Search Results (217)

Background/Objectives: Aging is a universal biological process characterized by progressive structural, cellular, and molecular alterations that contribute to functional decline and increased susceptibility to disease. In recent years, the cerebral meninges have emerged as an active regulatory interface between the central nervous system and peripheral tissues, with growing evidence supporting their involvement in immune surveillance, fluid homeostasis, and age-related neuropathology. Methods: This narrative review provides a comprehensive overview of the current state of knowledge regarding anatomical, immunological, and molecular remodeling of the aging meninges, with particular emphasis on features with potential diagnostic relevance for cerebral senescence. A systematic analysis of the literature was performed to summarize established and emerging meningeal biomarkers, including inflammatory mediators, immune cell population dynamics, vascular and lymphatic alterations, and extracellular matrix remodeling. Results: The available evidence indicates that age-related changes in meningeal immunity, lymphatic drainage, and fibrotic architecture are closely associated with impaired waste clearance, chronic low-grade neuroinflammation, and increased vulnerability to neurodegenerative processes. Importantly, this review highlights existing knowledge gaps and unresolved questions in the field, underscoring the need for integrated anatomical and molecular studies of meningeal aging. Conclusions: As a summary, by delineating current evidence and limitations, this work aims to provide a conceptual framework to guide future experimental and translational research focused on identifying novel diagnostic biomarkers of cerebral senescence. Full article

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article

Mumps virus (MuV) is a single-stranded, negative-sense RNA virus of the Family Paramyxoviridae. MuV is a highly contagious human pathogen that causes primarily mild symptoms, including hallmark swelling of the parotid glands. Severe cases can occur, leading to neurological complications, including deafness, meningitis, and encephalitis. The mumps vaccine, now included in combination with measles and rubella vaccines (MMR), was first made available in the 1960s. After its introduction, mumps incidence dropped dramatically to less than 500 cases annually in the US. However, even with long-standing vaccination programs, MuV continues to challenge the landscape of public health due to a resurgence of cases in the past several decades and a still present lack of approved antiviral drugs and treatments available for the disease. This review will explore the biology of MuV, focusing on how MuV replicates and interacts with the host immune system. Recent studies have also shed light on the role of protein phosphorylation in regulating viral RNA synthesis—particularly the dynamic interactions between the nucleoprotein (NP) and phosphoprotein (P)—offering new insights into how the virus controls its replication machinery both mechanistically and through utilizing host cell advantages. We also examine how the immune system responds to mumps infection and vaccination, and how those responses may vary across viral genotypes. Although the Jeryl Lynn vaccine strain has played a key role in controlling mumps for decades, outbreaks among vaccinated individuals have raised questions about the present vaccine’s efficacy against circulating and emerging genotypes and if novel strategies will be required to prevent future outbreaks. We review current epidemiological data, highlighting shifts in MuV transmission and genotype distribution, and discuss the need for updated or genotype-matched vaccines. By connecting molecular virology with real-world trends in disease spread and vaccine performance, this review aims to support ongoing efforts to strengthen mumps control strategies and inform the development of next-generation vaccines. Full article

Background: Vogt–Koyanagi–Harada (VKH) is a multisystem autoimmune disease that ophthalmologists often encounter first. The condition is caused by an immune response against tyrosinase-related proteins in pigment cells (melanocytes) of the uvea, inner ear, meninges, and skin, and the process may be triggered by genetic and environmental factors. Although much is known about the disease, establishing an accurate and timely diagnosis still requires a multidisciplinary team and strong clinical expertise. Treatment demands early and aggressive anti-inflammatory therapy with corticosteroids, often prolonged and combined with immunosuppressive or biological agents. Aim: The present article aims to present three unique cases of patients with VKH syndrome, diagnosed and monitored by Ophthalmologists using standard imaging techniques over the course of five years, to demonstrate the unusual manifestations of the already rare syndrome and to improve the general knowledge of the disease among Ophthalmology specialists. Methods: Three different patients with various subjective symptoms and unique clinical signs went through observation in University Specialized Eye Hospital for Active Treatment—Varna. Results: The three clinical cases presented diagnostic challenges, the key role of imaging studies and the importance of thorough medical history taking. Conclusions: The prognosis in VKH is variable—timely diagnosis and treatment are essential to reduce the risk of recurrence and chronic progression of the disease. Full article

Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir. Full article

Canine steroid-responsive meningitis–arteritis (SRMA) is a systemic, immune-mediated, inflammatory disease which occasionally leads to spontaneous haemorrhage, both within and outside the central nervous system, as a possible complication. No previous studies have investigated the haemostatic profile in a cohort of dogs with SRMA using viscoelastic monitoring. The aim of this study was to assess haemostatic function in a cohort of dogs affected by SRMA using the Entegrion VCM (Viscoelastic Coagulation Monitor) Vet™ device. This was a multicentre prospective study conducted between April 2023 and April 2025 recruiting dogs with SRMA from four veterinary referral hospitals in the United Kingdom. All four research centres used the Entegrion VCM Vet™ device for evaluation of haemostasis. Twenty dogs were included in the study. One dog had a hypercoagulable VCM result, and two dogs were considered hyperfibrinolytic based on their VCM results. No dogs had any clinical signs of vascular complications (ischaemic and/or haemorrhagic stroke, haematomas, or haemorrhages). Although the pathophysiology of vascular events in dogs with SRMA remains unclear, the results of this study suggest that further investigations into the fibrinolytic system and endothelial structure in dogs affected by SRMA are warranted. Full article

Central nervous system (CNS) infections caused by Salmonella species (spp.) are exceptionally rare in adults but are associated with significant morbidity and mortality, particularly in immunocompromised individuals. Clinical presentation is often nonspecific, including fever, headache, or altered mental status, while imaging may demonstrate meningeal enhancement, abscesses, or cytotoxic lesions. We present a systematic review of non-typhoidal Salmonella spp. infections involving the CNS across various immunosuppressive contexts, illustrated by the case of a 38-year-old HIV-positive man with well-controlled infection. He developed disseminated Salmonella enterica infection, with bacteremia, septic arthritis, and ultimately corpus callosum involvement, following chronic self-administration of corticosteroids for cluster headaches. This case underscores that corticosteroid exposure can precipitate systemic dissemination even in patients with preserved CD4 counts. Although this condition carries a high risk of mortality, early recognition, targeted antibiotic therapy, and careful multidisciplinary management of underlying immunosuppression are critical to improving survival and minimizing neurological sequelae. Full article

Central nervous system (CNS) cryptococcosis caused by Cryptococcus neoformans is a severe opportunistic infection that primarily affects individuals with impaired cellular immunity. Although the classic presentation includes headache, fever, and meningeal signs, chronically immunosuppressed patients may develop atypical neuropsychiatric manifestations, leading to diagnostic delays. We report the case of a 53-year-old man with rheumatoid arthritis (RA) receiving long-term prednisolone and etanercept therapy, who presented with a 7-day history of depressive mood, anhedonia, social withdrawal, irritability, and progressive confusion. Neurological examination revealed disorientation without focal deficits. Brain imaging showed only mild cortical atrophy, and cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, low glucose, and elevated protein levels. Multiplex PCR (FilmArray^®) of CSF identified Cryptococcus neoformans, CSF positive to C. neoformans. The patient was treated with liposomal amphotericin B followed by fluconazole, resulting in gradual improvement of both neurological and psychiatric symptoms. This case highlights an unusual presentation of CNS cryptococcosis in a non-HIV immunosuppressed patient with RA, emphasizing that acute psychiatric or cognitive changes can be the predominant manifestation. Clinicians should consider fungal infections in the differential diagnosis of acute neuropsychiatric symptoms in patients receiving chronic corticosteroid and biologic therapy. Early recognition and molecular diagnosis can facilitate timely antifungal treatment, potentially improving prognosis and reducing morbidity associated with delayed therapy. This report underscores the importance of awareness of atypical presentations of opportunistic infections in immunosuppressed populations. Full article

Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB), administered to >100 million neonates annually. It confers approximately 70–80% protection against tuberculous meningitis and miliary TB in early childhood, under-pinning its continued use in high-burden settings. As a live-attenuated vaccine, however, BCG can rarely cause adverse reactions ranging from self-limited local lesions to life-threatening disseminated BCG disease (BCGosis), which almost exclusively occurs in infants with severe primary or acquired immunodeficiencies such as SCID, MSMD, CGD, or symptomatic HIV infection. Implementation of universal newborn screening for severe combined immunodeficiency (SCID) using the T-cell receptor excision circle (TREC) assay now enables prospective identification and deferral of these high-risk neonates, virtually eliminating fatal BCGosis. Here we synthesize global data published since 2010 on the clinical spectrum, immunopathogenesis, and epidemiology of BCG-related complications, highlighting the impact of vaccine substrain, administration technique, and host immune status on adverse-event rates. On the basis of this evidence, we propose a practical, evidence-based risk-assessment checklist (BCG-RAKE) to support safer vaccine deployment while preserving the substantial TB-control benefits of universal BCG immunization. Full article

