Search Results (3,297)

Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable associations with skeletal and neurodevelopmental abnormalities. Duplication of the near-complete, isolated PAR1 with a comprehensive clinical description has not been reported. Case Presentation: We report a male patient with a 2.49 Mb duplication encompassing nearly the entire PAR1 region (chrX:200854–2692897, GRCh37). Clinical features included global developmental delay (GDD), autism spectrum disorder (ASD), recurrent seizures, hypotonia with joint hypermobility, dysmorphic features, and proportionate tall stature. The duplicated segment contains 30 genes, including 15 protein-coding genes that escape X-inactivation. Among these, SHOX, DHRSX, ASMT, and CSF2RA are notable candidates contributing to the observed phenotype. Conclusions: This report presents a detailed clinical characterization of a rare, near-complete, isolated PAR1 duplication in a male individual. The co-occurrence of tall stature, GDD, ASD, and seizures raises the possibility of a dosage-related phenotypic effect involving one or more genes within the duplicated interval. While causality cannot be definitively established, these observations contribute to the emerging understanding of the functional consequences of Xp22.33 duplications and suggest that increased copy number within this region may be associated with a clinically significant neurodevelopmental phenotype. Full article

The Bactrian camel (Camelus bactrianus), with its unique physiological adaptations and immune characteristics, represents a highly valuable model for innate immunity research. However, a systematic dissection of its innate immune gene repertoire and the key functional drivers within its immune response remains limited. This study integrated CRISPR-Cas9 knockout screening with time-resolved transcriptomic profiling to systematically unveil the immune regulatory mechanisms in camel dermal fibroblasts challenged with the viral mimic poly(I:C) and the bacterial mimic LPS. The CRISPR screen successfully identified 59 key genes conferring a survival advantage under lethal pathogenic challenge. The gene sets required for resisting viral versus bacterial mimics were entirely distinct, revealing divergent genetic underpinnings. Transcriptomic analysis further delineated a dynamic reprogramming of gene expression, uncovering a shared core immune response program alongside significant stimulus-specific regulation. Integrative analysis pinpointed pivotal genes, such as HSP90AA1 in the antiviral process and CSF1 in the antibacterial process, which played critical roles at both the functional screening and transcriptional regulatory levels. These key genes exhibited dynamic and evolving co-expression networks across different time points, indicating their temporally specific regulatory roles throughout the immune response. By combining functional genomics and transcriptomics, this study provides the first systematic mapping of the innate immune landscape and its dynamic regulation in the Bactrian camel, not only deepening the understanding of camelid immunobiology but also offering a new framework and insights for evolutionary studies of immune adaptation mechanisms in mammals. Full article

Multiple sclerosis (MS) pathogenesis involves not only immune-mediated myelin injury but also glial responses. We examined how three charge isomers of myelin basic protein (MBP)—native (C1), phosphorylated (C4), and citrullinated (C8)—modulate rat astrocytes. Cytokines were quantified and grouped (pro/anti-inflammatory, chemotactic, neurotrophic, angiogenic, tissue remodeling), and regulatory markers assessed. C1 strongly upregulated the lipid-sensing receptor LXR, and reduced global DNA methylation; C4 moderately enhanced LXR; C8 failed to activate LXR or alter methylation. Functionally, C1 attenuated IL-1β, IL-6 and GM-CSF while increasing IL-10 and certain chemokines. C4 elicited an intermediate pattern, inducing CX3CL1 (fractalkine), CCL20, VEGF-A and TIMP-1 with minor effects on classical cytokines. In contrast, C8 triggered a robust pro-inflammatory phenotype, increasing IL-1α/β, TNF-α and GM-CSF, with higher IL-10, fractalkine, CCL20, VEGF-A and TIMP-1. All isomers suppressed IFN-γ, IL-4 and CNTF. These data indicate that MBP post-translational modifications drive distinct astrocyte phenotypes through integrated cytokine, metabolic and epigenetic pathways: C1 favors immune regulation and repair, C4 blends inflammatory and reparative cues, and C8 amplifies neuroinflammation. Understanding how modified MBP shapes astrocyte behavior provides mechanistic insight into lesion evolution in MS and suggests astrocyte-directed strategies to modulate neuroinflammation and promote remyelination. Full article

