INTRODUCTION:Blepharospasm (BSP) has a high spreading risk, and the most common condition is becoming blepharospasm-oromandibular dystonia (BOM). We aimed to identify the shared and specific changes in the brain cerebral blood flow (CBF) covariance network between BSP and BOM. METHODS:This single-center study enrolled 21 BSP patients, 21 BOM patients, and 20 healthy controls (HC). Clinical information and MRI imaging including arterial spin labeling, three-dimensional T1-weighted and conventional sequences were obtained. CBF data were preprocessed, and group-level CBF covariance networks were constructed. Intergroup differences of network connections and properties were compared using a permutation test, and for all network metrics, the statistical significance was defined as p < 0.01 (uncorrected, 5000 times). RESULTS:In both patient groups, hypoperfusion is mainly located in the bilateral frontal lobe and cingulate gyrus. The global properties were standard, and spatial covariance analysis revealed whole-brain reconfiguration. CBF connections in BSP patients were partially increased, whereas they were mostly decreased in BOM patients. Two groups shared lost hubs in the vermis 8, left putamen, right superior temporal gyrus, right cerebellum 4-5, and left thalamus. Compared with BSP, the BOM group showed more widespread decreased connections linking these lost hubs to the rest of the brain, especially for the left putamen, left thalamus and right superior temporal gyrus hub. CONCLUSIONS:Loss function in the vermis 8, left putamen, right superior temporal gyrus, right cerebellum 4-5, and left thalamus are important features for the pathophysiology of both patient groups. Among them, decreased connections in the left putamen, left thalamus, and right superior temporal gyrus mainly unveiled the specific pathophysiological differences between groups.

Background:Previous studies have indicated that non-motor symptoms are primary problems in focal dystonia, but limited data are available about cognitive function and their correlation with motor severity in generalized dystonia (GD). Methods:In the present study, we performed a case-control study and enrolled isolated genetic or idiopathic GD patients and age-, sex- and education-matched healthy controls (HC). Clinical characteristics, motor symptoms, psychiatric symptoms, and cognitive performance were assessed in both groups using various standardized rating scales and a comprehensive neuropsychological battery. Group comparisons, multiple linear regression analyses, and correlation analyses were performed, with adjustment for demographic and affective variables and correction for multiple comparisons. Results:Twenty patients with GD and matched healthy controls were enrolled and completed the assessments. Compared with HC, GD patients showed mild impairments, particularly in MoCA, executive function/attention, spatial ability, some tests in memory and similarities while other cognitive function did not differ between patients and HC. After adjustment and multiple comparison correction, MOCA, MOCA, executive function/attention and episodic memory remained the most consistent deficits. Several other cognitive differences were no longer significant after correction. No significant associations were found between cognitive performance and motor severity or disease duration. Cognitive performance did not differ between genetic and idiopathic subgroups or between medication groups. Conclusion:GD is associated with mild and heterogeneous cognitive impairments, with only a subset of deficits remaining robust after adjustment. Cognitive performance appears largely independent of motor severity, disease duration, medication use, and disease etiology.

This study reveals that phospholipase A2 (PLA2), normally stable and nontoxic, can be activated specifically within the alveolar environment to induce rapid, "electric shock-like" lethality, akin to chemical toxins, while also exhibiting extreme toxicity comparable to that of biological toxins, and functioning as a potential "time bomb" in the body. When exacerbated inflammation impairs the pulmonary barrier, PLA2 from the circulation can penetrate into the lungs. Once activated in the alveolar space, it rapidly hydrolyzes pulmonary surfactant phospholipids, causing a drastic decline in surface tension (>30%). This leads to alveolar overdistension, instantaneous respiratory failure, and asphyxiation-an acute mortality effect strikingly similar to that observed in sepsis and severe pulmonary diseases. PLA2 penetration and lethality are more pronounced in aged animals. Based on these findings, a combination therapy comprising phospholipase (dioleoylphosphatidylserine) and an inhibitor (varespladib) was developed, which significantly improved survival rates from 0% to over 90% in mice with sepsis, acute lung injury, and PLA2 poisoning. This study provides critical theoretical foundations and intervention strategies for the clinical treatment of related diseases.

