Ectopic CD4+ T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon-γ induced microglia activation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4+ T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4+ T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4+ T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4+ T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4+ T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4+ T cells were positive for IFN-γ. Neutralizing intracerebral IFN-γ alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-γ antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4+ T-treated mice, while ICV injection of IFN-γ mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4+ T cells contribute to NPSLE-like symptoms in mice via Interferon-γ induced microglia activation. Depleting CP-resident lupus CD4+ T cells, interferon-γ, or activated microglia may be potential therapeutic targets for NPSLE.

Analysis of brain metabolites by gas chromatography-mass spectrometry reveals the risk-benefit concerns of prednisone in MRL/lpr lupus mice.

OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common cause of disability in systemic lupus erythematosus (SLE). This study aims to investigate the metabolic changes in the hypothalamus and frontal cortex in lupus-prone MRL/lpr mice. METHODS: Metabolic changes were analyzed using gas chromatography-mass spectrometry (GC-MS). RESULTS: According to the principal component analysis (PCA), the metabolic profiles were different between the frontal cortex and hypothalamus, but they were comparable between MRL/lpr and MRL/MpJ mice (16 weeks of age). By OPLS-DA, eight cortical and six hypothalamic differential metabolites were identified in MRL/lpr as compared to MRL/MpJ mice. Among these differential metabolites, we found a decrease of N-acetyl-L-aspartate (NAA, a potential marker of neuronal integrity), an increase of pyruvate and a decrease of glutamate in the frontal cortex but not in the hypothalamus. Prednisone treatment (3 mg/kg from 8 weeks of age) relieved the decrease of NAA but further increased the accumulation of pyruvate in the frontal cortex, additionally affected eight enriched pathways in the hypothalamus, and led to significant imbalances between the excitation and inhibition in both the frontal cortex and hypothalamus. CONCLUSION: These results suggest that the frontal cortex may be more preferentially affected than the hypothalamus in SLE. Prednisone disrupted rather than relieved metabolic abnormalities in the brain, especially in the hypothalamus, indicating that the risk-benefit balance of prednisone for SLE or NPSLE remains to be further evaluated.

Correction to: Oral prednisolone versus non-steroidal anti-inflammatory drugs in the treatment of acute gout: a meta-analysis of randomized controlled trials.

The authors would like to inform you that Jie Yu and Haimei Lu contributed equally to this study and should be considered as co-first authors.

Limited preventive effect of prednisone on neuropsychiatric symptoms in murine systemic lupus erythematosus.

OBJECTIVE: To investigate whether glucocorticoids, the hallmark medication for systemic lupus erythematosus (SLE), could prevent the development of neuropsychiatric SLE (NPSLE). METHODS: The protective effects of prednisone on NPSLE were tested using the open field, object recognition/placement, forced swim, tail suspension, and sucrose preference tests in MRL/lpr mice. Auto-antibody titres and the weight of lymph nodes were also measured. RESULTS: MRL/lpr mice exhibited mild depression at the age of 8 weeks before progressing with spatial cognitive impairment and severe depression-like behaviour at the age of 16 weeks. Treating MRL/lpr mice with prednisone (5 mg/kg) from the age of 8 weeks decreased anti-cardiolipin and anti-N-methyl-D-aspartate (NMDA) receptor antibody titres in the brain, reduced the weight of lymph nodes, and prolonged the floating latency in the forced swim test. However, prednisone (3 or 5 mg/kg) had no preventive effect on the development of spatial cognitive impairment and other depression-like behaviours in MRL/lpr mice. The dose of prednisone had a positive correlation with the floating latency in the forced swim test, while it offered no effects on all other behavioural tests. CONCLUSION: Our results provide evidence that early treatment with prednisone had a limited effect on the development of neuropsychiatric symptoms in MRL/lpr mice. Further work is needed in other models beyond NPSLE in MRL/lpr mice before any definitive conclusions are made on the efficacy of prednisone in human NPSLE.

Oral prednisolone versus non-steroidal anti-inflammatory drugs in the treatment of acute gout: a meta-analysis of randomized controlled trials.

