Neonatal diabetes mellitus （NDM） is a rare monogenic disorder primarily caused by insufficient insulin secretion resulting from mutations in the KCNJ11 and ABCC8 genes. Sulfonylureas， represented by glibenclamide， have become the standard therapy for this type of NDM by precisely closing the mutated ATP-sensitive potassium channels in pancreatic β cells， thereby restoring insulin secretion. Clinical studies confirm that sulfonylureas enable over 90% of patients to successfully transition from insulin to oral treatment， achieving long-term stable glycemic control and improving neurological outcomes to a certain extent. In terms of safety， severe hypoglycemia induced by sulfonylureas is relatively rare and gastrointestinal reactions are mild； moreover， sulfonylureas show good long-term tolerability， and have no adverse effects on child growth and development. In the future， by further refining the full-chain management pathway of “rapid genetic diagnosis-early intervention-specialized dosage forms-long-term follow-up”， the clinical application of sulfonylureas is expected to provide NDM patients with an optimized treatment regimen and maximize their health benefits.

BACKGROUND:Abutment screw loosening is one of the most common mechanical complications in implant restoration.Mechanical wear,as a potential cause of thread loosening,warrants attention due to its impact on mechanical performance and long-term stability.However,studies on the mechanical effects of thread wear in abutment screws remain limited,and no definitive conclusions have been reached.OBJECTIVE:To investigate the effect of different degrees of mechanical wear on the spatial stress distribution of the Morse taper connection implant system,with a view to providing a theoretical basis for the clinical assessment of the long-term stability of dental implants.METHODS:Three-dimensional finite element models of Morse taper implants with central screw thread wear levels of 0,0.1,1,10,and 100 μm were established using SolidWorks software,and simulation analysis with Ansys Workbench software was performed.The implant models were inserted into artificial bone blocks(simulating type Ⅱ bone,with a cortical bone thickness of 2 mm on the outer layer and cancellous bone inside).An alternating load of 300 N in the buccolingual direction was applied at the centroid of the abutment(forming an angle of 30° with the long axis of the implant).The von Mises stress,principal stress,displacement,and fatigue life of the abutment,central screw,implant,and bone tissue in the five groups of models were analyzed.RESULTS AND CONCLUSION:(1)As the degree of mechanical wear on the central screw thread increased,the von Mises stress,principal stress,and strain in the implant and abutment also increased.The stress in the model was concentrated at the top of the implant,at the shoulder level of the implant,at the neck of the abutment,and at the bottom edge of the abutment.(2)Under moderate wear conditions(≥ 10 μm),the fatigue life of the implant system decreased by 30％,and the maximum von Mises stress of the central screw decreased by 37％,with the stress still primarily concentrated at the transition area between the head and the body of the central screw.(3)Under significant wear conditions(≥ 100 μm),the von Mises stress of the central screw decreased by 98％,with the stress concentrated at the screw head,and the fatigue life of the implant system decreased by 63％.Therefore,when the wear level of the central screw thread reaches ≥ 10 μm,the risk of screw loosening is significantly increased,and the fatigue life of the implant system is markedly reduced,warranting clinical attention.

BACKGROUND:Abutment screw loosening is one of the most common mechanical complications in implant restoration.Mechanical wear,as a potential cause of thread loosening,warrants attention due to its impact on mechanical performance and long-term stability.However,studies on the mechanical effects of thread wear in abutment screws remain limited,and no definitive conclusions have been reached.OBJECTIVE:To investigate the effect of different degrees of mechanical wear on the spatial stress distribution of the Morse taper connection implant system,with a view to providing a theoretical basis for the clinical assessment of the long-term stability of dental implants.METHODS:Three-dimensional finite element models of Morse taper implants with central screw thread wear levels of 0,0.1,1,10,and 100 μm were established using SolidWorks software,and simulation analysis with Ansys Workbench software was performed.The implant models were inserted into artificial bone blocks(simulating type Ⅱ bone,with a cortical bone thickness of 2 mm on the outer layer and cancellous bone inside).An alternating load of 300 N in the buccolingual direction was applied at the centroid of the abutment(forming an angle of 30° with the long axis of the implant).The von Mises stress,principal stress,displacement,and fatigue life of the abutment,central screw,implant,and bone tissue in the five groups of models were analyzed.RESULTS AND CONCLUSION:(1)As the degree of mechanical wear on the central screw thread increased,the von Mises stress,principal stress,and strain in the implant and abutment also increased.The stress in the model was concentrated at the top of the implant,at the shoulder level of the implant,at the neck of the abutment,and at the bottom edge of the abutment.(2)Under moderate wear conditions(≥ 10 μm),the fatigue life of the implant system decreased by 30％,and the maximum von Mises stress of the central screw decreased by 37％,with the stress still primarily concentrated at the transition area between the head and the body of the central screw.(3)Under significant wear conditions(≥ 100 μm),the von Mises stress of the central screw decreased by 98％,with the stress concentrated at the screw head,and the fatigue life of the implant system decreased by 63％.Therefore,when the wear level of the central screw thread reaches ≥ 10 μm,the risk of screw loosening is significantly increased,and the fatigue life of the implant system is markedly reduced,warranting clinical attention.

