Search Results (879)

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens. Full article

The adrenal medulla and organs of Zuckerkandl consist of chromaffin cells that produce, store, and secrete catecholamines. In humans, the adrenal medulla is known to function throughout postnatal life, while the organs of Zuckerkandl degenerate by 2–3 years of postnatal life. Although the history of investigation of chromaffin cells goes back more than a century, little is known about the reciprocal organogenesis of the adrenal glands and organs of Zuckerkandl during human fetal development. In the current study, we compared these two organs using serial sectioning, routine histological staining, and immunohistochemical reactions in human embryos, prefetuses, and fetuses from 8 to 26 gestational weeks. In our study, we used antibodies for tyrosine hydroxylase, dopamine beta-hydroxylase, and phenylethanolamine N-methyltransferase, which are enzymes of catecholamine synthesis, β-III tubulin, and S100. We found two morphological cell types (large and small) in the developing ganglia, organs of Zuckerkandl, and adrenal medulla, and two migration patterns of large cells and small cells. The immunohistochemical characteristics of these cells were determined. We revealed that the number of small cells increased significantly at the ages from 16 to 21–22 gestational weeks, followed by a decrease at 22.5–26 gestational weeks. The presence of two large cell subpopulations was suggested—those that migrate primarily from organs of the Zuckerkandl region and those that differentiate later from the small cells. We also determined that 12 gestational weeks was the age of the first appearance of phenylethanolamine N-methyltransferase reactivity in developing chromaffin cells, temporally correlating with synaptogenesis events. This is important data in the light of the controversial glucocorticoid theory of phenylethanolamine N-methyltransferase induction in humans. Full article

Background/Objectives: Huntington’s disease (HD) is a neurodegenerative disorder involving the basal ganglia and is characterized by psychiatric, cognitive, and movement dysfunction, including gait and balance impairment. Given the limited efficacy of pharmacological treatments for HD motor symptoms, nonpharmacological approaches like rhythmic auditory stimulation are being explored. This study aims to describe walking performance in people with HD during rhythmic auditory stimulation using external musical cues and internal singing cues. Methods: Individuals in the manifest stage of HD performed walking in four conditions: (1) comfortable pace, (2) cognitive dual task, (3) musical cue (music was played aloud), and (4) singing cue (participants sang aloud). Sensors measured cadence, velocity, stride length, and variability. Relationships between change in cadence and motor and cognitive measures were explored. Results: While no direct measurements of synchronization were performed, limiting our interpretation, neither the external musical cue nor the singing cue significantly improved walking performance. Both cues increased variability, similar to what was observed during the dual task. Greater subjective balance confidence and better cognitive performance were associated with positive cadence change during cueing. Conclusions: Musical cues may be too cognitively demanding for individuals with Huntington’s disease as they worsen gait variability without increasing gait speed, cadence, or stride length. Although global cognition and perceived balance confidence were related to the ability to increase cadence, very few people were able to increase their cadence during either cue. Therefore, the results do not support the use of musical cues to improve gait for individuals with Huntington’s disease. Full article

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some cases, CTX also includes parkinsonism. The goals of this study are to develop a data source that provides improved characterization and awareness of parkinsonism in CTX. Methods: We conducted a systematic review of the literature according to PRISMA guidelines to identify all published individuals diagnosed with CTX and parkinsonism. Clinical signs, imaging findings and treatment response to both chenodeoxycholic acid and dopaminergic medications were examined for 72 subjects. Results: The average age of onset of parkinsonism in these CTX patients was 42 years, illustrating the early onset nature of parkinsonism in CTX. Functional dopaminergic imaging revealed the loss of presynaptic dopaminergic neurons in the substantia nigra which points to neurodegeneration of the dopaminergic system as the underlying pathophysiology for parkinsonism in CTX. Brain MRI showed abnormalities in the basal ganglia in 38% of subjects. MRI also showed abnormalities in the cerebellum in 88% of subjects which is typical for CTX and can be utilized to distinguish subjects with CTX and parkinsonism from individuals with other forms of atypical parkinsonism. Dopaminergic medication mitigated parkinsonism signs in most individuals with CTX. Conclusion: CTX is a neurometabolic disease that can result in levodopa-responsive parkinsonism that should be included in the differential for atypical parkinsonism. Full article

