Severe Central Nervous System Research Articles

Hymenoptera sting as atypical causative factor for Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy – A case report and insights on pathophysiology

Introduction. Neurological manifestations secondary to Hymenoptera stings are rare. However, the literature describes cases of severe central and peripheral nervous system damage. Suspected pathophysiological mechanisms include hypoxic-ischemic damage, demyelination, and the direct neurotoxic effect of venoms. In this context, bee stings could be a possible atypical causative factor for Guillan–Barré syndrome and chronic inflammatory demyelinating polyneuropathy. Case report. We present the case of a 32-year-old patient who declared the presence of a bee sting two weeks before the onset of neurological manifestations (flaccid quadriparesis, predominantly distal, with paresthesia at the same level) that were initially diagnosed as a Guillain Barré syndrome. Despite the treatment with immunoglobulins in the acute phase, the worsening of the motor deficit after one month required a new course of immunoglobulins, associating corticosteroids, with initially favorable evolution. However, the presence of a new relapse after eight weeks, correlated with changes such as albumin-cytological dissociation in the examination of the cerebrospinal fluid and the appearance of active denervation on the electroneuromyography study, established the final diagnosis of chronic inflammatory demyelinating polyneuropathy. Conclusions. We consider the presented case proof of the relationship between the Hymenoptera sting and various peripheral nervous system pathologies. Inflammatory and demyelinating changes common to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy appear to be the primary pathophysiological mechanism to explain this uncommon correlation.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease

IntroductionThe standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. MethodWe identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. ResultsAll six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DiscussionAmong a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Antiviral Mechanisms of Saucerneol from Saururus chinensis against Enterovirus A71, Coxsackievirus A16, and Coxsackievirus B3: Role of Mitochondrial ROS and the STING/TKB-1/IRF3 Pathway.

Enterovirus A71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus B3 (CVB3) are pathogenic members of the Picornaviridae family that cause a range of diseases, including severe central nervous system complications, myocarditis, and pancreatitis. Despite the considerable public health impact of these viruses, no approved antiviral treatments are currently available. In the present study, we confirmed the potential of saucerneol, a compound derived from Saururus chinensis, as an antiviral agent against EV71, CVA16, and CVB3. In the in vivo model, saucerneol effectively suppressed CVB3 replication in the pancreas and alleviated virus-induced pancreatitis. The antiviral activity of saucerneol is associated with increased mitochondrial ROS (mROS) production. In vitro inhibition of mROS generation diminishes the antiviral efficacy of saucerneol. Moreover, saucerneol treatment enhanced the phosphorylation of STING, TBK-1, and IRF3 in EV71- and CVA16-infected cells, indicating that its antiviral effects were mediated through the STING/TBK-1/IRF3 antiviral pathway, which was activated by increased mROS production. Saucerneol is a promising natural antiviral agent against EV71, CVA16, and CVB3 and has potential against virus-induced pancreatitis and myocarditis. Further studies are required to assess its safety and efficacy, which is essential for the development of effective antiviral strategies against these viruses.

Severe central nervous system demyelination in Sanfilippo disease.

Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients. Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms. Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice. Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Clinical and molecular characteristics of the 2022 Enterovirus-D68 outbreak among hospitalized children, Ohio, USA

BackgroundEnterovirus-D68 (EV-D68) has appeared biennially in the United States following the 2014 outbreak. It has gained epidemiologic and clinical relevance and was identified as an important pathogen associated with severe respiratory and central nervous system diseases. We aim to describe the clinical and molecular characteristics of the post-pandemic 2022 Enterovirus-D68 outbreak in children evaluated in a tertiary pediatric hospital in Columbus, Ohio. MethodsEV-D68 RT-PCR was performed on nasopharyngeal specimens collected during Jun—Nov 2022 from children (<18 years), identified by 1) physician-order or 2) random selection of 10–15 specimens weekly that were Rhinovirus/Enterovirus-positive by physician-ordered respiratory virus panel. Patients who tested positive for EV-D68 were identified and clinical data and outcomes were analyzed. Partial viral VP1 region was sequenced and characterized. ResultsForty-four children positive for EV-D68 were identified, among which 88.6 % of patients presented with respiratory symptoms and 61.4 % required PICU admission. Two patients presented with AFM that was attributed to EV-D68. EV-D68 sequences from 2022 clustered within the B3 subclade. ConclusionsA significant proportion of children identified with EV-D68 during the 2022 outbreak had respiratory compromise requiring PICU admission. As the virus continues evolving, it is important to monitor the activity of EV-D68, characterizing these strains clinically and genetically, which will help to understand the viral pathogenicity and virulence.