Triptolide （TP）， the core active component of the traditional Chinese medicine Tripterygium wilfordii ， exhibits remarkable pharmacological activities including anti-inflammatory， immunosuppressive and anti-tumor effects， and holds broad application prospects in the treatment of major diseases such as autoimmune diseases and malignant tumors. However， TP has a narrow therapeutic window and causes multi-organ toxicities including liver， kidney and reproductive toxicities， which severely restrict its safe clinical application and new drug development. Therefore， toxicity reduction and efficacy enhancement has become a core scientific problem urgently to be solved in this field. This paper systematically reviews the four core strategies for TP toxicity reduction and efficacy enhancement， including structural modification， dosage form improvement， herbal compatibility， and external therapies of traditional Chinese medicine. Among them， structural modification optimizes the toxic and efficacy characteristics of TP from the molecular structure level， with typica l derivatives including （5 R ）-5-hydroxy triptolide， ZT01， PG490-88， etc. Dosage form modification achieves toxicity reduction and efficacy enhancement via targeted and sustained-controlled drug release of diverse delivery systems. It includes triptolide preparations such as nanoparticles， liposomes， microemulsion gels and liquid crystals， possessing favorable clinical transformation potential. The herbal compatibility and external therapies of traditional Chinese medicine conform to the holistic view of traditional Chinese medicine and have a profound clinical application foundation， but their mechanisms of action are insufficiently elucidated， and they lack unified standardized specifications and high-quality evidence-based proof. In the future， we should rely on multi-omics technology to elucidate the toxic and efficacy mechanisms， integrate technologies to optimize preparations， improve the evaluation system and promote clinical transformation.

Super-pulse thulium fiber laser (hereinafter referred to as thulium laser) has shown broad application prospects in medical research, especially in the treatment of urinary tract stones.Thulium laser has a thin fiber diameter, which reduces the occupation of the working channel and increases the irrigation water flow.Currently, the peak power reaches up to 500 W, the single pulse energy to 6 J, and the frequency to 2000 Hz.The stone-breaking mechanism of thulium laser is photothermal and photomechanical.Different combinations of energy and frequency will significantly affect the volume of stone fragments. "High energy and low frequency" is more suitable for "fragmentation" stone breaking, while "low energy and high frequency" is more suitable for "powderization" stone breaking.Some in vitro experiments have confirmed that thulium laser has higher stone-breaking efficiency, less stone displacement, and more obvious thermal effects compared to holmium laser.Clinically, thulium laser has been applied to ureteroscopic lithotripsy and percutaneous nephrolithotomy., and the stone free rate and safety are relatively high.This article reviews the stone-breaking principles, in vitro experiments, and clinical applications of thulium laser, aiming to provide better theoretical support and practical experience for the development and application of super-pulse thulium fiber laser in the future.

Steroid-induced osteonecrosis of the femoral head （SONFH） is a severe musculoskeletal disorder often induced by the prolonged or excessive use of glucocorticoids. Characterized by ischemia of bone cells， necrosis， and trabecular fractures， SONFH is accompanied by pain， femoral head collapse， and joint dysfunction， which can lead to disability in severe cases. The pathogenesis of SONFH involves hormone-induced osteoblast apoptosis， bone microvascular endothelial cell （BMEC） apoptosis， oxidative stress， and inflammatory responses. The phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway plays a pivotal role in the development of the disease. Modulating the PI3K/Akt signaling pathway can promote Akt phosphorylation， thereby stimulating the osteogenic differentiation of bone marrow mesenchymal stem cells and osteoblasts， promoting angiogenesis in BMECs， and inhibiting osteoclastogenesis. The research on the treatment of SONFH with traditional Chinese medicine （TCM） has gained increasing attention. Recent studies have shown that TCM monomers and compounds have potential therapeutic effect on SONFH by intervening in the PI3K/Akt signaling pathway. These studies not only provide a scientific basis for the application of TCM in the treatment of SONFH but also offer new ideas for the development of new therapeutic strategies. This review summarized the progress in Chinese and international research on the PI3K/Akt signaling pathway in SONFH over the past five years. It involved the composition and transmission mechanisms of the signaling pathway， as well as its regulatory effects on osteoblasts， mesenchymal stem cells， osteoclasts， BMECs， and other cells. Additionally， the review explored the TCM understanding of SONFH and the application of TCM monomers and compounds in the intervention of the PI3K/Akt pathway. By systematically analyzing and organizing these research findings， this article aimed to provide references and point out directions for the clinical prevention and treatment of SONFH and promote further development of TCM in this field. With in-depth research on the PI3K/Akt pathway and the modern application of TCM， it is expected to bring safer and more effective treatment options for patients with SONFH.

