Acquired paralytic strabismus is a common neuromuscular disorder in adults,characterized by diplopia, visual confusion, impaired ocular motility, and ocular deviation, which severely affects the patient's quality of life and overall health. The disease has a complex etiology, encompassing multiple pathological mechanisms such as vascular pathologies, trauma, inflammation, neoplasms, and immune-related disorders. Treatment primarily focuses on addressing the underlying cause. While conventional Western approaches, such as medication and surgery, can alleviate symptoms, some carry the risk of adverse effects, and their long-term recurrence rates warrant careful consideration. Traditional Chinese medicine utilizes distinctive therapies such as herbal medicine, acupuncture, and other adjunctive therapies, which have shown promising therapeutic effects but are constrained by a lack of high-quality evidence from large-scale randomized controlled trials. This review systematically summarizes recent advances in the etiological classification and traditional Chinese and Western medical treatments of acquired paralytic strabismus. It innovatively summarizes the clinical features associated with different causes, analyzes current therapeutic strategies and research landscape, aiming to inform clinical practice and suggest future research directions.

BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

Tumor metastasis is the leading cause of high mortality in most cancers, and numerous studies have demonstrated that the malignant crosstalk of multiple components in the tumor microenvironment (TME) together promotes tumor metastasis. Cancer-associated fibroblasts (CAFs) are the major stromal cells and crosstalk centers in the TME of various kinds of tumors, such as breast cancer, pancreatic cancer, and prostate cancer. Recently, the CAF-induced pro-tumor metastatic TME has gained wide attention, being considered as one of the effective targets for tumor therapy. With in-depth research, CAFs have been found to promote tumor metastasis through multiple mechanisms, such as inducing epithelial-mesenchymal transition in tumor cells, remodeling the extracellular matrix, protecting circulating tumor cells, and facilitating the formation of a pre-metastatic niche. To enhance the anti-tumor metastasis effect, therapeutic strategies designed by combining nano-drug delivery systems with CAF modulation are undoubtedly a desirable choice, as evidenced by the research over the past decades. Herein, we introduce the physiological properties of CAFs, detail the possible mechanisms whereby CAFs promote tumor metastasis, categorize CAFs-based nano-drug delivery strategies according to their anti-metastasis functions and discuss the current challenges, possible solutions, as well as the future directions in order to provide a theoretical basis and reference for the utilization of CAFs-based nano-drug delivery strategies to promote tumor metastasis therapy.

Due to the difficulty of overcoming the abnormal epidermal barriers and addressing S. aureus infections without disrupting indigenous skin microbiota, effective treatment of bacterial infection atopic dermatitis (AD) remains a significant clinical challenge. Skin microbiota-derived extracellular vesicles (EVs) shows protentional for skin disease treatment, but the lack of antimicrobial activity and limited skin penetration hamper their application in bacterial infection AD treatment. Here, we developed novel nanoantibiotics by loading Lev into S. epidermidis-derived EVs (Lev@SE-EVs), with supreme antimicrobial activity, regulating epidermal immune responses and enhanced epidermal barrier functionality. The nanoantibiotics were further integrated into hyaluronic acid-based microneedle (MN) for efficient transdermal delivery of therapeutic agents and effectively treating bacterial infection in AD. Upon insertion into the skin, the rapidly released Lev@SE-EVs from MN are uptake by S. aureus in a selective manner, fibroblasts, and surrounding immune cells to exert therapeutic effects in the infected dermal layer, resulting in mitigated skin inflammation, reduced S. aureus burden and increased dermis repair. Notably, Lev@SE-EVs induce IL-17A⁺ CD8⁺ T-cell accumulation in the skin in an unrelated inflammation manner, which may represent heterologous protection. This EVs-integrated MN assisted Lev@SE-EVs to alleviate skin inflammation, repair skin, and provide an effective and safe therapeutic approach for bacterial infection AD treatment.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Lingguizhugan Decoction (LGZG) demonstrates significant efficacy in treating various cardiovascular diseases clinically, yet its precise mechanism of action remains elusive. This study aimed to elucidate the potential mechanisms and effects of LGZG on isoproterenol (ISO) continuous stimulation-induced chronic heart failure (CHF) in mice, providing direct experimental evidence for further clinical applications. In vivo, continuous ISO infusion was administered to mice, and ventricular myocytes were utilized to explore LGZG?s potential mechanism of action on the ?1-adrenergic receptor (?1-AR)/Gs/G protein-coupled receptor kinases (GRKs)/?-arrestin signaling deflection system in the heart. The findings reveal that LGZG significantly reduced the messenger ribonucleic acid (mRNA) expression of hypertrophy-related biomarkers [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] and improved cardiac remodeling and left ventricular diastolic function in mice with ISO-induced CHF. Furthermore, LGZG inhibited the overactivation of Gs/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling and downregulated the downstream transcriptional activity of cAMP-response element binding protein (CREB) and the expression of the coactivator CBP/P300. Notably, LGZG downregulated the expression of ?-arrestin1 and GRK 2/3/5 while upregulating the expression of ?1-AR and ?-arrestin2. These results suggest that LGZG inhibits Gs/cAMP/PKA signaling and ?-arrestin/GRK-mediated desensitization and internalization of ?1-AR, potentially exerting cardioprotective effects through the synergistic regulation of the ?1-AR/Gs/GRKs/?-arrestin signaling deflection system via multiple pathways.
Animals ; Heart Failure/genetics* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Mice ; Male ; G-Protein-Coupled Receptor Kinases/genetics* ; Mice, Inbred C57BL ; Humans ; Isoproterenol ; Arrestins/genetics* ; Chronic Disease