OBJECTIVES: To evaluate the efficacy and safety of oral prednisolone in the treatment of acute gout compared with non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: A comprehensive search of databases in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. RESULTS: Three double-blind, randomized, controlled trials were included in the final analysis, with a total of 584 patients. Regarding the efficacy, oral prednisolone (30-35 mg/day) was comparable with NSAIDs (naproxen at 500 mg/day or indomethacin at 50-100 mg/day) on the pain relief scale, both in activity (difference in means 0.259, 95% CI - 1.532 to 2.050, P = 0.777) and at rest (difference in means - 0.502, 95% CI - 4.961 to 3.956, P = 0.825) during the first 2-6 h. During the following 4 to 6 days, prednisolone acted with comparable efficacy either in activity (difference in means - 0.552, 95% CI - 1.364 to 0.260, P = 0.183) or at rest (difference in means - 0.164, 95% CI - 0.463 to 0.134, P = 0.281). Regarding safety, prednisolone did not increase the total adverse events (AEs) (risk ratios [RR] 0.765, 95% CI 0.473 to 1.238, P = 0.275) and reduced the withdrawal rate because of the AEs (RR 0.127, 95% CI 0.021-0.763, P = 0.024). Prednisolone decreased the risks of several AEs (including indigestion: RR 0.544, 95% CI 0.311-0.952, P = 0.033; nausea: RR 0.296, 95% CI 0.136-0.647, P = 0.002; and vomiting: RR 0.155, 95% CI 0.033-0.722, P = 0.018) but increased the risk of skin rashes (RR 4.049, 95% CI 1.241-13.158, P = 0.021). CONCLUSIONS: Oral prednisolone may be of similar efficacy and a slightly safer strategy for treatment of active, acute gout compared with NSAIDs. Further clinical studies are still warranted to investigate its long-term efficacy and safety.

Age-Dependent Phenomena of 6-Hz Corneal Kindling Model in Mice.

Although numerous studies have acknowledged disparities in epilepsy-related disease processes between young and aged animals, little is known about how epilepsy changes from young adulthood to middle age. This study investigates the impact of aging on 6-Hz corneal kindling in young-adult mice and middle-aged mice. We found that the kindling acquisition of the 6-Hz corneal kindling model was delayed in middle-aged mice when compared to young-adult mice. While the seizure stage and incidence of generalized seizures (GS) were similar between the two age groups, the duration of GS in the kindled middle-aged mice was shorter than that in the kindled young-adult mice. Besides, all kindled mice, regardless of age, were resistant to phenytoin sodium (PHT), valproate sodium (VPA), and lamotrigine (LGT), whereas middle-aged mice exhibited higher levetiracetam (LEV) resistance compared to young-adult mice. Both age groups of kindled mice displayed hyperactivity and impaired memory, which are common behavioral characteristics associated with epilepsy. Furthermore, middle-aged mice displayed more pronounced astrogliosis in the hippocampus. Additionally, the expression of Brain-Derived Neurotrophic Factor (BDNF) was lower in middle-aged mice than in young-adult mice prior to kindling. These data demonstrate that both the acquisition and expression of 6-Hz corneal kindling are attenuated in middle-aged mice, while hippocampal astrogliosis and pharmacological resistance are more pronounced in this age group. These results underscore the importance of considering age-related factors when utilizing the 6-Hz corneal kindling model in mice of varying age groups.

Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.

OBJECTIVE: This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice. METHODS: MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH+) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA. RESULTS: TaVNS activated the TH + neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH+ neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH+ neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH+ neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice. CONCLUSION: This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH+ neurons.

Vison transformer adapter-based hyperbolic embeddings for multi-lesion segmentation in diabetic retinopathy.

