Search Results (2,813)

Hepatitis E virus (HEV) infection, once regarded as a self-limiting hepatic disease confined to endemic regions, is now recognized as a systemic condition with a broad spectrum of extrahepatic manifestations. Among these, neurological complications—including peripheral neuropathies such as Guillain–Barré syndrome and neuralgic amyotrophy, and central nervous system involvement such as meningitis, encephalitis, and meningoencephalitis—are the most clinically relevant. Meningoencephalitis, though less common, is the most severe and underdiagnosed neurological expression of HEV infection. This narrative review examines current evidence on HEV-associated meningoencephalitis, covering epidemiology, pathogenesis, clinical features, and therapeutic strategies. Neurological disease is dominated by genotype 3 and frequently anicteric, with symptoms preceding or masking hepatic involvement. Pathogenesis is multifactorial, combining direct viral neurotropism—supported by HEV RNA detection in cerebrospinal fluid and replication in induced pluripotent stem cell (iPSC)-derived neurons and brain organoids—with immune-mediated mechanisms such as molecular mimicry and microglia-driven neuroinflammation. Diagnosis is often delayed by the absence of jaundice and low clinical suspicion, even though HEV remains an unrecognized cause in many unexplained encephalitis cases in high-income settings. Ribavirin remains the antiviral mainstay, but viral persistence within CNS sanctuary sites raises concerns about treatment adequacy and relapse; emerging antiviral and immunomodulatory strategies remain under investigation. HEV should be systematically considered in the diagnostic workup of unexplained neurological syndromes, regardless of overt hepatitis; heightened clinical awareness remains the most immediately actionable step toward reducing the burden of this still under-recognized condition. Full article

This study evaluated clinical characteristics, treatment outcomes, and CNS relapse patterns in patients with breast-involved diffuse large B-cell lymphoma (DLBCL), a rare extranodal presentation with limited real-world data. We conducted a retrospective study on 33 consecutive patients with newly diagnosed breast-involved DLBCL treated from 2019 to 2024. All patients received R-CHOP. Baseline CNS screening—including neurological examination, fundoscopy, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis—was routinely performed. High-dose methotrexate (HD-MTX) was offered as CNS prophylaxis after completion of systemic therapy based on multidisciplinary team evaluation and clinician–patient shared decision-making according to institutional treatment protocols. Median age was 52.6 years; 84.8% had ECOG 0. Non-GCB subtype predominated (84.8%), and Ki-67 >70% was present in 69.7%. The overall response rate was 90.9%, with 84.8% complete responses. At a median follow-up of 44 months, 5-year Overall Survival (OS) and Progression-Free Survival (PFS) were 84.8% and 66.7%. CNS relapse occurred in 4 of 6 patients (66.7%) without prophylaxis, all within 5–11 months after R-CHOP, whereas no CNS relapses were observed among prophylaxis recipients (p < 0.001), although this observation should be interpreted with extreme caution given the very small non-prophylaxis subgroup (n = 6), limited statistical power, and non-randomized treatment allocation. Exploratory analyses suggested that bulky disease was associated with inferior OS. R-CHOP achieved high response rates and favorable long-term outcomes in breast-involved DLBCL. The absence of CNS relapse among HD-MTX prophylaxis recipients, contrasted with a high relapse rate in those without prophylaxis, provides only a hypothesis-generating observation that requires confirmation in larger prospective studies; this warrants further investigation of the role of systemic CNS prophylaxis. Full article