Multidrug-resistant (MDR) Streptococcus suis (S. suis) is a zoonotic pathogen capable of infecting pigs across all age groups, leading to conditions such as meningitis, arthritis, and endocarditis. In humans, infections can result in septic arthritis, meningitis, necrotizing fasciitis, and septicemia, which may be fatal. The absence of a complete genome sequence hinders comprehensive bioinformatic studies of MDR S. suis derived from pigs. In this study, we present the whole-genome sequence of MDR S. suis serotype 2 ST01 isolated from joint fluid samples obtained from pigs. Whole-genome analysis revealed that the ST01 chromosome carries 19 antibiotic resistance genes that confer resistance to major classes of antibiotic including aminoglycosides, tetracyclines, fluoroquinolones, lincosamides, polypeptide, and nitrofurans. Additionally, it contains 15 virulence factors associated with immune modulation, bacterial adherence, and stress survival. Whole-genome analysis identified 84 horizontal gene transfer elements in ST01 (comprising 28 genomic islands, 52 transposons, and 4 prophages), alongside mutations resulting in reduced virulence (302 instances) and loss of pathogenicity (34 instances). Furthermore, 18 antibiotic targets along with 21 lethal mutations were identified as potential targets for preventing, controlling, and treating infection caused by MDR S. suis serotype 2 ST01. In vivo infection experiments demonstrated that intraperitoneal inoculation with ST01 resulted in mortality among Kunming mice, with a median lethal dose (LD₅₀) of 5.62 × 10⁹ CFU/mL. Histopathological analysis revealed varying degrees of lesions in the infected organs of the mice. This study thus provides valuable insights into strategies aimed at combating S. suis infections and their transmission within swine populations. Full article

Primary meningeal melanocytoma is an uncommon, pigmented neoplasm that rarely undergoes malignant transformation, and therapeutic guidelines remain undefined. We report a 43-year-old woman who initially presented with a sudden headache and a right temporal intraparenchymal mass. Subtotal resection revealed a melanocytoma (WHO grade I); residual tumor was treated with Gamma Knife. About 15 months later, she deteriorated rapidly due to malignant transformation with cerebral hemorrhage and spinal leptomeningeal metastasis. Pembrolizumab was initiated within four weeks of the malignant diagnosis and produced transient neurological improvement. Due to symptomatic progression, ipilimumab plus nivolumab was commenced and achieved temporary radiographic stabilization, but the patient succumbed to diffuse progression later. Including this case, only five intracranial melanocytomas with malignant transformation treated with immune checkpoint inhibitors have been reported. Our experience supports initiating immunotherapy promptly after malignant transformation and suggests that sequential dual-agent blockade may modestly extend disease control. Full article

Glaesserella parasuis (G. parasuis), a common pathogenic bacterium in the porcine respiratory tract, can cause porcine polyserositis, arthritis, and meningitis. Alveolar macrophages are the first line of defense in the pulmonary innate immunity, and their abnormal apoptosis plays a critical role in the pathogenic process of G. parasuis. Long non-coding RNA maternally expressed gene 3 (MEG3) is associated with G. parasuis infection, but its mechanism remains incompletely unclear. This study aimed to investigate the role of MEG3 in G. parasuis-induced apoptosis of the porcine alveolar macrophage cell line 3D4/21 and its detailed molecular mechanism. Here, we found that MEG3 overexpression promoted G. parasuis-induced apoptosis and upregulated key extrinsic pathway proteins caspase-8 (CASP8) and caspase-3 (CASP3). Mechanistically, MEG3 functioned as a competing endogenous RNA by sponging ssc-miR-135, which directly targets and inhibits CASP8. Consequently, MEG3 overexpression alleviated ssc-miR-135-mediated repression of CASP8. Functional rescue experiments confirmed that either ssc-miR-135 mimic or CASP8 siRNA reversed the pro-apoptotic effect of MEG3. In conclusion, this study reveals that MEG3 relieves the inhibitory effect of ssc-miR-135 on CASP8 through competitively binding, thereby regulating G. parasuis-induced apoptosis of 3D4/21 cells. This study provides new insights into the pathogenic molecular mechanism of G. parasuis. Full article