The treatment of pulmonary diseases via nucleic acid drugs faces major challenges in targeting specificity and transfection efficiency. While messenger RNA (mRNA) therapeutics hold great potential, their clinical translation requires advanced delivery systems. In this study, inspired by first-principles thinking-deconstructing the mRNA delivery process to its fundamental physicochemical requirements-a simplified lipid system for lungtargeted mRNA delivery was constructed, using the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) for lung targeting, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) for enhancing biosafety via steric hindrance and alanine-derived carbon quantum dots (Ala-CQDs) for further enhancing transfection efficiency. Comprehensive safety evaluations confirmed that DSPE-PEG2000 effectively reduced DOTAP-induced cytotoxicity, hemolysis, coagulation dysfunction, and organ damage. Mechanistic studies revealed that Ala-CQDs enhance lung-targeting and transfection efficiency through formation of a lung-tropic protein corona and promotion of endolysosomal escape. Compared with the reported lung-selective organ-targeting lipid nanoparticle (Lung-SORT LNP), the streamlined delivery system-retaining only functionally essential components-not only yielded an approximately 40-fold increase in lung-targeted transfection efficiency but also exhibited markedly improved biocompatibility and reduced toxicity. The system enabled the co-loading of matrix metalloproteinase 13 (MMP13) mRNA and the tyrosine kinase inhibitor nintedanib (Nin) to formulate the nanomedicine mMMP13@Lipo(Nin)/Ala-CQDs. As a combination regimen for pulmonary fibrosis, it proved effective in promoting collagen degradation, restoring lung function, and mitigating alveolar damage. Collectively, this work establishes a streamlined yet potent and biosafe lipid system, providing a novel strategy for mRNA-based therapy for pulmonary diseases.

Alacrima-achalasia-mental retardation syndrome(AAMR) is an extremely rare autosomal recessive genetic disorder caused by mutation in the GMPPA gene. Its pathogenesis is associated with congenital disorders of glycosylation. The clinical manifestations involve multiple system impairments, with alacrima, achalasia, and mental retardation as the core features. This article reports the diagnosis, treatment process and long-term follow-up outcomes after deep brain stimulation in one patient with AAMR complicated with dystonia, aiming to improve clinicians' understanding of this disease.

Paclitaxel (PTX) kills tumor cells by stabilizing microtubules to induce apoptosis, but its efficacy is limited by resistance mediated by the anti-apoptotic protein survivin. Targeted inhibition of survivin with siRNA could synergistically enhance PTX-induced apoptosis; however, nucleic acid-based therapeutics, such as siRNA, exhibit high instability and susceptibility to degradation, making their efficacy highly dependent on specialized delivery systems. Thus, co-delivery systems for PTX and siRNA are critical to achieving synergistic antitumor activity. Natural products present several advantages, including wide availability, high biocompatibility, and multi-target synergistic effects, offering promising approaches for constructing a co-delivery system. In this study, a co-delivery system integrating siRNA and PTX based on natural products was developed. Ginsenoside Rg3 (Rg3) not only serves as the structural backbone but also enhances tumor-targeting capability and inhibits tumor cell migration. The edible cationic polymer chitooligosaccharide (COS) efficiently encapsulates siRNA, ensuring safe and efficient delivery. This co-delivery system based on natural synergy enables multi-level cooperation: Rg3 mediates targeted transport, PTX triggers apoptosis, and COS-assisted siRNA silences survivin, thereby ensuring precise targeting and promoting complete tumor apoptosis, highlighting a promising strategy for the application of natural products in cancer therapy.

Juvenile systemic sclerosis (jSSc) can lead to permanent and irreversible anatomical or physiological dysfunction. The Scleroderma Clinical Trials Consortium-Damage Index (SCTC-DI), which has been employed and validated in adult patients, can quantify organ damage and predict mortality and morbidity. However, its application in paediatric patients remains unexplored. Clinical data, laboratory results, and prognostic information were collected for patients with jSSc at Peking Union Medical College Hospital (PUMCH) from January 2012 and January 2024. Differences between the SCTC-DI and the juvenile systemic sclerosis severity score (J4S) were recorded and compared. Furthermore, we compared the SCTC-DI between jSSc and adult systemic sclerosis (SSc) patients. A total of 64 jSSc patients were included. Facet joint contractures, fingertip ulcers and interstitial lung disease are common manifestations. Compared with adult SSc patients, jSSc patients had a lower incidence of gastrointestinal and urinary system involvement. The baseline J4S levels were significantly correlated with SCTC-DI levels at follow-up. A higher baseline SCTC-DI score was associated with a greater progression of organ damage (P = 0.001). There are differences in clinical presentations between adult SSc patients and jSSc patients. The SCTC-DI can be applied to JSSc patients, and it is recommended that JSSc patients undergo regular evaluations of the J4S as well as the SCTC-DI.