Background: Assessment of cerebrovascular reserve capacity (CVRC) is central to treatment planning in adult Moyamoya disease. [¹⁵O]-water-PET with acetazolamide challenge (PET-ACZ) serves as the reference standard but is resource-intensive and not universally available, whereas breathhold BOLD MRI (bh-fMRI) may offer a practical noninvasive alternative for screening and triage. Methods: This retrospective diagnostic accuracy study compared bh-fMRI and PET-ACZ in 67 adult MMD patients (1072 ROIs across 402 supratentorial vascular territories) to determine correlation and clinically useful MRI thresholds for impaired cerebrovascular reserve. Data were analyzed using Pearson’s correlation and ROC curves (STARD-compliant). Cerebellum-normalized percent signal change (CN-PSC) was referenced against PET-ACZ < 66% for pathological CVRC. Results: Supratentorial territories showed strong correlation (r = 0.71, 95%CI 0.62–0.80). Optimal diagnostic threshold was <28.2% CN-PSC on bh-fMRI (Youden index; sensitivity 83.8%, specificity 80.9%, AUROC = 0.87); screening threshold < 60% CN-PSC yielded sensitivity 94.6% and NPV 91.1%. No patient factors (age, Suzuki stage, etc.) influenced agreement (univariate/multivariate analyses). Conclusions: Bh-fMRI supplements PET-ACZ as a screening and diagnostic tool for cerebrovascular reserve impairment in adult MMD. PET remains the reference standard for confirmation, especially in intermediate or discordant cases, and the proposed thresholds (<30% CN-PSC: impaired CVRC; 30–60%: confirm with PET-ACZ; >60%: monitor) require prospective validation before routine decision-making use. Full article

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis. Full article

Objective: Diagnosis-to-treatment interval (DTI) has been investigated in several lymphoma subtypes, but its significance in T-lymphoblastic lymphoma (T-LBL) remains unclear. We evaluated whether DTI reflects clinical urgency, disease burden and early outcomes in newly diagnosed T-LBL. Methods: We retrospectively analyzed 220 patients with newly diagnosed, mass-dominant, and histologically diagnosed T-LBL treated at four centers between 2003 and 2025. DTI was operationally defined as the interval from diagnostic biopsy to first systemic anti-lymphoma therapy and was primarily analyzed as a continuous variable per 7-day increase. Descriptive DTI groups were <15, 15–29 and ≥30 days. Results: Median DTI was 20 days (interquartile range [IQR], 14–32). Shorter DTI was associated with advanced stage, elevated lactate dehydrogenase (LDH), multiple extranodal involvement, central nervous system (CNS) involvement, B symptoms, lower hemoglobin and higher International Prognostic Index (IPI) score. CNS involvement remained independently associated with DTI < 15 days. In adjusted analyses, each 7-day increase in DTI was associated with lower odds of early treatment failure within 2 years (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.58–0.88), lower hazards of progression-free survival (PFS) events (hazard ratio [HR] 0.84, 95% CI 0.74–0.94) and lower mortality (HR 0.84, 95% CI 0.73–0.98), but not complete response. Conclusions: Shorter DTI appears to reflect clinical urgency and disease burden rather than a causal effect of early treatment. Full article

Background: Elevated plasma homocysteine (HCY) is a risk factor for Alzheimer’s disease (AD), but its relationship with structural brain changes across the AD continuum remains unclear. The choroid plexus (CP) regulates cerebrospinal fluid homeostasis and may interface with peripheral metabolic signals. Whether HCY relates to CP structural alterations and disease progression remains unknown. Methods: We analyzed 819 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (229 cognitively normal (CN), 397 with mild cognitive impairment (MCI), and 193 with AD dementia). Multinomial logistic regression assessed associations between HCY and diagnosis under stepwise covariate adjustment. Phenotype-wide structural magnetic resonance imaging (MRI) mapping identified HCY-associated signals. Cox models evaluated associations of CP volume (CPV) with CN-to-MCI and MCI-to-AD dementia conversion and whether CPV added prognostic discrimination beyond baseline disease-severity markers. Independent human CP single-nucleus and spatial transcriptomic datasets were reanalyzed to characterize epithelial expression states and their spatial organization in a hypothesis-generating analysis. Results: Higher HCY was associated with MCI and AD dementia; however, the AD association attenuated after adjustment for renal function, vitamin B12, and medications, whereas the MCI association remained stable. CPV was among the HCY-associated MRI signals that persisted after progressive covariate adjustment. Right and bilateral CPV showed model-dependent associations with MCI-to-AD dementia conversion. In the disease-severity sensitivity analysis, larger right and bilateral CPV remained associated with a higher risk of progression from MCI to AD dementia. Single-nucleus analysis identified two CP epithelial states with relatively high expression of one-carbon metabolism-related genes, termed one-carbon metabolism-enriched epithelial state A (OCM-Epi-A) and state B (OCM-Epi-B). Donor-level pseudobulk analysis did not identify pathway enrichment after false discovery rate correction, whereas OCM-Epi-A–like spots were located near endothelial spots more often than expected by chance in three of the four spatial samples. Conclusions: Circulating HCY was associated with larger CPV, and larger CPV showed model-dependent associations with MCI-to-AD dementia progression. Independent transcriptomic reanalysis identified one-carbon metabolism-enriched epithelial states and their spatial organization in postmortem CP tissue, providing hypothesis-generating tissue-level context for the ADNI associations. Full article