Analysis of Vacuum-Assisted Closure-Assisted Antibiotic Irrigation in Treatment of Severe Neurosurgical Central Nervous System Infections.

Objective: Severe neurosurgical central nervous system infections (sNCNSIs) are among the most serious complications of neurosurgical disease. Conventional methods have shown a poor prognosis. This study aims to analyze the clinical characteristics of vacuum-assisted closure (VAC) in sNCNSIs with the help of antibiotic irrigation treatment. Patients and Methods: A retrospective study was performed for patients diagnosed with sNCNSIs. A VAC device was placed on the incision after debridement and the surgical cavity was rinsed with antibiotic agents in the VAC group. Meanwhile the surgical cavity was drained after debridement in the control group. Medical data were reviewed and analyzed. Results: Twenty-eight patients met the inclusion criteria, including 18 cases in the VAC group and 10 cases in the control group. The basic medical data showed no differences. Bacteria was isolated from 24 (85.7%) patients. The cure rate was significantly higher in the VAC group (p < 0.05). The cure rate in patients with multi-drug-resistant (MDR) infections was significantly higher in patients treated with VAC therapy (p < 0.05). The prognosis evaluated by Glasgow Outcome Score (GOS) between the two groups showed significant difference (p < 0.05). No re-infection in the VAC group occurred in the follow-up period. Conclusions: It is suggested that VAC-assisted antibiotic irrigation is safe and effective for patients with severe NCNSIs and can improve the prognosis dramatically. The results can provide a new effective and reasonable therapeutic strategy for patients with sNCNSIs.

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia during remission induction chemotherapy: a single-center retrospective study.

This study investigated the clinical characteristics, cranial magnetic resonance imaging (MRI) features, MRI follow-up, and prognosis of children with acute lymphoblastic leukemia (ALL) who developed posterior reversible encephalopathy syndrome (PRES) during remission induction chemotherapy. We analyzed the age, gender, PRES symptoms and signs, cranial MRI findings, therapeutic effect, and prognosis of children with ALL who developed PRES during chemotherapy from January 2010 to December 2013 at the Hematology Oncology Center of Beijing Children's Hospital. Changes in cranial MRI findings were analyzed, and intelligence (IQ) and cognitive function were evaluated using the Wechsler Scale and the Wisconsin Card Score Test after the children completed chemotherapy. There were 850 children with newly diagnosed ALL in this period; 13 (1.5%), 6 boys and 7 girls, developed PRES. All were diagnosed as B-cell ALL. The median age at PRES onset was 7 years (2-11 years). The median day of PRES onset was day 28 (day 17-34) of remission induction chemotherapy. Of the 13 children with PRES onset and seizures, 4 had visual disturbances and 2 had consciousness disturbances. Cranial MRI showed hyperintensity in the subcortical white matter on T2-weighted axial and fluid-attenuated inversion recovery (FLAIR) images. The lesion locations were as follows: occipital lobe, 12 (92.3%) patients; frontal lobe, 7 (53.8%) patients; temporal lobe, 5 (38.4%) patients; parietal lobe, 3 (23.1%) patients; and cerebellum, 1 (7.7%) patient. There were 8 (61.5%) patients with vasogenic edema and 5 (38.5%) with cytotoxic edema. After treatment, all children recovered within one month, when their PRES symptoms were relieved, they continued to receive chemotherapy. However, 1 child (1.07%) died of severe central nervous system infection one year after PRES treatment, and 3 (25%) had recurrent seizures and were diagnosed with epilepsy after three months of PRES treatment. Their cranial MRIs showed cytotoxic edema, which was acute stage on day 15, with aggravated lesions on cranial MRI. The cranial MRI lesions returned to normal at one month in 3 (23.1%) patients, at three months in 6 (46.1%) patients, at one year in 8 (61.5%) patients, and at two years in 12 (92.3%) patients. The 12 surviving children all returned to school, and their full-scale, verbal, and performance IQs were normal, with no significant differences in intelligence or cognitive function compared with children with ALL without PRES during the same period. PRES can occur during remission induction chemotherapy treatment of children with ALL, but the incidence is low. Cranial MRI can be used for diagnosis and to characterize lesions. The children recover about a month after treatment, and cranial MRI lesions return to normal within two years. The time for complete resolution of MRI lesions differs, and children with cytotoxic edema have worse prognosis with sequelae, such as epilepsy, which requires close monitoring. PRES does not affect intelligence or cognitive development.