Objective:To compare the clinical characteristics of neovascular age-related macular degeneration (nAMD) patients with or without secondary subretinal fibrosis (SF).Methods:A retrospective case-control study. A total of 88 patients (92 eyes) diagnosed with nAMD at Department of Ophthalmology, Xiyuan Hospital of China Academy of Chinese Medical Sciences from January 2020 to January 2024 were enrolled in this study. All eyes underwent best-corrected visual acuity (BCVA), color fundus photography, and optical coherence tomography (OCT) examinations. BCVA was measured using the international standard visual acuity chart and converted to logarithm of the minimum angle of resolution for statistical analysis. SF area was measured on color fundus images. OCT was used to assess the presence of shallow irregular retinal pigment epithelial (RPE) elevation, RPE detachment, ellipsoid zone/external limiting membrane disruption, subretinal fluid and/or intraretinal fluid, thinning of the inner nuclear layer or inner plexiform layer, complete RPE and outer retinal atrophy (cRORA), epiretinal membrane, and suprachoroidal fluid. Device-integrated software measured central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and the height and width of subfoveal fibrosis in SF eyes. Based on the presence of SF, patients were divided into the SF group (47 eyes) and the non-SF (NSF) group (45 eyes). Baseline characteristics, OCT, and color fundus photography imaging features were compared between groups. Independent samples t tests were used for intergroup comparisons, and multiple linear regression was performed to analyze potential factors influencing SF height. Results:Compared with the NSF group, the SF group had a longer disease duration, longer symptom onset to initial treatment interval to receiving anti-vascular endothelial growth factor (VEGF) drug treatment, a lower proportion of patients receiving 3 anti-VEGF drug injections within 6 months, worse BCVA, thicker SFCT, higher rates of pigment epithelial detachment and inner nuclear layer or inner plexiform layer thinning, and a lower rate of subretinal fluid ( P<0.05). No significant differences were observed in CRT or the proportions of irregular retinal pigment epithelia, ellipsoid zone/external limiting membrane disruption, cRORA, suprachoroidal fluid, or epiretinal membrane between the two groups ( P>0.05). Conclusion:nAMD eyes with secondary SF exhibit distinct OCT imaging features compared to NSF eyes.