The electrical ventricular storm (VES) is defined as multiple sustained ventricular arrhythmias arising in a short time, often refractory to standard antiarrhythmic treatment. The three pillars of the physiopathogenesis of the VES are autonomic dysfunction, triggers, and an altered ventricular substrate. Incessant or highly recurrent ventricular arrhythmia impacts the hemodynamic status by worsening heart failure and increasing mortality. A stepwise, team-based, and tailored therapeutic approach is required to stop ventricular arrhythmia and regain the hemodynamic and electric stability of the patient. The authors focused on describing all currently available therapeutic approaches for VES, intending to establish the best VES therapeutic approaches. This process involves considering the patient’s specific condition, responses to previous treatments, and the potential risks and benefits of each approach. The options range from adjusting antiarrhythmic therapy to reprogramming of the ICD, sedation, epidural anaesthesia, stellate ganglia anaesthetic block, and the use of ECMO or left ventricular assist devices and radiofrequency catheter ablation. Particular attention is paid to the detailed management of genetic primary arrhythmia syndromes like long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and Wolff–Parkinson–White syndrome, early repolarisation syndrome, right ventricular arrhythmogenic dysplasia, and idiopathic ventricular fibrillation. After overcoming the acute events of VES and obtaining hemodynamic stability, the treatment should shift toward an optimal balance of heart failure therapy, controlling the substrate by revascularisation procedures and resolving other pathology-generating ventricular arrhythmias. This article provides a comprehensive overview of ESV’s current management options using the most efficient strategies known to date. Full article

Background: Vascular risk factors (VRFs) are known to influence cerebral small vessel disease (cSVD) burden and progression. However, their specific impact on the presence and distribution of each cSVD imaging marker (white matter hyperintensity [WMH], perivascular spaces [PVSs], lacunes, and cerebral microbleeds [CMBs]) and their spatial distribution remains unclear. Methods: We conducted a retrospective analysis of 93 patients with lacunar stroke with a standardized investigational magnetic resonance imaging protocol using a 3T scanner. WMH and PVSs were segmented semi-automatically, and lacunes and CMBs were manually segmented. We assessed the univariable associations of four common VRFs (hypertension, hyperlipidemia, diabetes, and smoking) with the load of each cSVD marker. Then, we assessed the independent associations of these VRFs in multivariable regression models adjusted for age and sex. Spatial lesion patterns were explored with regional volumetric comparisons using Pearson’s coefficient analysis, which was adjusted for multiple comparisons, and by visually examining heatmap lesion distributions. Results: Hypertension was the VRF that exhibited stronger associations with the cSVD markers in the univariable analysis. In the multivariable analysis, only lacunes (p = 0.009) and PVSs in the basal ganglia (p = 0.014) and white matter (p = 0.016) were still associated with hypertension. In the regional analysis, hypertension showed a higher WMH load in deep structures and white matter, particularly in the posterior periventricular regions. In patients with hyperlipidemia, WMH was preferentially found in hippocampal regions. Conclusions: Hypertension was confirmed to be the VRF with the most impact on cSVD load, especially for lacunes and PVSs, while the lesion topography was variable for each VRF. These findings shed light on the complexity of cSVD expression in relation to factors detrimental to vascular health. Full article

Background: Chronic primary orofacial pain (COFP) affects approximately 7% of the population and often leads to reduced quality of life. Patients frequently undergo multiple assessments and treatments across healthcare disciplines, often without a definitive diagnosis. The 2019 ICD-11 classification of chronic primary pain clusters together COFP subtypes based on chronicity and associated functional and emotional impairment. Objective: This study aimed to evaluate whether these subtypes of COFP share common underlying mechanisms by comparing neuroimaging findings. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Searches were performed using Medline (OVID) and Scopus up to April 2025. Inclusion criteria focused on MRI-based neuroimaging studies of participants diagnosed with COFP subtypes. Data extraction included participant demographics, imaging modality, brain regions affected, and pain assessment tools. Quality assessment used a modified Coleman methodological score. Results: Fourteen studies met the inclusion criteria, all utilising MRI and including two COFP subtypes (temporomandibular disorder and burning mouth syndrome). Resting- and task-state imaging revealed overlapping alterations in several brain regions, including the thalamus, somatosensory cortices (S1, S2), cingulate cortex, insula, prefrontal cortex, basal ganglia, medial temporal lobe, and primary motor area. These changes were consistent across both TMD and BMS populations. Conclusions: The findings suggest that chronic primary orofacial pain conditions (TMD and BMS) may share common central neuroplastic changes, supporting the hypothesis of a unified pathophysiological mechanism. This has implications for improving diagnosis and treatment strategies, potentially leading to more targeted and effective care for these patients. Full article