We reviewed vancomycin-resistant Enterococcus (VRE) colonisation of inpatients of a spinal cord injury centre. The centre consists of one single occupancy en suite room and ten multi-occupancy rooms where two to six patients stay in a cubicle. These patients share bathroom and toilet facilities. Active screening for VRE is performed by taking rectal swabs on admission of patients to the spinal unit. The patients, who are colonised with VRE, are not isolated due to constraints in resources. During a twelve-month period (April 2024 to April 2025), 33 patients tested positive for VRE. In April 2025, 17 of 40 in-patients tested positive for VRE. During the last six 12-month periods from 2019, the number of patients testing positive for VRE has shown an upward trend from 18 during 2019–2020 to 33 during 2024–2025. No patient developed systemic infection with VRE (blood stream infection, endocarditis, meningitis, intra-abdominal sepsis, infection of a spinal implant or baclofen pump) during the study period. Twelve patients underwent implantation of a baclofen pump during 2024–2025. No patient developed VRE infection from the implant. We believe that non-isolation of patients colonised with VRE may be a pragmatic approach in a resource-poor healthcare facility. It is possible that non-isolation could have contributed to an increase in the number of patients who became colonised with VRE. Attention should be paid to infection prevention measures including hand washing and environmental cleaning to prevent the spread of VRE colonisation of inpatients and VRE infection of at-risk patients, e.g., immune-compromised individuals. Full article

Background: Invasive meningococcal disease (IMD) is an uncommon but potentially life-threatening condition, resulting in life-long sequelae or death in up to 20% of cases. Most IMD cases are caused by Neisseria meningitidis serogroups (Men) A, B, C, W, X, and Y. The highest IMD incidence is among children < 5 years of age (YOA). We reviewed IMD epidemiology data and existing national immunization programs (NIP) in the Americas and identify unmet needs to decrease IMD burden in young children. Methods: Using national surveillance data and published literature from 2006 to 2024, we evaluated the IMD burden and national vaccination strategies for children < 5 YOA in the Americas, focusing on Canada, the United States, Brazil, Chile, Argentina. Results: The highest IMD incidence was among infants, followed by children 1–4 YOA, with MenB infections predominating in both age groups. Chile has both MenACWY (2014) and MenB (2023) infant vaccination in its NIP. Argentina and Brazil’s NIPs include MenACWY (2017) and MenC (2010) vaccinations for infants, respectively. In Canada, MenC (2002) vaccination is recommended at 1 YOA (replaced by MenACWY in 2024 in Manitoba); MenB vaccination is selectively recommended. In each country, the incidence of IMD caused by vaccine-preventable serogroups decreased following the introduction of the respective meningococcal vaccination in the NIP. Conclusions: Comprehensive meningococcal vaccination programs in the Americas have the potential to reduce the IMD burden in children < 5 YOA. National recommendations and NIPs could reduce IMD burden by offering equitable access to protection against IMD, aligning with the WHO roadmap to defeat meningitis by 2030. Full article

Coccidioidomycosis (CM) is an endemic disease in the western United States, northern Mexico, and Central and South America. The severity of coccidioidal infection is highly variable, with potential factors including comorbidities and the patient’s innate and adaptive immune response. Based on data from a predominantly healthy and mainly Caucasian male survey conducted nearly a century ago, approximately 60% of infections are asymptomatic, with an estimated 40% of people experiencing some respiratory symptoms; with 10% of those diagnosed with CM. Disseminated disease occurs in approximately 1% of cases and can involve the meninges and, potentially, any place in the body. It is not yet fully understood why some people experience severe disease while many people do not; it is understood that the immune response has a major role. Immunomodulators, including dupilumab and interferon-gamma (IFN-γ), have shown promise in treating patients with disseminated infection. This article summarizes the latest genetic and immunologic evidence demonstrating immune dysfunction. Immunomodulators and potential therapeutic strategies based on the above are reviewed. Full article