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-β (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Successful Treatment of Carbapenem-Resistant Klebsiella pneumoniae Meningitis with Combination Therapy of Meropenem and Amikacin

Introduction: The widespread use of carbapenems increased the prevalence of Carbapenem-resistant Enterobacteriaceae with subsequent increases in mortality due to extremely limited treatment options. Following neurosurgical procedures, carbapenem-resistant Klebsiella pneumoniae (CRKP) is the main cause of central nervous system (CNS) infections. The optimal antimicrobial treatment of such infections has not yet been defined. Case Presentation: We present a 4-month-old boy with an extra-ventricular drain-related central nervous system (CNS) infection with CRKP. Although meropenem minimum inhibitory concentration (MIC) for the bacterial isolate was ≥ 16 mg/L and it harbored blaNDM, blaVIM, and blaOXA-48-like Carbapenemase genes, this infection was effectively treated with a combination therapy of intravenous (IV) double dose extended infusion of meropenem in addition to amikacin. Conclusions: This successful treatment regimen for CRKP-causing meningitis may pave the way to manage severe CNS infections with extensive-drug-resistant bacteria in infants and children without inserting an external drain or intra-thecal antibiotic administration.

Optik sinir hipoplazisi;Olgu sunumu

Optic nerve hypoplasia (ONH) is a rare neurodevelopmental disorder described by the optic disc is abnormally small regardless of sex or race. Imaging methods are frequently used in the diagnosis. In our case, a 17-year-old male patient, came to the clinic because of a deviation in his left eye, the examination showed hypoplasia of the optic nerve in the left eye. In ON hypoplasia, reported cases may include severe Central nervous system (CNS) malformations. However, we recommend periodic systemic examinations along with occupational rehabilitation, parental education and mobility training for these unique children.

BDNF-TrkB/proBDNF-p75NTR pathway regulation by lipid emulsion rescues bupivacaine-induced central neurotoxicity in rats

Bupivacaine (BPV) can cause severe central nervous system toxicity when absorbed into the blood circulation system. Rapid intravenous administration of lipid emulsion (LE) could be used to treat local anaesthetic toxicity. This study aimed to investigate the mechanism by which the BDNF-TrkB/proBDNF-p75NTR pathway regulation by LE rescues BPV induced neurotoxicity in hippocampal neurons in rats. Seven- to nine-day-old primary cultured hippocampal neurons were randomly divided into 6 groups: the blank control group (Ctrl), the bupivacaine group (BPV), the lipid emulsion group (LE), the bupivacaine + lipid emulsion group (BPV + LE), the bupivacaine + lipid emulsion + tyrosine kinase receptor B (TrkB) inhibitor group (BPV + LE + K252a), the bupivacaine + lipid emulsion + p75 neurotrophic factor receptor (p75NTR) inhibitor group (BPV + LE + TAT-Pep5). All hippocampal neurons were incubated for 24 h, and their growth state was observed by light microscopy. The relative TrkB and p75NTR mRNA levels were detected by real-time PCR. The protein expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, TrkB, p75NTR and cleaved caspase-3 were detected by western blotting. The results showed that primary hippocampal neuron activity was reduced by BPV. As administration of LE elevated hippocampal neuronal activity, morphology was also somewhat improved. The protein expression and mRNA levels of TrkB and p75NTR were decreased when BPV induced hippocampal neuronal toxicity, while the expression of BDNF was increased. At the same time, BPV increased the original generation of cleaved caspase-3 protein content by hippocampal neurons, while the content of cleaved caspase-3 protein in hippocampal neurons cotreated with LE and BPV was decreased. Thus, this study has revealed LE may reduce apoptosis and promote survival of hippocampal neurons by regulating the BDNF-TrkB pathway and the proBDNF-p75NTR pathway to rescue BPV induced central neurotoxicity in rats.