Intracerebral hemorrhage (ICH), a severe stroke subtype common in the elderly, often results in high morbidity and mortality, with limited treatment options for long-term recovery. While glial scar formation is increasingly recognized as key to central nervous system (CNS) repair, its role and characteristics in the aging brain post-ICH remain unclear. This study investigated glial scar formation after ICH (100 μL autologous blood injected into the right basal ganglia model) in aged Fischer 344 rats and assessed the effects of deferoxamine (DFX) treatment. Histological and immunohistochemical analyses were conducted on days 7, 28, and 60 post-ICH using cell-specific and iron-related markers, with DFX administered at 100 mg/kg daily for 14 days in separate groups. Over time, the lesion core showed increased hemosiderin accumulation and astrogliosis. By day 60, the area of astrogliosis corresponded to an area with persistent neuronal loss (DARPP-32-negative). Glial composition shifted from microglia dominance on day 28 to astrocyte predominance by day 60. DFX treatment reduced iron deposition, astrogliosis, and DARPP-32-negative regions while enhancing oligodendrocyte presence. Iron-related markers (HO-1, ferritin, Perls’ staining) and PDGFRβ-positive fibrotic cells were concentrated in the scar core. These findings provide novel insights into scar formation after ICH in aged rats and suggest DFX as a potential therapy to improve outcomes in elderly stroke patients. Full article

Neuropathic pain is a significant global clinical issue that poses substantial challenges to both public health and the economy due to its complex underlying mechanisms. It has emerged as a serious health concern worldwide. Recent studies involving dorsal root ganglion (DRG) stimulation have provided strong evidence supporting its effectiveness in alleviating chronic pain and its potential for sustaining long-term pain relief. In addition to that, there has been ongoing research with clinical evidence relating to the role of small non-coding ribonucleic acids known as microRNAs in regulating gene expressions affecting pain signals. The signal pathway involves alterations in neuronal excitation, synaptic transmission, dysregulated signaling, and subsequent pro-inflammatory response activation and pain development. When microRNAs are dysregulated in the dorsal root ganglia neurons, they polarize macrophages from anti-inflammatory M2 to inflammatory M1 macrophages causing pain signal generation. By reversing this polarization, a therapeutic activity can be induced. However, the direct delivery of these nucleotides has been challenging due to limitations such as rapid clearance, degradation, and reduction in half-life. Therefore, safe and efficient carrier vehicles are fundamental for microRNA delivery. Here, we present a comprehensive analysis of miRNA-based nano-systems for chronic neuropathic pain, focusing on their impact in dorsal root ganglia. This review provides a critical evaluation of various delivery platforms, including viral, polymeric, lipid-based, and inorganic nanocarriers, emphasizing their therapeutic potential as well as their limitations in the treatment of chronic neuropathic pain. Innovative strategies such as hybrid nanocarriers and stimulus-responsive systems are also proposed to enhance the prospects for clinical translation. Serving as a roadmap for future research, this review aims to guide the development and optimization of miRNA-based therapies for effective and sustained neuropathic pain management. Full article