Diabetic Retinopathy (DR) is a major cause of blindness worldwide. Early detection and treatment are crucial to prevent vision loss, making accurate and timely diagnosis critical. Deep learning technology has shown promise in the automated diagnosis of DR, and in particular, multi-lesion segmentation tasks. In this paper, we propose a novel Transformer-based model for DR segmentation that incorporates hyperbolic embeddings and a spatial prior module. The proposed model is primarily built on a traditional Vision Transformer encoder and further enhanced by incorporating a spatial prior module for image convolution and feature continuity, followed by feature interaction processing using the spatial feature injector and extractor. Hyperbolic embeddings are used to classify feature matrices from the model at the pixel level. We evaluated the proposed model's performance on the publicly available datasets and compared it with other widely used DR segmentation models. The results show that our model outperforms these widely used DR segmentation models. The incorporation of hyperbolic embeddings and a spatial prior module into the Vision Transformer-based model significantly improves the accuracy of DR segmentation. The hyperbolic embeddings enable us to better capture the underlying geometric structure of the feature matrices, which is important for accurate segmentation. The spatial prior module improves the continuity of the features and helps to better distinguish between lesions and normal tissues. Overall, our proposed model has potential for clinical use in automated DR diagnosis, improving accuracy and speed of diagnosis. Our study shows that the integration of hyperbolic embeddings and a spatial prior module with a Vision Transformer-based model improves the performance of DR segmentation models. Future research can explore the application of our model to other medical imaging tasks, as well as further optimization and validation in real-world clinical settings.

Efficacy and safety of traditional Chinese medicine for the treatment of epilepsy: A updated meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) in the treatment of epilepsy. METHODS: A comprehensive search of the database in both Chinese and English was performed. Data from the selected studies were extracted and analyzed independently by two authors. RESULTS: 30 randomized controlled trials (RCTs) were included in the meta-analysis with a total of 2471 patients. Among them, 4 trials (n = 235) focused on TCM monotherapy, while the other 26 trials (n = 2236) assessed the benefit of TCM as an add-on therapy to antiseizure medications (ASMs). For the efficacy, the meta-analysis found (1) The effective rate in TCM monotherapy group was higher than that in control group (OR = 4.92, 95 % CI: 2.29-10.57, Z = 4.08, P 0.0001); (2) The add-on of TCM also increased the effective rate (OR = 3.37, 95 % CI: 2.65-4.30, Z = 9.85, P 0.00001) and seizure freedom rate (OR = 1.93, 95 % CI: 1.53-2.44, Z = 5.58, P 0.00001). In terms of safety, the add-on of TCM reduced the rate of total adverse events (OR = 0.46, 95 % CI: 0.31-0.67, Z = 3.96, P 0.0001) as well as adverse events of the gastrointestinal and nervous system. 26 different TCM prescriptions were used in these included RCTs. Among them, the 5 most frequently used herbs were Acorus tatarinowii (19 out of 26), Glycyrrhiza uralensis (13 out of 26), Gastrodia elata (12 out of 26), Pinellia ternata (11 out of 26) and Poria cocos (11 out of 26). CONCLUSION: This study suggested that TCM may be a relatively efficacious and safe clinical strategy for the treatment of epilepsy. Several limitations still exist, such as the risk of bias in the included studies, the diversified composition of TCM prescriptions, and the relatively low quality of study design.

Fabrication of an ion-enhanced low-temperature tolerant graphene/PAA/KCl hydrogel and its application for skin sensors.

Flexible sensors based on conductive hydrogels show great potential in wearable displays and smart devices. However, a water-based hydrogel inevitably freezes or loses its conductivity under extremely cold temperatures, leading to inadequate fulfillment of sensor performance. Herein, a well-designed strategy is proposed for fabricating a low-temperature-tolerant water-based hydrogel for sensor applications. By immersing a multi-crosslinking graphene(GO)/polyacrylic acid (PAA)-Fe3+ hydrogel into a KCl solution, an ion-enhanced conductive (GO/PAA/KCl) hydrogel is obtained with excellent conductivity (24.4 S m-1 at 20 °C; 16.2 S m-1 at -20 °C; 0.8 S m-1 at -80 °C) and outstanding antifreezing properties. The conductive hydrogel also possesses good mechanical properties with a fracture stress of 2.65 MPa and an elongation at break of 1511% and maintains its flexibility even at -35 °C. Then, a strain sensor is assembled to monitor the human motion at 20 °C and the movement of a wooden mannequin at -20 °C. Under both conditions, the sensor presents high sensitivity (GF = 8.66 at 20 °C, 7.93 at -20 °C) and good durability (300 cycles under 100% strain). Consequently, the anti-freezing ion-enhanced hydrogel will meet the needs of flexible sensors designed for intelligent robots, health monitoring, etc., which have to work in cold regions or extreme climates.