We retrospectively analyzed consecutive patients with HER2-positive metastatic breast cancer who received T-DXd at a single Chinese cancer center between March 2023 and March 2026. Progression-free survival (PFS), overall survival (OS), systemic and intracranial response, safety, prognostic factors, and exploratory subsequent treatment strategies were assessed. Among 173 eligible patients, 80.3% had received prior HER2-directed TKIs and 41.6% had CNS metastases. After a median follow-up of 14.3 months, median PFS and OS were 14.1 and 31.1 months, respectively. The objective response rate was 54.5% among 154 patients with measurable systemic disease, while the CNS objective response rate was 46.3% among 67 patients with measurable CNS lesions. Among patients with measurable CNS lesions, the CNS-ORR was comparable between patients with and without peri-T-DXd local treatment (53.8% vs. 44.4%, p = 0.21). Greater prior treatment exposure was associated with shorter PFS, whereas HER2 IHC 3+ disease was independently associated with longer OS and showed a trend toward improved PFS compared with HER2 IHC 2+/FISH-positive disease. Interstitial lung disease occurred in 13 patients (7.5%), all grade 1–2. Among 148 patients included in the maintenance analysis, 23 switched to alternative maintenance regimens after initial benefit from T-DXd. In an exploratory analysis, no statistically significant differences in PFS or OS were observed between patients who continued T-DXd and those who switched to maintenance therapy. However, these findings require cautious interpretation because of immortal-time bias, selection bias, and limited sample size. T-DXd demonstrated clinically meaningful systemic and intracranial activity with manageable toxicity in this heavily pretreated real-world cohort. Full article

The Tau protein is traditionally recognized for stabilizing axonal microtubules in neurons. However, emerging evidence indicates that astrocytes also show basal expression of the microtubule-associated protein Tau (MAPT) gene, with potential implications for central nervous system (CNS) homeostasis. Under physiological conditions, astrocytes support functions essential to CNS integrity, including metabolic support, neurotransmitter uptake, blood–brain barrier maintenance, and immune surveillance, all of which may be influenced by endogenous Tau expression. This review examines the current literature on the mechanisms that govern astrocytic Tau regulation, mainly in primary tauopathies with glial cytopathology. Available data indicate that Tau accumulation in these glial cells arises from endogenous synthesis, uptake from neighboring neurons, or a combination of these pathways, while failed extracellular clearance may favor this process by increasing Tau availability in the extracellular space. Once internalized, Tau can be processed, degraded through proteolytic and autophagic-lysosomal pathways, or re-released into the extracellular space, potentially facilitating its propagation; insufficient degradation, in contrast, promotes reactive astrogliosis and disrupts vital processes such as metabolic support and neurotransmitter handling. Taken together, this evidence suggests that distinguishing endogenous synthesis from neuronal uptake is essential to define glial-mediated pathology and recognize astrocytic Tau as a relevant contributor to neurodegenerative disease progression. Full article