BACKGROUND:The safety and effectiveness of deep brain stimulation of the subthalamic nucleus (STN-DBS) for the treatment of dystonia lack high-level evidence-based medical support. This study aimed to clarify the efficacy and safety of STN-DBS and perform a post hoc analysis comparing it with DBS of the internal globus pallidus (GPi-DBS). METHODS:This multicentre, randomised, double-blind, controlled trial included 67 patients aged 6-60 years old diagnosed with genetic or idiopathic isolated generalised or segmental dystonia. They were enrolled from seven hospitals in China and randomly assigned to undergo GPi-DBS or STN-DBS. After surgery, they were randomised to receive either neurostimulation or sham stimulation for 3 months. At the 3-month follow-up, neurostimulation was also initiated in the sham stimulation group, and all patients were followed up for more than 3 years after treatment. The primary outcome was the Burke-Fahn-Marsden Dystonia Rating Scale movement (BFMDRS-M) score. RESULTS:In the STN group, the neurostimulation subgroup exhibited significant improvement (p<0.001), which is also superior to the sham stimulation subgroup (p=0.028) at 3-month follow-up. At the 6-month and >3-year follow-ups, all patients receiving STN-DBS showed a significant improvement in BFMDRS-M scores (p<0.001). Further post hoc analysis revealed that both STN-DBS and GPi-DBS could produce similar therapeutic effects on motor symptoms (P6 months=0.865, P>3 years=0.905). There were no ongoing serious adverse events throughout the study. CONCLUSIONS:For isolated generalised and segmental dystonia patients, the STN is a selectable DBS target with ensured safety and efficacy. STN-DBS and GPi-DBS may achieve comparable therapeutic effects on motor symptoms. TRIAL REGISTRATION NUMBER:NCT03017586.

Background:The most common spread of blepharospasm (BSP) is to the oromandibular region, labeled as blepharospasm-oromandibular dystonia (BOM). We aimed to identify shared and different functional changes in BSP and BOM, trying to unveil the pathogenesis of these disorders and the mechanism of dystonic spread. Materials and methods:This single center study recruited 16 BSP patients, 16 BOM patients and 20 healthy controls (HC). Clinical information and resting-state fMRI images were collected. Dynamic amplitude of low-frequency fluctuations (dALFF) was calculated using the sliding window method. Intergroup differences in static ALFF (sALFF) and dALFF were examined. Using dALFF results, seed-based static and dynamic functional connectivity (FC) were constructed to compare connectivity changes in BSP and BOM networks. Correlations between dynamic parameters and disease severity scores were analyzed using Spearman partial correlation. Results:Compared with HC, BSP and BOM presented increased dALFF in the bilateral basal ganglia, bilateral supplementary motor area, right precentral gyrus, and bilateral cingulate gyrus. BOM further demonstrated decreased sALFF in the left cerebellum. Compared with HC, BOM patients had decreased sFC in the network involving the sensorimotor cortex, supplementary motor area, basal ganglia, cerebellum, and brainstem. In addition, decreased dFC strength was found between the right pallidum and cerebellum. Comparing with BSP patients, BOM patients showed decreased sFC and dFC strength in a similar but limited pattern. Clinical scores of BSP severity were significantly correlated with dALFF in some of these important regions. Conclusions:Our results demonstrated common brain regions with impaired functional activity in BSP and BOM patients. Further, BOM is featured with widespread connectivity reduction in the sensorimotor cortico-basal ganglia-brainstem-cerebellar network deriving from these key regions. These findings could help investigate mechanisms of dystonia spread and potentially facilitate disease-modifying therapies.