Clinical features, etiologies, and outcomes of central nervous system infections in intensive care: A multicentric retrospective study in a large Brazilian metropolitan area

PurposeThe goal of this study was to investigate severe central nervous system infections (CNSI) in adults admitted to the intensive care unit (ICU). We analyzed the clinical presentation, causes, and outcomes of these infections, while also identifying factors linked to higher in-hospital mortality rates. Materials and methodsWe conducted a retrospective multicenter study in Rio de Janeiro, Brazil, from 2012 to 2019. Using a prediction tool, we selected ICU patients suspected of having CNSI and reviewed their medical records. Multivariate analyses identified variables associated with in-hospital mortality. ResultsIn a cohort of 451 CNSI patients, 69 (15.3%) died after a median 11-day hospitalization (5–25 IQR). The distribution of cases was as follows: 29 (6.4%) had brain abscess, 161 (35.7%) had encephalitis, and 261 (57.8%) had meningitis. Characteristics: median age 41 years (27–53 IQR), 260 (58%) male, and 77 (17%) HIV positive. The independent mortality predictors for encephalitis were AIDS (OR = 4.3, p = 0.01), ECOG functional capacity limitation (OR = 4.0, p < 0.01), ICU admission from ward (OR = 4.0, p < 0.01), mechanical ventilation ≥10 days (OR = 6.1, p = 0.04), SAPS 3 ≥ 55 points (OR = 3.2, p = 0.02). Meningitis: Age > 60 years (OR = 234.2, p = 0.04), delay >3 days for treatment (OR = 2.9, p = 0.04), mechanical ventilation ≥10 days (OR = 254.3, p = 0.04), SOFA >3 points (OR = 2.7, p = 0.03). Brain abscess: No associated factors found in multivariate regression. ConclusionsPatients' overall health, prompt treatment, infection severity, and prolonged respiratory support in the ICU all significantly affect in-hospital mortality rates. Additionally, the implementation of CNSI surveillance with the used prediction tool could enhance public health policies.

Neurological Complications Associated with Hereditary Bleeding Disorders.

Hereditary bleeding disorders may have a wide variety of clinical presentations ranging from mild mucosal and joint bleeding to severe central nervous system (CNS) bleeding, of which intracranial hemorrhage (ICH) is the most dreaded complication. In this review, we will discuss the pathophysiology of specific hereditary bleeding disorders, namely, hemophilia A, hemophilia B, and von Willebrand disease (vWD); their clinical manifestations with a particular emphasis on neurological complications; a brief overview of management strategies pertaining to neurological complications; and a review of literature guiding treatment strategies. ICH is the most significant cause of morbidity and mortality in patients with hemophilia. Adequate control of bleeding with the administration of specific factors or blood products, identification of risk factors for bleeding, and maintaining optimal coagulant activity are essential for appropriately managing CNS bleeding complications in these patients. The administration of specific recombinant factors is tailored to a patient's pharmacokinetics and steady-state levels. During acute bleeding episodes, initial factor activity should be maintained between 80 and 100%. Availability of monoclonal antibody Emicizumab has revolutionized prophylactic therapies in patients with hemophilia. Management of ICH in patients with vWD involves using plasma-derived factor concentrates, recombinant von Willebrand factor, and supportive antifibrinolytic agents individualized to the type and severity of vWD. Hemophilia and vWD are the most common hereditary bleeding disorders that can predispose patients to life-threatening CNS complications-intracranial bleeds, intraspinal bleeding, and peripheral nerve syndromes. Early care coordination with a hematologist can help develop an effective prophylactic regimen to avoid life-threatening bleeding complications in these patients. Further research is needed to evaluate using emicizumab as an on-demand treatment option for acute bleeding episodes in patients with hemophilia.