Long- or post-COVID-19 syndrome, which is also designated by WHO as Post COVID-19 Condition (PCC), is characterized by the persistent symptoms that remain after recovery from SARS-CoV-2 infection. A worldwide consortium of Long COVID-19 Host Genetics Initiative (Long COVID-19 HGI) identified an SNP rs9367106 (G>C; chr6:41,515,652, GRCh38, p = 1.76 × 10⁻¹⁰, OR = 1.63, 95% CI: 1.40–1.89) that is associated with PCC. Unraveling the functional significance of this SNP is of prime importance to understanding the development of the PCC phenotypes and their therapy. Here, in Silico, I explored how the risk allele of this SNP alters the functional mechanisms and molecular pathways leading to the development of PCC phenotypes. Bioinformatic methods include physical interactions using HI-C and Chia-PET analysis, Transcription Factors (TFs) binding ability, RNA structure modeling, epigenetic, and pathway analysis. This SNP resides within two long RNA genes, LINC01276 and FOXP4-AS1, and is located at ~31 kb upstream of a transcription factor FOXP4. This DNA region, including this SNP, physically interacts with FOXP4-AS1 and FOXP4, implying that this regulatory SNP could alter the normal cellular function of FOXP4-AS1 and FOXP4. Furthermore, rs9367106 is in eQTL with the FOXP4 gene in lung tissue. rs9367106 carrying DNA sequences act as distant enhancers and bind with several transcription factors (TFs) including YY1, PPAR-α, IK-1, GR-α, and AP2αA. The G>C transition extensively modifies the RNA structure that may affect the TF bindings and enhancer functions to alter the interactions and functions of these RNA molecules. This SNP also includes an ALU/SINE sequence and alteration of which by the G>C transition may prevent IFIH1/MDA5 activation, leading to suppression of host innate immune responses. LINC01276 targets the MED20 gene that expresses mostly in brain tissues, associated with sleep disorders and basal ganglia abnormalities similar to some of the symptoms of PCC phenotypes. Taken together, G>C transition of rs9367601 may likely alter the function of all three genes to explain the molecular basis of developing the long-term symptomatic abnormalities in the lungs and brain observed after COVID-19 recovery. Full article

Background: Primary focal hyperhidrosis, characterized by excessive sweating primarily affecting the hands and axillae, can significantly impact quality of life. Bilateral thoracic sympathectomy is the gold standard treatment, providing permanent resolution of palmar hyperhidrosis. Most studies evaluating outcomes and patient satisfaction after sympathectomy focus on short- to medium-term follow-up, typically up to 5 years. This study aimed to assess anxiety, satisfaction, and sweat redistribution 20 years after bilateral endoscopic thoracic sympathectomy. Methods: Between January 2002 and December 2003, 106 patients with primary hyperhidrosis underwent bilateral endoscopic thoracic sympathectomy targeting ganglia T2–T3 at our center. The patients were contacted via telephone in 2023 and asked to complete the same survey they had filled out preoperatively and 12 months postoperatively. The survey evaluated sweat redistribution, anxiety, hyperhidrosis-related symptoms, and satisfaction. Anxiety, satisfaction, and perceived sweating were rated using a 5-point visual analog scale (VAS) ranging from 0 (unsatisfied/no symptoms) to 4 (very satisfied/severe symptoms). Results: Of the 106 eligible patients, 24 (22.6%) completed the survey. Most reported persistent anhidrosis (palmar or palmar–axillary) 20 years post-surgery. The survey results remained consistent with those at the 1-year follow-up. Significant sweat redistribution to the abdomen and back was observed. Patient satisfaction remained high, with no significant differences between the 1-year and 20-year assessments. Anxiety significantly decreased compared to preoperative levels (p < 0.001). Conclusions: Bilateral endoscopic thoracic sympathectomy is an effective long-term treatment for reducing excessive sweating. Patient satisfaction remains high over time, despite the persistence of compensatory sweating. Full article

Objective: Burning mouth syndrome (BMS) is a chronic and often debilitating orofacial pain condition characterized by a burning sensation in the oral mucosa without clear abnormal lesions. While its etiology is considered multifactorial, the underlying pathophysiology remains unclear. This narrative review aims to synthesize existing functional magnetic resonance imaging (fMRI) studies to shed light on the central neural mechanisms contributing to BMS. Methods: A focused electronic search was conducted across the PubMed and J-STAGE databases for relevant articles published in English from January 2000 to May 2025. The review prioritized studies investigating brain structure and function using fMRI in individuals with BMS. Results: Our synthesis of the literature consistently demonstrated that the brains of individuals with BMS exhibit augmented connectivity within the medial pain system and a diminished gray matter volume in the medial prefrontal cortex (mPFC). These findings suggest a crucial role for altered brain circuitry, particularly a reduction in the output of the basal ganglia dopamine system, in the experience of BMS pain. Conclusions: The consistent fMRI findings strongly indicate that BMS involves significant functional and structural brain alterations. The observed changes in the mPFC and its connections to the basal ganglia dopamine system highlight this pathway as a potential target for both pharmacological and non-pharmacological neurological interventions for individuals with BMS. Full article