We aimed to determine the prevalence of cardiovascular involvement in our Blau syndrome (BS) cohort and provide detailed analysis of their cardiovascular manifestations and outcome. We also tried to find out the risk factors for developing cardiovascular involvement. Clinical manifestations, laboratory findings, and treatments were reviewed. Clinical features were compared between children with cardiovascular involvement and those without angiocardiopathy. A total of 38 BS children were eligible for final analysis. Among them, 13 (34.2

Developmental dysplasia of the hip is a common musculoskeletal disorder in newborns and young children, attracting considerable controversy. The purpose of the present study was to analyze the research trends and hotspots over the past three decades in this field. All related publications were collected from the Web of Science Core Collection from 1994 to 2023. Of these, characteristics of the top 50 cited articles for each decade (1994–2003, 2004–2013 and 2014–2023) were evaluated in detail. Visualized studies were operated via VOSviewer. GraphPad Prism and Microsoft Excel were used to perform statistical analysis. The characteristic of the present study is a cross-sectional study. In total, 1,300 publications with 19,815 citations from 1994 to 2023 were selected. The number of publications increased significantly during the past three decades, from 23 in 1994 to 132 in 2023 (P < 0.0001). Studies with collaboration among institutions have raised significantly over time (P < 0.0001). The United States was the leading country to the top 50 publications in each decade. Publications with evidence level IV led the way every ten years. Visualized co-occurrence analysis clustered the keywords into four clusters: hip arthroplasty, congenital dislocation, ultrasound diagnosis and developmental dysplasia of the hip. This study analyzed the global tendency and collaborations on developmental dysplasia of the hip over the past three decades. Even though the research trend has evolved to be collaborative with more multi-institutional publications and authors, studies with high evidence levels are still missing.

Monogenic lupus is defined as systemic lupus erythematosus (SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance. However, because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE, it causes a delay in diagnosis and treatment. Currently, there is a lack of early identification models for clinical practitioners to provide early clues for recognition. Our goal was to create a clinical model for the early identification of pediatric monogenic lupus, thereby facilitating early and precise diagnosis and treatment for patients. This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022. The control group consisted of classical SLE patients recruited at a 1:2 ratio. Patients were randomly divided into a training group and a validation group at a 7:3 ratio. A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot. The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve (AUC) index. A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included. Among the monogenic lupus cases (with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years), a total of 18 gene mutations were identified. The variables included in the coefficient plot were age of onset, recurrent infections, intracranial calcifications, growth and developmental delay, abnormal muscle tone, lymphadenopathy/hepatosplenomegaly, and chilblain-like skin rash. Our model demonstrated satisfactory diagnostic performance through internal validation, with an AUC value of 0.97 (95

BackgroundIntranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson’s disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial.MethodsThis was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy.Results7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels.ConclusionsTreatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Skin damage caused by chemical corrosion is currently one of the common skin diseases and poisoning symptoms, with nitrogen mustard compounds causing the most persistent and severe damage. These chemicals penetrate the top layer of the skin, enter the dermis, and cause DNA damage, oxidative stress, and inflammation. However, to date, no effective drug treatment has been found. Even the potential antidotes could not effectively penetrate the top layer of the skin to exert their effects due to the skin barrier. To address this problem, an innovative transdermal drug delivery strategy based on aspirin microneedles was proposed. The classic medicine aspirin was first discovered not only to reduce inflammation and oxidative stress but also to promote DNA repair and reduce DNA damage. The aspirin microneedles directly delivered the drug to the damaged area, released aspirin through the skin barrier, and exhibited good biocompatibility. These findings indicate that aspirin microneedles have great potential for promoting wound healing and broad application prospects.

Treatment for acute brain conditions remains a major challenge owing to the unavailability of antidotes, especially for organophosphorus compounds, exposure to which leads to rapid death. Despite recent advances in brain-targeted nano delivery systems (BTNDS), the traditional ones which have been developed will likely not lead to the quick release of an antidote, which is essential to counteract fast neurotoxic effects. Herein, we present a BTNDS using thermosensitive liposomes, without the need for functionalization, to obtain a platform for brain-targeted delivery, which has a simple structure and thus can be easily synthesized and scaled-up. The brain-targeting effect of BTNDS was amplified by phospholipase A2 (PLA2), an inflammatory biomarker. The combination of PLA2 and BTNDS significantly improved brain targeting, leading to an excellent emergency rescue effect - 83- and 4.8-fold better cerebral AChE reactivation response and survival time, respectively. These findings provide a promising strategy to generate a facile, druggable, and effective BTNDS.