Background: Macrophages play a key role in clearing Borrelia burgdorferi infection and express somatostatin receptor subtype 2 (SSTR2), a potential imaging target. This study investigates immune activation in neuroborreliosis (NB) and assesses the diagnostic value of ⁶⁴Cu-DOTATATE positron emission tomography/computed tomography (PET/CT) alongside magnetic resonance imaging (MRI). Methods: Prospective cohort study (2024–2025) enrolling patients with suspected NB from four Danish hospitals. NB was defined by the following ≥2 criteria: neurological symptoms, cerebrospinal fluid (CSF) pleocytosis, and intrathecal B. burgdorferi-specific antibodies; patients not meeting these criteria served as controls. Results: The study included 20 participants: 15 NB patients (75%) and 5 controls (25%). PET/CT was performed after a median of 9.5 days of antibiotic treatment. Symmetric ⁶⁴Cu-DOTATATE uptake in dorsal root and paravertebral ganglia was observed in 10 of 15 patients, with cervical involvement in 8 and lumbosacral in 9. All of them had symptoms that corresponded to the anatomical distribution of the uptake. No controls had lumbosacral involvement (p = 0.04). One control with erythema migrans and systemic symptoms showed cervical ganglia uptake. MRI showed cranial or spinal nerve enhancement in five patients. Only one patient had focal PET uptake matching MRI findings and clinical facial palsy. Conclusions: Symmetric ⁶⁴Cu-DOTATATE ganglionic uptake in NB patients may reflect immune activation or altered ganglionic physiology. One patient had focal ⁶⁴Cu-DOTATATE uptake corresponding with palsy and MRI and ⁶⁴Cu-DOTATATE PET/CT did not contribute additional diagnostic value beyond standard clinical evaluation. Full article

Alzheimer’s disease (AD) is the most common cause of neurocognitive disorder, and the integration of cognitive assessment with biological markers remains essential for clinical characterization. The Clock Drawing Test (CDT) is a brief and widely used screening tool assessing visuospatial and executive functions, which may reflect underlying neurodegenerative processes. This study investigated the diagnostic performance of the CDT and its association with cerebrospinal fluid (CSF) biomarkers within the A/T/(N) research framework. Ninety-seven patients with mild or major neurocognitive disorder were classified as AD or non-AD according to CSF amyloid-β, phosphorylated tau, and total tau profiles, and compared with 36 healthy participants. All subjects underwent a comprehensive neuropsychological evaluation, including the CDT scored using the quantitative–qualitative method proposed by Rouleau et al. Group comparisons, ROC analyses, and regression models adjusted for age, sex, and education were performed. CDT scores effectively distinguished patients from healthy participants, showing large effect sizes, and modestly differentiated AD from non-AD profiles, particularly on the Hands subscale. Diagnostic accuracy was fair, with adjusted AUC values ranging from 0.65 to 0.75. Lower CDT performance was significantly associated with higher CSF total tau levels, while associations with amyloid-β and phosphorylated tau were not robust after correction. These findings suggest that the CDT is sensitive to cognitive impairment severity and shows limited but meaningful relationships with neurodegenerative biomarkers, supporting its role as a practical complementary tool alongside biological assessment. Full article

Background: Highly potent vaccines are essential for the effective control of classical swine fever (CSF). Since CSF re-emerged in 2018 in Japan, the live CSF virus (CSFV) vaccine—a guinea pig exaltation of Newcastle disease virus-negative strain vaccine (GPE⁻, genotype 1.1)—has been applied to domestic pigs, contributing to a reduction in outbreaks. Meanwhile, the persistence and continued expansion of CSFV in wild boar populations have raised concerns regarding potential antigenic divergence. Methods: We systematically evaluated the neutralizing reactivity of sera from GPE⁻-vaccinated pigs against CSFV strains (genotype 2.1) recently circulating in Japan against identified a representative strain that showed markedly reduced neutralization. We directly assessed the protective efficacy of the GPE⁻ vaccine against this strain in a controlled challenge experiment. At 4 weeks post-vaccination, both vaccinated and unvaccinated pigs were orally challenged with the representative Japanese strain and monitored for 3 weeks thereafter. Results: Among the Japanese CSFV strains, the JPN/SM/WB/2022 isolate exhibited markedly reduced neutralizing reactivity—over 32-fold lower than that against the vaccine strain—when tested with GPE⁻ vaccine-induced antisera. In the experimental infection in pigs, unvaccinated pigs exhibited typical clinical signs of CSF and viremia, and two pigs reached the humane endpoint. In contrast, none of the vaccinated pigs showed any clinical signs of infection. Robust humoral and cellular immune responses were induced in vaccinated pigs, which may correlate with the observed complete protection. Conclusions: The GPE^– live vaccine provides protective immunity against an antigenically distinct strain, prevents disease, and limits viral spread in domestic pigs. Full article