Azithromycin pretreatment exacerbates atopic dermatitis in trimellitic anhydride-induced model mice accompanied by correlated changes in the gut microbiota and serum cytokines.

Atopic dermatitis (AD) is a common inflammatory skin disease. This study aims to investigate the effect of azithromycin (AZI) pretreatment, a common macrolide-type antibiotic, on the trimellitic anhydride (TMA) induced AD-like symptoms in mice. AZI (25 mg/kg, once daily, 5 days) was administered intragastrically before the 10-day TMA challenge. AD-like symptoms were assessed by ear thickening, scratching behavior, and pathological or immunofluorescence staining; Cytokines in the skin tissue and serum were measured by cytometric bead array; and the compositions of gut microbiota were assessed by 16S rRNA gene sequencing. AZI pretreatment accelerated the development of ear thickening and enhanced the severity of developed AD-like symptoms. AZI pretreatment promoted the infiltrations of neutrophil-like cells, T cells, and mast cells in ear skin. AZI pretreatment elevated the levels of IL-4, IL-6, and IL-17A in the ear skin of AD model mice, but it increased serum TNF-α and IL-6. AZI-pretreatment increased four gut bacterial genera (Bacteroides, Candidatus_Saccharibacteria_unclassified, Acetatifactor, Firmicutes_unclassified) but depleted three short-chain fatty acids producing gut bacterial genera (Alistipes, Clostridiales_unclassified, Butyricicoccus). AD-associated symptoms were positively associated with skin IL-4 and IL-17A, serum TNF-α, and IL-6, and Acetatifactor, but they negatively correlated to the three decreased gut bacterial genera (Alistipes, Clostridiales_unclassified, Butyricicoccus). Thus, our results demonstrate that AZI exposure deteriorates TMA-induced AD-like symptoms in mice, which is related to the imbalances of gut microbiota and skin/serum cytokines.

Risk of epilepsy in rheumatoid arthritis: a meta-analysis of population based studies and bioinformatics analysis.

BACKGROUND: An increasing number of studies support an association between rheumatoid arthritis (RA) and brain disorders. This study aims to determine the association between RA and epilepsy. METHODS: A comprehensive search of databases in both English and Chinese was performed. Data from the selected studies were extracted and analyzed independently by two authors. Genes associated with epilepsy and RA were also collected and analyzed. RESULTS: We included six nationwide population based studies (n = 7,094,113 cases in total) for the meta-analysis. The risk of epilepsy was increased in RA patients [risk ratio (RR) = 1.601; 95% confidence interval (CI): 1.089-2.354; p = 0.017; n = 3,803,535 cases] and children born to mothers with RA (RR = 1.475; 95% CI: 1.333-1.633; p < 0.001, n = 3,290,578 cases). Subgroup analysis and meta-regression showed the RR of epilepsy in RA was negatively correlated with age. Furthermore, we found that 433 identified genes in a coexpression network from the hippocampi of 129 epileptic patients were enriched in the RA and related Kyoto Encyclopedia of Genes and Genomes pathways, while 13 genes (mainly related to inflammatory cytokines and chemokines) were identified as potential key genes bridging the RA and epilepsy. CONCLUSIONS: Our study, utilizing meta-analysis and bioinformatical data, highlights a close association between epilepsy and RA. Further studies are still warranted to expand these findings, especially for a population that is exposed to RA during fetal and childhood periods.

Wnt signaling in physiological and pathological bone formation.

Wnt signaling, canonical or non-canonical, plays conserved roles in numerous physiological and pathological processes. However, it is well beyond the scope of this review to cover all functional aspects of Wnt signaling in different contexts at reasonable depth; therefore this review intends to cover only the roles of Wnt signaling in bone biology; more specifically, we intend to first update the roles of Wnt signaling in physiological bone process, including in osteogenesis and chondrogenesis, since recent years have witnessed tremendous progressions in this area, and then we seek to extend our understanding to the pathological bone process, especially to the heterotopic ossification (HO), even though the understanding of Wnt signaling in HO has been limited. We then further clarify the potential crosstalking between Wnt and other conserved signaling pathways, including FGF, GPCR and Hif1α pathways. Overall, our goal is to update the progressions, identify the general theme and the knowledge gaps and discuss the potential promising avenue for future applications in HO prevention and treatment.