ObjectiveTo explore the possible mechanisms of Wenyang Huazhuo Formula （温阳化浊方， WHF） in improving reproductive aging from the perspective of the ovarian mechanical microenvironment. MethodsThe experiment included five groups， 3-month group （20 female mice at 3 months of age）， 6-month group （20 female mice at 6 months of age）， 6-month + WHF group （20 female mice at 5 months of age treated with WHF）， 9-month group （20 female mice at 9 months of age）， and 9-month + WHF group （20 female mice at 8 months of age treated with WHF）. The 6-month + WHF group and 9-month + WHF group were orally administered WHF 41.2 g/（kg·d） once daily for 4 consecutive weeks. The other three groups received no intervention. Reproductive hormone levels were measured by ELISA. HE staining was used to count the numbers of various stages of follicles. Ovarian hyaluronic acid （HA） content and collagen fiber content were measured to evaluate the ovarian mechanical microenvironment. Superovulation was performed to observe the number of eggs obtained， as well as the number of offspring and birth weight to assess fertility. The in vitro fertilization and blastocyst culture of oocytes from female offspring in each group were observed to evaluate the effect of WHF on offspring reproductive potential. ResultsCompared with the 3-month group， the 6-month group and 9-month group showed significantly decreased serum levels of gonadotropin-releasing hormone （GnRH）， follicle-stimulating hormone （FSH）， and luteinizing hormone （LH）， decreased ovarian collagen content， and reduced numbers of primordial and secondary follicles. In contrast， the numbers of primary follicles， antral follicles， and atretic follicles increased. The levels of anti-Müllerian hormone （AMH）， ovarian HA content， and the fertilization rate， cleavage rate， and blastocyst formation rate of oocytes from offspring were significantly lower （P＜0.05）. Compared with the 6-month group， the 6-month + WHF group showed significantly reduced serum levels of GnRH， FSH， and LH， with a significant decrease in primary follicles， antral follicles， and atretic follicles as well as increase of AMH levels， ovarian HA content， number of primordial and secondary follicle， egg count， and offspring birth weight （P＜0.05）. Compared with the 9-month group， the 9-month + WHF group exhibited reduced GnRH， FSH， and collagen fiber content， as well as reduced number of primary follicles， antral follicles， and atretic follicles. However， AMH levels， ovarian HA content， number of primordial and secondary follicle， egg count， offspring numbers， birth weight， fertilization rate， cleavage rate， and blastocyst formation rate of oocytes from offspring all significantly increased （P＜0.05）. ConclusionWHF can significantly improve the ovarian reserve， fertility， and reproductive potential in offspring during reproductive mid-life and late-life stages. Its effect may be related to the remodeling of the mechanical microenvironment of aging ovaries. Moreover， the effect on the mechanical microenvironment remodeling of late-stage ovaries and the improvement of the offspring reproductive potential is more significant.