The glymphatic system is a fluid-transport framework in which cerebrospinal fluid (CSF) enters the brain along perivascular routes, exchanges with interstitial fluid (ISF), and exits toward venous, perineural, and meningeal lymphatic pathways enabling waste clearance. Recent studies have clarified the anatomical components that regulate solute movement. The perivascular astrocyte endfeet, which are enriched in polarized aquaporin-4 (AQP4) expression, create a high-permeability water interface that facilitates CSF–ISF exchange. Multiscale physical drivers such as cardiac pulsation, arteriolar vasomotion, and brain-state changes during sleep regulate the timing and efficiency of the glymphatic transport. A broad spectrum of solutes is transported through this pathway, from small metabolites to extracellular proteins including amyloid-β and tau, as well as exogenous tracers and some lipid-associated species. Glymphatic redistribution may interface with other clearance systems, including the brain-to-blood efflux via blood–brain barrier (BBB) transport, intramural periarterial drainage (IPAD) that clears along vascular basement membranes and the meningeal lymphatic pathways that drain macromolecules to deep cervical lymph nodes. These different routes may be interconnected and may represent a waste clearance network with complementary roles assigned to different mechanisms. Moreover, state dependence (notably sleep) and vascular health modulate glymphatic flux, offering plausible links between glymphatic system dysfunction, aging and neurodegeneration. Methodological advances—from intrathecal contrast magnetic resonance imaging (MRI) to in vivo two-photon imaging and tracer-kinetic modeling—have provided new insights into the anatomical scaffold and kinetics of the glymphatic system. Advances in glymphatic anatomy, together with growing evidence implicating glymphatic dysfunction in neurodegeneration, point towards a unifying framework that is urgently needed. Our synthesis spans glymphatic structure, fluid routing, and the repertoire of transported solutes and links to complementary clearance routes, supporting a unified model in which glymphatic clearance represents an important contributor of cerebral homeostasis. Understanding glymphatic dysfunction may guide the establishment of diagnostic imaging biomarkers that have the potential to assist in therapeutic modulation of neurodegenerative diseases. Full article

The glymphatic system supports metabolic waste clearance during sleep and is essential for brain homeostasis. Disruption of this system has been linked to sleep disorders, yet the overall prevalence of sleep disorders in populations showing impaired glymphatic-related function remains unclear. This systematic review and meta-analysis evaluated the prevalence of sleep disorders in human cohorts with structural, functional, or biochemical imaging markers of impaired glymphatic activity. Following PRISMA guidelines, major databases were searched up to August 2025. Eligible observational studies reported sleep disorder prevalence in populations characterized by enlarged perivascular spaces, white matter hyperintensities, DTI-ALPS (DTI-ALPS: Diffusion tensor image analysis along perivascular space) alterations, ultrafast fMRI (fMRI: functional magnetic resonance) indices, or CSF/PET (CSF: cerebrospinal fluid; PET: positron emission tomography) clearance deficits. Random-effects models generated pooled estimates, and heterogeneity, publication bias, and moderators were examined using I² statistics, Egger’s test, trim-and-fill, and meta-regression. Nineteen studies (≈4500 participants) met the inclusion criteria. The pooled prevalence of sleep disorders in populations with impaired glymphatic-related function was 44.9% (95% CI: 34.9–55.3%), with substantial heterogeneity (I² ≈ 95%). Meta-regression identified older age and case–control design as significant contributors, while imaging modality, sex distribution, and sample size were not. Publication bias was minimal. Sleep disorders are common among individuals with impaired glymphatic-related markers, reflecting co-occurrence rather than causality. Standardized longitudinal studies are needed to clarify mechanisms and clinical relevance. Full article