BMP-dependent, injury-induced stem cell niche as a mechanism of heterotopic ossification.

BACKGROUND: Heterotopic ossification (HO), either acquired (aHO) or hereditary, such as fibrodysplasia ossificans progressiva (FOP), is a serious condition without effective treatment. Understanding of the core process of injury-induced HO is still severely limited. METHODS: Double-pulse thymidine analog labeling was used to explore the distinctive domains evolved in injury-induced lesions in an animal model of HO (Nse-BMP4). Histological studies were performed to see whether a similar zonal pattern is also consistently found in biopsies from patients with aHO and FOP. In vivo clonal analysis with Rainbow mice, genetic loss-of-function studies with diphtheria toxin A (DTA)-mediated depletion and lineage tracing with Zsgreen reporter mice were used to obtain further evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells. Immunohistochemistry was used to test whether vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Similar methods also were employed to further understand the signaling pathways that regulate the niche and the resultant HO. RESULTS: We found that distinctive domains evolved in injury-induced lesions, including, from outside-in, a mesenchymal stem cell (MSC) niche, a transient domain and an inner differentiated core in an animal model of HO (Nse-BMP4). A similar zonal structure was found in patients with aHO and FOP. In vivo clonal analysis with Rainbow mice and genetic loss-of-function studies with DTA provided evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells; consistently, vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Further mechanistic study found that BMP and hedgehog (Hh) signaling co-regulate the niche and the resultant HO. CONCLUSIONS: Available data provide evidence of a potential core mechanism in which multiple disease-specific cellular and extracellular molecular elements form a unique local microenvironment, i.e., an injury-induced stem cell niche, which regulates the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). The implication for HO is that therapeutic approaches must consider several different disease specific factors as parts of a functional unit, instead of treating one factor at a time.

Conserved signaling pathways underlying heterotopic ossification.

Heterotopic ossification (HO), a serious disorder of extra-skeletal bone formation, occurs as a common complication of trauma or in rare genetic disorders. Many conserved signaling pathways have been implicated in HO; however, the exact underlying molecular mechanisms for many forms of HO are still unclear. The emerging picture is that dysregulation of bone morphogenetic protein (BMP) signaling plays a central role in the process, but that other conserved signaling pathways, such as Hedgehog (HH), Wnt/ß-catenin and Fibroblast growth factors (FGF), are also involved, either through cross-talk with BMP signaling or through other independent mechanisms. Deep understanding of the conserved signaling pathways is necessary for the effective prevention and treatment of HO. In this review, we update and integrate recent progress in this area. Hopefully, our discussion will point to novel promising, druggable loci for further translational research and successful clinical applications.

Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification.

Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations of adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model. Hedgehog (Hh) signaling was abnormal at endochondral HO lesion sites with increased signaling surrounding the lesion but diminished signaling within it. Thus, local dysregulation of Hh signaling participates in the pathophysiology of endochondral HO. However, unlike a previous report of intramembranous HO, systemic inhibition of Hh signaling was insufficient to prevent the initiation of the endochondral HO process or to treat the existing endochondral HO, suggesting that Hh participates in, but is not essential for endochondral HO in this model. This could potentially reflect the underlying difference between intramembranous and endochondral HO. Nevertheless, identification of this novel stem/precursor cell population as a HO-contributing cell population provides a potential drugable target.

Microenvironmental factors that regulate mesenchymal stem cells: lessons learned from the study of heterotopic ossification.

Bone marrow contains a non-hematopoietic, clonogenic, multipotent population of stromal cells that are later called mesenchymal stem cells (MSC). Similar cells that share many common features with MSC are also found in other organs, which are thought to contribute both to normal tissue regeneration and to pathological processes such as heterotopic ossification (HO), the formation of ectopic bone in soft tissue. Understanding the microenvironmental factors that regulate MSC in vivo is essential both for understanding the biology of the stem cells and for effective translational applications of MSC. Unfortunately, this important aspect has been largely underappreciated. This review tries to raise the attention and highlight this critical issue by updating the relevant literature along with discussions of the key issues in the area.