Therefore, in the event of a sudden or suspicious death in a young individual, our findings suggest that butane's harmful use/misuse should be considered as a potential differential diagnosis.

Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase‐3 deficiency

ABSTRACTIntroductionPathogenic variants in PLOD3, encoding lysyl hydroxylase‐3 (LH3), can cause a hereditary connective tissue disorder that has rarely been reported. It is a multi‐system disease, presenting with craniofacial dysmorphisms, skeletal and eye manifestations, sensorineural hearing loss, and variable skin manifestations. Severe central nervous system involvement has not been reported.Case presentationA 10‐month‐old girl was admitted with development delay and clustered epileptic spasms. Hypertelorism, an upturned nose, and low‐set ears were noted in physical examination. Cerebral magnetic resonance imaging showed multiple intracranial malacias and bleeding foci, extensive abnormal signals in the white matter, and obvious brain atrophy, which was consistent with cerebral small vessel disease (SVD). Electroencephalography suggested hypsarrhythmia. The vertebrae were flattened. The distal end of the metacarpal bone in the left hand was irregular. She was diagnosed with West syndrome. Whole‐exome sequencing revealed a novel homozygous variant of c.1216_1218delCTC (p.L406del) in PLOD3, which was found to be inherited from her heterozygous parents.ConclusionWe report a patient with pathogenic PLOD3 mutation who presented with cerebral SVD. This report expands the phenotypic spectrum of LH3 deficiency.

Ocular involvement in STEC-associated hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a systemic thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and variable kidney involvement. Extrarenal thrombotic microangiopathy occurs in central nervous system (CNS), colon, and other organ systems, but ocular involvement is rarely recognized. This study aimed to analyze frequency and severity of ocular involvement in STEC-HUS, and the relationship between ocular involvement and disease severity, with emphasis on CNS, kidney, and colonic disease. Prospective, longitudinal, observational study. STEC-HUS patients September 2014-January 2019. Funduscopic examination (FE) was performed within 48h of admission. We evaluated severity of CNS disease, kidney involvement, and presence of hemorrhagic colitis (HC). Ninety-nine patients were included (female 52), mean age 39.4months (DE: 29.8; range 9-132). Thirteen patients (13.1%) had abnormal FE, 10 showing variable degrees of hemorrhagic exudates and 2 with typical Purtscher-like retinopathy. Other findings included tortuous vascularity, cotton wool spots, and transient retinal edema. CNS involvement was present in 16/99 patients, severe in 12 (75%). Abnormal FE occurred in 5/12 (31%) patients with severe CNS involvement vs. 8/87 (9.2%) with mild, moderate, or no CNS disease (p = 0.0191). Abnormal FE was present in 2/33 (6%) patients without dialysis vs. 11/66 (16.6%) requiring dialysis (p = 0.20). Finally, there were FE abnormalities in 6/20 patients with HC vs. 7/79 without HC (p = 0.012). FE abnormalities were present in 13% of HUS patients. Abnormal FE significantly associated with more severe disease, including severe CNS involvement and HC. We suggest FE should be performed in severe HUS, especially in cases with severe CNS disease. A higher resolution version of the Graphical abstract is available as Supplementary information.