Growth-associated protein-43 (GAP43) is a neuronal protein essential for synaptic function and plasticity, and its reduction has been observed in brains of prion diseases (PrDs) and rodent models. However, its status in the cerebrospinal fluid (CSF) of patients with PrDs remains unclear. CSF samples from 140 PrD cases, including 48 sCJD, 35 T188K-gCJD, 22 E200K-gCJD, 35 D178N-FFI, and 36 non-PrD controls, were analyzed for GAP43 by Western blot. The results were compared with 14-3-3 and calmodulin (CaM) detected by WB, and associated with clinical features. GAP43 positivity was significantly higher in sCJD (70.83%), T188K-gCJD (65.71%), and E200K-gCJD (72.73%) than in non-PrD controls (27.78%). The sensitivity and specificity of GAP43 (around 70–75%) were comparable to 14-3-3 and CaM, though inferior to RT-QuIC and total tau reported elsewhere. CSF GAP43 positivity correlated with sCJD-associated MRI changes, periodic sharp-wave complexes (PSWC) on EEG, and with 14-3-3 and CaM positivity. Our data here indicate the feasibility of usage of GAP43 by Western blot analysis as a diagnostic, at least as a screening, biomarker for sCJD and certain types of gPrDs. Full article

Cerebrospinal fluid (CSF) liquid biopsy has been recently recommended by the National Comprehensive Cancer Network (NCCN) as a molecular diagnostic tool for central nervous system (CNS) lymphoma that offers a minimally invasive method to detect key biomarkers when traditional diagnostics are limited by sensitivity or feasibility. This brief report describes the clinical use of two novel CLIA/CAP-approved CSF liquid biopsy tests from Belay Diagnostics, Summit™ and Vantage™, to aid in the diagnosis and management of CNS lymphoma. Results from both tests were reviewed for 50 CSF samples in the context of clinical information provided with the test order. Summit™ and Vantage™ detected clinically significant alterations in CNS lymphoma-associated genes such as MYD88, CD79B, and TP53 as well as MGMT methylation when other modalities (e.g., CSF cytology, MRI, or brain biopsy) were inconclusive. In several cases of suspected secondary CNS lymphoma, Summit™ detected pathogenic genomic variants as well as mild to high levels of aneuploidy, suggesting CNS involvement. Belay testing impacted management in 41 of 50 (82%) cases by informing CNS lymphoma diagnosis, stratification, or progression as well as therapeutic response with an overall false negative rate of 18% (2/11). This report contributes to the growing body of literature that demonstrates how comprehensive molecular profiling of CSF enhances detection and characterization of CNS lymphoma and offers a promising adjunct to conventional diagnostics. Full article

Cystic fibrosis (CF) is characterized by neutrophil-driven airway inflammation and acute respiratory events (AREs) that contribute to progressive lung damage. AREs are clinically heterogeneous and often occur without measurable changes in lung function. This study aimed to evaluate the utility of molecular airway inflammatory markers for detecting AREs in school-age children with CF. We performed a secondary analysis of a prospective observational study of children with CF (ages 6.7–16.8 years) followed for two years. Sputum samples were collected from 50 participants during stable visits and AREs. Concentrations of 14 inflammatory cytokines were measured using ELISA and multiplex assays. Associations with lung function (ppFEV₁ and lung clearance index [LCI]) and time to next ARE were assessed. A total of 179 sputum samples were analyzed, including 64 collected during AREs. Calprotectin, interleukin-8 (IL-8), and IL-1β were increased during AREs compared with stable visits, although concentrations frequently remained within ranges observed at stable visits. Other cytokines, including GM-CSF, IL-17A, IL-1α, TNF-α, and SPLUNC-1, were predictive of shorter time to subsequent AREs. No biomarker correlated with lung function measures. These findings indicate that airway inflammatory cytokine changes are associated with clinically diagnosed AREs but not with pulmonary function, supporting their potential role as complementary biomarkers in CF care. Full article

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA species and circulating tumor cells (CTC), LB provides dynamic molecular information that cannot be captured by neuroimaging or single-site tissue sampling. Cerebrospinal fluid (CSF) currently yields the highest sensitivity for detecting tumor-specific alterations, while plasma enables repeat monitoring despite lower biomarker abundance. EVs have gained particular prominence due to their ability to preserve DNA, RNA, and protein cargo that reflects key genomic changes, treatment resistance mechanisms, and immune evasion. Although advances are substantial, clinical implementation remains constrained by low analyte concentrations, methodological variability, limited standardization and the high cost of testing, which is rarely reimbursed by insurers. This review summarizes current evidence on circulating biomarkers in GB and highlights research priorities essential for integrating LB into future diagnostic and therapeutic workflows. Full article