Neurogenic heterotopic ossification: A review. Part 1

BACKGROUND: Heterotopic ossification is the formation of bone tissues in the soft tissues of the body. A distinct form of heterotopic ossification is neurogenic, that is, resulting from severe injury to the brain or spinal cord of different genesis. Neurogenic heterotopic ossification is a complex multifactorial process of differentiated bone formation in the paraarticular soft tissues of large joints. Heterotopic ossification leads to the formation of persistent contractures and ankylosis, which cause severe disability and complicate rehabilitation.&#x0D; AIM: To analyze publications dealing with various aspects of neurogenic heterotopic ossification.&#x0D; MATERIALS AND METHODS: In the first part of our review, we present the results of the literature analysis on the epidemiology, risk factors, pathogenesis, and clinic and laboratory diagnosis of neurogenic heterotopic ossification. Scientific literature databases PubMed, Google Scholar, Cochrane Library, Crossref, and eLibrary were searched for without language limitations.&#x0D; RESULTS: Current literature data on heterotopic ossification in patients with central nervous system pathologies are presented. Topical questions of etiology, risk factors, pathogenesis, and clinic and laboratory diagnostics of this pathological process are highlighted.&#x0D; CONCLUSIONS: Understanding the risk factors of heterotopic ossification development and their prevention in the context of the modern knowledge of heterotopic ossification pathogenesis may help reduce the incidence of heterotopic ossification in patients with severe central nervous system injury.

Can vitamin B6 alleviate the adverse reactions of quadruple anti-Helicobacter pylori regimen? : randomized controlled trial

BackgroundVitamin B6 is an essential water-soluble vitamin for humans. It is often used to prevent a variety of neuropathies, relieve vomiting, and relieve symptoms such as hand and foot neuritis.AimTo evaluate whether vitamin B6 can alleviate the adverse reactions caused by the quadruple anti-Helicobacter pylori treatment regimen containing minocycline and metronidazole.MethodsIn this randomized controlled trial, 280 patients with H. pylori infection were randomly placed into one of two treatment groups—the conventional treatment group and the vitamin B6 supplement treatment group—for 2 weeks. The primary endpoint was the total incidence of adverse reactions up to 2 weeks after treatment initiation. The study was designed according to CONSORT Medicinal Interventions. And it was registered with Chinese Clinical Trial Registry under the number ChiCTR2100053833.ResultsIn terms of efficacy, vitamin B6 does not affect the efficacy of conventional regimen. In the vitamin B6 supplement treatment group, the incidence of adverse reactions was 56.92%, which was significantly lower than the 74.62% observed in the conventional treatment group. In addition, the severity of adverse reactions was also significantly reduced. The proportion of moderate to severe central nervous system symptoms decreased from 58.7 to 14.63%. And, the proportion of moderate to severe gastrointestinal reactions decreased from 33.33 to 0%. We speculate that the mechanism of vitamin B6 of reducing adverse reaction may be related to the production of GABA in the brain.ConclusionsVitamin B6 can alleviate adverse reactions of the quadruple anti-H. pylori regimen containing minocycline and metronidazole.

Development and evaluation of neutralizing antibodies for cross-protection against West Nile virus and Japanese encephalitis virus

BackgroundWest Nile virus is a severe zoonotic pathogen that can cause severe central nervous system symptoms in humans and horses, and is fatal for birds, chickens and other poultry. With no specific drugs or vaccines available, antibody-based therapy is a promising treatment. This study aims to develop neutralizing antibodies against West Nile virus and assess their cross-protective potential against Japanese encephalitis virus. MethodsMonoclonal antibodies against WNV and JEV were isolated by hybridoma technology. The therapeutic efficacy of these antibodies was evaluated using a mouse model, and a humanized version of the monoclonal antibody was generated for potential human application. ResultsIn this study, we generated eight monoclonal antibodies that exhibit neutralizing activity against WNV. Their therapeutic effects against WNV were validated both in vivo and in vitro. Among these antibodies, C9-G11-F3 also exhibited cross-protective activity against JEV. We also humanized the antibody to ensure that it could be used for WNV infection treatment in humans. ConclusionThis study highlights the importance of neutralizing antibodies as a promising approach for protection against West Nile virus infection and suggests their potential utility in the development of therapeutic interventions.

Reverse genetics of parrot bornavirus 4 reveals a unique splicing of the glycoprotein gene that affects viral propagation.