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy primarily affecting the kidneys, can also involve the central nervous system (CNS), often leading to significant morbidity and mortality. Neurologic manifestations are among the most severe extra-renal complications, particularly in children and during outbreaks of Shiga toxin-producing Escherichia coli (STEC)-associated HUS (typical (tHUS)). This review explores the clinical spectrum, pathophysiology, diagnostic workup, and age-specific outcomes of neurologic involvement in both typical (tHUS) and atypical (aHUS). Neurologic complications occur in up to 11% of pediatric and over 40% of adult STEC-HUS cases in outbreak settings. Presentations include seizures, encephalopathy, focal deficits, movement disorders, and posterior reversible encephalopathy syndrome (PRES). Magnetic resonance imaging (MRI) commonly reveals basal ganglia or parieto-occipital lesions, though subtle or delayed findings may occur. Laboratory workup typically confirms microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and kidney damage, with additional markers of inflammation or metabolic dysregulation. Eculizumab is the first-line treatment for aHUS with CNS involvement, while its utility in STEC-HUS remains uncertain. Although many children recover fully, those with early CNS involvement are at greater risk of developing epilepsy, cognitive delays, or fine motor deficits. Adults may experience lingering neurocognitive symptoms despite apparent clinical recovery. Differences in presentation and imaging findings between age groups emphasize the need for tailored diagnostic and therapeutic strategies. Comprehensive neurorehabilitation and long-term follow-up are crucial for identifying residual deficits. Continued research into predictive biomarkers, neuroprotective interventions, and standardized treatment protocols is needed for improving outcomes in HUS patients with neurological complications. Full article

For centuries, researchers have been fascinated by the composition of scorpion venom and its local and systemic effects on humans. During a sting, scorpions inject peptides and proteins that can affect immune cells and neurons. While the immune and nervous systems have been studied independently in the context of scorpion stings, here we reveal part of the mechanism by which Tityus serrulatus venom induces hyperalgesia in mice. Through behavioral, immune, imaging assays, and mice genetics, we demonstrate evidence of neuroimmune crosstalk during scorpion stings. Tityus serrulatus venom induced mechanical and thermal hyperalgesia in a dose-dependent manner, as well as overt pain-like behavior. The venom directly activated dorsal root ganglia neurons and increased the recruitment of macrophages and neutrophils, releasing pro-inflammatory cytokines TNF-α and IL-1β. Blocking TRPV1⁺ neurons, TNF-α, IL-1β, and NFκB reduced the mechanical and thermal hyperalgesia, overt pain-like behavior, and the migration of macrophages and neutrophils induced by Tityus serrulatus venom. Collectively, Tityus serrulatus venom targets primary afferent nociceptive TRPV1⁺ neurons to induce hyperalgesia through the recruitment of macrophages and neutrophils and the release of pro-inflammatory cytokines. Full article

Bovine alphaherpesvirus 1 (BoAHV-1) is a promising oncolytic virus that can infect the human lung carcinoma cell line A549. In an effort to adapt the virus to grow more rapidly in these cells through the serial passaging of viral progeny, we were unsuccessful. Here, we found that extracellular vesicles (EVs) secreted by BoAHV-1-infected A549 cells (referred to as EDVs) contain 59 viral proteins, including both viral structure proteins (such as gC and gD) and viral regulatory proteins (such as bICP4 and bICP22), as identified via a proteomic analysis. These EDVs can bind to and enter target cells, inhibit viral particles binding to cells, and stimulate the production of IFN-α and IFN-β in A549 cells. When EDVs are inoculated into rabbits via either the conjunctival sacs or intravenously, they can be readily detected in neurons within the trigeminal ganglia (TG), where they reduce viral replication and promote the transcription of IFN-γ. Furthermore, incorporation of the known anti-herpesvirus drug Acyclovir (ACY) into the EDVs leads to synergistically enhanced antiviral efficacy. Collectively, the EDVs exhibit antiviral effects by blocking viral binding to target cells and stimulating the innate immune response, thereby leading to the failure of the serial passaging of viral progeny in these cells, and these EDVs may serve as a promising vector for delivering drugs targeting TG tissues for antiviral purposes. Full article