Background/Objectives: Miller–Fisher syndrome (MFS) is a rare Guillain–Barré variant defined by ophthalmoplegia, ataxia, and areflexia. Pediatric MFS is uncommon, and infectious triggers remain underrecognized. Human herpesvirus 6 (HHV-6) is neurotropic but rarely linked to immune-mediated neuropathies. In this paper, we describe a child with MFS associated with HHV-6 detected in cerebrospinal fluid (CSF) and review reported pediatric infections related to MFS. Methods: A 5-year-old girl presented with acute ophthalmoplegia, ataxia, and diminished reflexes. Neuroimaging, ophthalmologic tests, CSF analyses, and serologic andpolymerase chain reaction (PCR) assays were performed, including multiplex reverse transcription–PCR of cerebrospinal fluid using the BioFire^® Meningitis/Encephalitis panel. A literature search was performed on Pubmed to identify pediatric (0–18 years) MFS cases with infectious triggers. Two reviewers independently screened and summarized the literature, and a PRISMA-style flow diagram was used to transparently report the study selection process. Results: HHV-6 DNA was detected via CSF PCR twice, while tests for other pathogens were negative. Anti-GQ1b and related antibodies were negative or borderline. The patient received intravenous immunoglobulin and corticosteroids, with full recovery after one month. Among 20 published pediatric cases (1997–2021), Campylobacter jejuni was most frequent, followed by Mycoplasma pneumoniae and influenza viruses. Anti-GQ1b IgM positivity and favorable outcomes were commonly reported, including cases managed conservatively. Conclusions: This case raises the hypothesis that HHV-6 may represent a potential post-infectious association in pediatric MFS. The review findings indicate that pediatric MFS generally follows infection, responds well to immunotherapy, and has an excellent prognosis. Viral testing may be considered in selected, hypothesis-generating contexts in atypical or seronegative pediatric MFS presentations. Full article

Background: To compare postoperative outcomes between partial resection and preservation of the middle turbinate (MT) in patients with chronic rhinosinusitis undergoing endoscopic sinus surgery (ESS). Methods: A comprehensive search was undertaken across multiple major bibliographic databases, including PubMed, Scopus, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL). Our outcome assessment measures included postoperative complications such as bleeding, synechia formation, MT lateralization, crustations, CSF leak, orbital injury, middle meatal antrostomy obstruction, frontal recess obstruction, revision surgery rate, smell test scores, and patient-reported outcomes (PROMs). Data were pooled using STATA software as risk ratio, mean difference, or standardized mean difference. Results: Fifteen clinical trials involving 2037 patients were analyzed. Partial MT resection was significantly associated with reduced rates of postoperative synechiae, MT lateralization, middle meatal obstruction, and frontal recess obstruction. Rates of postoperative bleeding, crusting, CSF leak, orbital injury, and revision surgery were comparable between the partial resection and preservation groups. No significant differences were found in olfactory outcomes. While PROMs, nasal obstruction, and headaches improved with partial resection, SNOT scores and nasal discharge remained similar. Conclusions: Partial MT resection demonstrated a safe and effective technique during ESS. Further large-scale RCTs are warranted to confirm and extend these findings. Full article

Background: Human polyomavirus JC (JCV) causes progressive multifocal leukoencephalopathy (PML), a deadly brain demyelinating illness stemming from oligodendrocyte lytic infection in immunocompromised patients, especially those with untreated HIV infection. Methods: We conducted a case series report on patients with HIV/AIDS who presented progressive multifocal leukoencephalopathy and were hospitalized at the “St. Parascheva” Clinical Hospital of Infectious Diseases in Iasi, northeastern Romania, to emphasize the comorbidities of HIV/AIDS cases. Hospital medical data from 10 January 2025 to 30 September 2025 served as the basis for this investigation. Results: We examined three cases that presented neurological symptoms (ataxia, aphasia, language comprehension, and expression disorders). The cases were evaluated imagistically via nuclear magnetic resonance, and we conducted a polymerase chain reaction test on the spinal fluid to confirm the presence of JCV. It was necessary to take a multidisciplinary approach with a neurologist or pneumologist. All cases were evaluated immunologically, revealing low Ly T CD4 levels and increased HIV viremia levels. Progressive multifocal leukoencephalopathy is an AIDS-defining disease, manifesting in immunocompromised patients, including late presenter cases, and patients who are non-adherent to their antiretroviral treatment. Therefore, it is important to test every patient who has mild to severe neurological symptoms for HIV. Furthermore, some cases require a multidisciplinary approach to ensure a better quality of life. Conclusions: Treating a patient with HIV requires a multidisciplinary strategy that includes a neurology specialist and access to antiretroviral treatment. To boost ART uptake, we must identify and remove barriers that impact patients and the healthcare system. Full article