Wolfram syndrome (WS) is a neurodegenerative disorder caused by mutations in the endoplasmic reticulum (ER) transmembrane protein WFS1. Mutations in WFS1 lead to ER stress and dysregulated calcium signaling, resulting in progressive neurological dysfunction. Myelination is a core pathological process in various central nervous system (CNS) diseases. However, the role of WFS1 in oligodendrocyte development and myelination remains unknown. Here, using CRISPR-Cas9-generated wfs1a/wfs1b double-knockout (wfs1^−/−) zebrafish, we demonstrated that wfs1 deficiency significantly delayed the dorsal distribution of oligodendrocyte precursor cells (OPCs) along Mauthner axons. Furthermore, wfs1 mutation was associated with early hypomyelination of axons at 5 dpf, with partial recovery observed by 8 dpf. Mechanistically, combined transcriptomic and pharmacological analysis revealed that wfs1 mutation led to the suppression of the steroid biosynthesis pathway through downregulation of hmgcs1, which encodes the upstream condensation enzyme of the mevalonate pathway and supplies substrate for the downstream rate-limiting enzyme HMGCR, thereby potentially reducing isoprenoid precursor availability. Pharmacological supplementation with geranylgeraniol (GGOH) specifically rescued dorsal distribution defects, supporting involvement of the isoprenylation pathway, although direct regulation of hmgcs1 by wfs1 and complete rescue of myelin structure require further mechanistic validation. Taken together, our study supports a novel wfs1-hmgcs1 axis, which may regulate dorsal distribution and myelination through the isoprenylation pathway; notably, classical ER stress markers were also concurrently upregulated in wfs1^−/− larvae, although whether the isoprenylation deficiency and ER stress act independently or synergistically remains to be determined. These findings provide new insights into WS-associated early hypomyelination and suggest hmgcs1 as a potential therapeutic target for myelin defects caused by WS. Full article

The mitigation measures adopted to reduce the spread of COVID-19 have not only impacted the transmission of respiratory infections but also other infectious diseases. In this study, we explored the effect of the pandemic on the epidemiology of Central Nervous System (CNS) infections by conducting a retrospective analysis of diagnostic data obtained from cerebrospinal fluids (CSFs) collected before, during, and after the pandemic from patients with acute-suspected neuro-infectious syndrome. The samples were analyzed using a meningitis/encephalitis molecular syndromic panel. A total of 4203 CSFs were split into three groups: pre-pandemic (August 2018–February 2020), pandemic (March 2020–March 2022) and post-pandemic (April 2022–March 2024). Each pathogen was statistically assessed individually, comparing one group vs. another. Results showed that viral pathogens were the most frequently detected across all groups; however, Streptococcus pneumoniae was the single most identified pathogen. Comparison of the pre-pandemic and pandemic groups by statistical analysis showed a significant reduction in neuro-infections caused by enterovirus, S. pneumoniae and N. meningitidis, while the other pathogens were not affected. In conclusion, a reduction in CNS infections caused by respiratory and close-contact-transmitted pathogens, including both viral and bacterial agents, was observed during the period when COVID-19 containment measures were in effect. Full article

Acute myeloid leukemia (AML) harboring KMT2A rearrangements (KMT2A-r) accounts for approximately 5–10% of newly diagnosed cases and represents a high-risk AML subtype associated with poor clinical outcomes despite intensive treatment strategies, including allogeneic hematopoietic stem cell transplantation (HSCT). KMT2A-r AML is also characterized by a higher incidence of extramedullary disease compared with other AML subtypes. Therapeutic options for patients with relapsed/refractory (R/R) disease, particularly after post-HSCT relapse, remain extremely limited. In recent years, menin inhibitors have emerged as a promising targeted therapeutic class for KMT2A-r and NPM1-mutated AML by disrupting the aberrant HOX/MEIS1 transcriptional program. Revumenib, a first-in-class menin inhibitor, has shown encouraging efficacy in early-phase clinical trials. Other menin inhibitors, including ziftomenib, bleximenib, and enzomenib, have also demonstrated clinical activity, with distinct pharmacokinetic, pharmacodynamic, and safety profiles. We report the case of a 36-year-old patient with KMT2A-r AML who relapsed after HSCT with both bone marrow and hepatic involvement. Compassionate-use treatment with revumenib (160 mg twice daily on days 1–28 of each 28-day cycle) induced, after two treatment cycles, complete hematologic remission with no detectable abnormal myeloid blast population by multiparameter flow cytometry (MFC) and complete radiological resolution of hepatic lesions. However, despite prior intrathecal CNS-directed therapy and sustained systemic disease control, the patient subsequently developed an isolated central nervous system (CNS) relapse. This case highlights a potential discordance between systemic and CNS disease control during menin inhibitor therapy and emphasizes the need for further investigation into CNS surveillance and disease management in patients achieving deep systemic responses. Full article