Viruses can utilize host splicing machinery to enable the expression of multiple genes from a limited-sized genome. Orthobornaviruses use alternative splicing to regulate the expression level of viral proteins and achieve efficient viral replication in the nucleus. Although more than 20 orthobornaviruses have been identified belonging to eight different viral species, virus-specific splicing has not been demonstrated. Here, we demonstrate that the glycoprotein (G) transcript of parrot bornavirus 4 (PaBV-4; species Orthobornavirus alphapsittaciforme), a highly virulent virus in psittacines, undergoes mRNA splicing and expresses a soluble isoform termed sGP. Interestingly, the splicing donor for sGP is not conserved in other orthobornaviruses, including those belonging to the same orthobornavirus species, suggesting that this splicing has evolved as a PaBV-4-specific event. We have also shown that exogenous expression of sGP does not affect PaBV-4 replication or de novo virion infectivity. In this study, to investigate the role of sGP in viral replication, we established a reverse genetics system for PaBV-4 by using avian cell lines and generated a recombinant virus lacking the spliced mRNA for sGP. Using the recombinant viruses, we show that the replication of the sGP-deficient virus is significantly slower than that of the wild-type virus and that the exogenous expression of sGP cannot restore its propagation efficiency. These results suggest that autologous or controlled expression of sGP by splicing may be important for PaBV-4 propagation. The reverse genetics system for avian bornaviruses developed here will be a powerful tool for understanding the replication strategies and pathogenesis of avian orthobornaviruses. IMPORTANCE Parrot bornavirus 4 (PaBV-4) is the dominant cause of proventricular dilatation disease, a severe gastrointestinal and central nervous system disease among avian bornaviruses. In this study, we discovered that PaBV-4 expresses a soluble isoform of glycoprotein (G), called sGP, through alternative splicing of the G mRNA, which is unique to this virus. To understand the role of sGP in viral replication, we generated recombinant PaBV-4 lacking the newly identified splicing donor site for sGP using a reverse genetics system and found that its propagation was significantly slower than that of the wild-type virus, suggesting that sGP plays an essential role in PaBV-4 infection. Our results provide important insights not only into the replication strategy but also into the pathogenesis of PaBV-4, which is the most prevalent bornavirus in captive psittacines worldwide.

Parechovirus Neonatal Meningitis: A Case Report

Neonatal meningitis is a serious, potentially life- threatening condition that requires prompt diagnosis and treatment. Bacterial pathogens are usual suspects; however, viral cause should not be overlooked. We report a case of Parechovirus neonatal meningitis in an 8 days old male infant, emphasizing the importance of considering uncommon viral pathogens in the diagnostic work up. Human Parechovirus belongs to the family of Picornaviridae virus. It is very uncommon and has been associated with a benign clinical course of respiratory and gastrointestinal infection in most cases, however, it is emerging as one of the causes for emergency admission of neonates in hospital due to certain serotypes. The HPeV type 3 has been found mostly in children and young infants presenting with meningitis and sepsis like illness. Infants with severe Central Nervous System (CNS) infections are at an increased risk of long-term sequelae. In this case we describe the clinical presentation, diagnostic challenges, management and outcome of this rare infection. An 8 days old baby presented to our emergency department with sepsis like illness. He was admitted in neonatal unit for further investigations and management. Despite initial presentation the inflammatory markers were normal. Symptomatic-supportive treatment was given till baby made full recovery. Antibiotics were discontinued after 48 hours as culture was negative for bacteria. This case highlights the importance of considering Parechovirus as possible cause of neonatal meningitis when inflammatory markers are normal and plan the management appropriately.

The gut microbiota and associated metabolites in multiple sclerosis

Multiple sclerosis (MS) is a severe central nervous system autoimmune inflammatory disease featured by the presence of infiltrated immune cells, demyelination, and degeneration. Recent research has shown that gut microbiota, including some commensal bacteria, is capable of interacting with the host immune system and remarkably influencing the development and outcome of experimental autoimmune encephalomyelitis, a classic animal model of MS. In addition, gut dysbiosis, presented with a significantly altered composition of commensal bacteria, is linked to the immune response and inflammation, such as Th17 activation and B cell function. Moreover, it has been observed that microbiota impacts the immune system by regulating the metabolites in the gut. In this review, we summarize the new research on the relationship and mechanism between the gut microbiota and MS, as well as the implications for developing new strategies in MS by modulating the gut microbiota and metabolites.

Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.

Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.