Psychogenic nonepileptic seizures (PNES) are involuntary experiential behavioral responses to psychological stimuli, resembling epileptic seizures but without neuropathophysiological changes. This paper reports a 28-year-old female patient who complained of"repeated limb convulsions, falls, and unresponsiveness for over 7 years". She had been misdiagnosed with epilepsy for many years. Based on systematic physical and mental examination, long-term symptom observation, brain imaging and repeated ambulatory-electroencephalography (EEG) results, the patient was ultimately diagnosed with PNES. Following a combination of pharmacological treatment and psychotherapy, her symptoms significantly improved, and her social functioning was restored. PNES displays a complex etiology, diverse clinical manifestations, and is difficult to distinguish from epilepsy, leading to frequent misdiagnosis. This case report aims to provide a reference for clinicians in the differential diagnosis and treatment of such patients.

Objective To explore the effect of miR-125a-5p on thymic regulatory T cell(Treg)in mice with experimental auto-immune myasthenia gravis(EAMG).Methods The EAMG model was established by immunoinduction with murine-derived acetylcho-line receptor α subunit 97-116 peptide and randomly divided into control group and EAMG group,and the mice were subjected to Len-non scoring and low-frequency repetitive electrical stimulation experiments to evaluate the model.To further explore the effect of miR-125a-5p on Treg cells,EAMG mice were injected with negative control adenovirus and miR-125a-5p-inhibited adenovirus by tail vein injection respectively,and the experimental groups were the negative control group and miR-125a-5p inhibiting group.The mRNA expression levels of miR-125a-5p and forkhead box protein P3(Foxp3)were detected by real-time fluorescence quantitative polymer-ase chain reaction(RT-qPCR),while the protein expression level of Foxp3 was detected by Western blot.The percentage of the number of Treg cells was detected by flow cytometry,and serum concentrations of interleukin-10(IL-10)and transforming growth factor-β1(TGF-β1)were assessed using enzyme-linked immunosorbent assay(ELISA).Results The EAMG mouse model was successfully established.Compared to the control group,the EAMG group exhibited a significantly higher Lennon score,positive responses to low-frequency repetitive electrical stimulation at 5Hz,and an upregulated expression of miR-125a-5p,downregulated of Foxp3mRNA and protein,reduced percentage number of Treg cells,and decreased expression of IL-10 and TGF-β1.Upon inhibition of miR-125a-5p expression in EAMG mice,compared with the negative control group,the expression of miR-125a-5p in the miR-125a-5p inhibiting group was decreased,and the Lennon score was decreased,Foxp3mRNA and protein expression were increased,with a significant in-crease in the percentage of Treg cells and enhanced expression of IL-10 and TGF-β1,and the differences were all statistically signifi-cance(P＜0.05).Conclusion The expression of miR-125a-5p was upregulated in EAMG.Inhibition of miR-125a-5p expression led to upregulation of Foxp3,an increase in the number of Treg cells,elevated levels of IL-10 and TGF-β1,and attenuation of myas-thenia gravis symptoms in EAMG mice.These results suggest that miR-125a-5p may be involved in developing myasthenia gravis dis-ease by affecting Foxp3,leading to decreased Treg cell numbers and abnormal function.

Objective To explore the effectiveness of multimodal comprehensive diabetes management teaching in the standardized training of endocrinology residents.Methods Fifty-nine resident physicians rotating through the endocrinology department from March to October 2024 were selected.They underwent a multimodal comprehensive diabetes management teaching model that integrated standardized theoretical instruction,case dis-cussions,teaching ward rounds,practical operations,and interdisciplinary pharmaceutical education.The effec-tiveness of this teaching model was evaluated through multiple dimensions using a comprehensive diabetes man-agement evaluation form,Mini-Clinical Evaluation Exercise(Mini-CEX)scale,and satisfaction surveys.Results After two months of multimodal standardized training,the results showed:1)The resident physicians demonstra-ted significant improvements in all aspects of comprehensive diabetes management(P＜0.05).2)The Mini-CEX scores of the resident physicians generally reached excellent levels(P＜0.05).3)Both the resident physicians and teaching faculty showed significantly higher satisfaction with the comprehensive diabetes management program after the training(P＜0.05).Conclusions Multimodal comprehensive diabetes management teaching is effective in enhancing the standardized diagnosis and treatment abilities of resident physicians in the endocrinology depart-ment regarding diabetes.