Columnar cacti do not provide direct economic benefits; they are vital for maintaining the ecological balance of flora and fauna in desert ecosystems. Over the past 20 years, necrotic disease has been observed in the southern part of the peninsula, leading to a decline in populations. The infectious nature of the disease associated with cactus necrosis syndrome (CNS) was determined by estimating the incidence, severity, and dispersion index. The pathogenic fungi were studied based on symptoms, dispersion patterns, morphological features, and molecular analysis. To determine the pathogenicity and severity of the isolated fungi, experimental inoculations were performed on small cacti. Results showed that at least five fungi (Phoma spp., Nigrospora sphaerica, Chaetomium spp., Coniochaeta spp., and Alternaria alternata) may be associated with CNS, with responses varying depending on whether infections are mixed or straightforward. Common symptoms included canker and pustules, with prevalence rates of 78.87% and 85.3%, respectively. An increase in incidence of 9.89% was noted compared to 2019 (74.83%) and 2020 (84.72%). The average severity rate for all observed symptoms was 55.21%. These findings identify the causal agents involved in necrotic diseases, which could influence the severity and progression of CNS in B.C.S. Full article

Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood–brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics—integrated diagnostic and therapeutic platforms—focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic “one-pill-for-one-disease” model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies. Full article

Background/Objectives: Axillary management in breast cancer continues to de-escalate, with trials showing similar outcomes between sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) in clinically node-negative patients. However, equivalence has not been demonstrated in estrogen receptor-positive (ER+), clinically node-positive (cN1) patients. We hypothesize that SLNB would not be associated with inferior outcomes compared to ALND among this population. Methods: Using the TriNetX Network, we identified women aged ≥18 years with cN1, ER+ breast cancer who underwent axillary surgery, inclusive of both upfront surgery and neoadjuvant-treated patients. Stage IV disease was excluded. The index event was the first axillary surgery (SLNB or ALND). Propensity score matching (1:1) was performed, balancing for age, receptor status, tumor characteristics, treatment, surgical procedure, and comorbidities. Outcomes included overall survival (OS) and local recurrence (LR). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox models. Results: A total of 1162 women were identified (SLNB 641, ALND 521). After matching, 435 patients remained in each cohort. At up to 10 years, OS was similar between groups (77% vs. 76%, HR 0.9, 95% CI 0.66–1.27). Breast recurrence occurred in 5% versus 7% (HR 0.82, 95% CI 0.47–1.42). Axillary recurrence occurred in 21% versus 24% (HR 0.9, 95% CI 0.69–1.21). None of these differences reached statistical significance. Conclusions: In ER+, cN1 node-positive breast cancer, SLNB was not associated with worse survival or recurrence compared with ALND. These real-world findings are hypothesis-generating but support the continued investigation and refinement of axillary de-escalation guidelines for clinically node-positive disease. Full article

Canine periodontitis is one of the most prevalent chronic diseases for dogs over two years of age. Periodontal pockets may serve as a reservoir for opportunistic bacteria including Pasteurella stomatis, Neisseria animaloris, and Streptococcus canis; however, data on their antimicrobial susceptibility and potential One Health relevance remain limited. This pilot study investigated culturable bacterial isolates recovered from periodontal pockets of dogs with different stages of periodontal disease. Subgingival samples were collected under general anesthesia after periodontal probing and dental radiographic assessment during routine comprehensive oral health assessment and treatment (COHAT) procedures. Bacterial isolates were cultured, identified using MALDI-TOF MS, and tested for minimum inhibitory concentrations (MIC) against amoxicillin (AML), doxycycline (DX), trimethoprim–sulfamethoxazole (SXT), gentamicin (CN), chloramphenicol (C), and ciprofloxacin (CIP). In total, 122 isolates from 101 dogs were analyzed, including Pasteurella stomatis (n = 54), Neisseria animaloris (n = 33), and Streptococcus canis (n = 35). MIC distributions varied between bacterial species and antimicrobial agents, while interpretation was limited by the lack of species-specific veterinary medicine breakpoints for some isolates. These preliminary findings highlight the need for larger standardized studies to support antimicrobial resistance surveillance in canine oral microbiota. Full article