BACKGROUND:Ossification of the ligamentum flavum was previously considered to be rare in the population.As research has progressed,its incidence rate is increasing gradually,which has aroused the interest of a large number of researchers. OBJECTIVE:To visualize and analyze the research results on ossification of the ligamentum flavum from the Web of Science Core Collection since 1999 using bibliometric methods,and to review the research history of ossification of the ligamentum flavum,highlighting important literature,summarizing research hotspots,and providing ideas for researchers to find research directions. METHODS:Using the Web of Science Core Collection as the data source,relevant papers on ossification of the ligamentum flavum were searched and screened.VOSviewer 1.6.19 and CiteSpace 6.2.R6 were used to conduct the visual analysis of annual publication volume,research countries,institutions,citations,journals,authors,and keywords. RESULTS AND CONCLUSION:(1)A total of 347 papers were included.Since 1999,the number of published papers has increased in a spiral pattern.China's research started later than Japan's,but the number of publications has come up later,with Peking University being the institution with the most publications,and Prof.Chen Zhongqiang from Peking University being the scholar with the most publications.(2)Five of the 10 most frequently cited publications were related to the surgical treatment of the disease.(3)Excluding keywords directly related to the research topic and synthetically analyzing frequencies and betweenness centralities of key words,terms such as"thoracic myelopathy,""dural ossification,""minimally invasive surgery,"and"ossification of the posterior longitudinal ligament"occupied a central position in this field.(4)Keywords clustering analysis showed that clinical manifestations and surgical treatment of ossification of the ligamentum flavum accounted for a large proportion of study.(5)The timeline and burst analysis of keywords revealed that"minimally invasive surgery"appeared as a keyword around 2015,with the highest burst strength and the latest burst start time,and began to receive extensive attention from researchers in 2019.The burst of the keyword"dural ossification"has not yet ended.(6)Surgical treatment for ossification of the ligamentum flavum has been at the forefront of research.Development and research of minimally invasive surgery and research on dural ossification secondary to ossification of the ligamentum flavum are both current research hotspots and possible future research trends.

BACKGROUND:Gradient artificial bone repair scaffolds can mimic unique anatomical features in musculoskeletal tissues,showing great potential for repairing injured musculoskeletal tissues. OBJECTIVE:To review the latest research advances in gradient artificial bone repair scaffolds for tissue engineering in the musculoskeletal system and describe their advantages and fabrication strategies. METHODS:The first author of the article searched the Web of Science and PubMed databases for articles published from 2000 to 2023 with search terms"gradient,bone regeneration,scaffold".Finally,76 papers were analyzed and summarized after the screening. RESULTS AND CONCLUSION:(1)As an important means of efficient and high-quality repair of skeletal system tissues,gradient artificial bone repair scaffolds are currently designed bionically for the natural gradient characteristics of bone tissue,bone-cartilage,and tendon-bone tissue.These scaffolds can mimic the extracellular matrix of native tissues to a certain extent in terms of structure and composition,thus promoting cell adhesion,migration,proliferation,differentiation,and regenerative recovery of damaged tissues to their native state.(2)Advanced manufacturing technology provides more possibilities for gradient artificial bone repair scaffold preparation:Gradient electrospun fiber scaffolds constructed by spatially differentiated fiber arrangement and loading of biologically active substances have been developed;gradient 3D printed scaffolds fabricated by layered stacking,graded porosity,and bio-3D printing technology;gradient hydrogel scaffolds fabricated by in-situ layered injections,simple layer-by-layer stacking,and freeze-drying method;and in addition,there are also scaffolds made by other modalities or multi-method coupling.These scaffolds have demonstrated good biocompatibility in vitro experiments,were able to accelerate tissue regeneration in small animal tests,and were observed to have significantly improved histological structure.(3)The currently developed gradient artificial bone repair scaffolds have problems such as mismatch of gradient scales,unclear material-tissue interactions,and side effects caused by degradation products,which need to be further optimized by combining the strengths of related disciplines and clinical needs in the future.

BACKGROUND:Research has demonstrated a close association between ferroptosis and vascular dementia.Tongmai Kaiqiao Pill has a certain effect on improving the cognitive function of vascular dementia patients,but its mechanism is unclear. OBJECTIVE:To explore the interventional effects and molecular mechanisms of Tongmai Kaiqiao Pill for vascular dementia based on the regulation of ferroptosis by the nuclear factor erythroid-2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/glutathione peroxidase 4(GPX4)signaling pathway. METHODS:Among eighty-four SD male rats,12 rats were used as the sham-operated group,and the rest of them were prepared as a model of vascular dementia by the modified 2-VO method,and then randomly divided into the model group,the Tongmai Kaiqiao Pills high-,moderate-,and low-dosage(27.6,13.8,and 6.9 g/kg)groups,the combined group(Tongmai Kaiqiao Pill high-dosage+ML385,20 mg/kg),and the donepezil hydrochloride group(0.45 mg/kg).The drug was given once a day by intragastric administration.The combined group was also intraperitoneally injected Nrf2 inhibitor ML385,once a day,for 4 weeks.Morris water maze was used to detect the learning memory ability of rats.Hematoxylin-eosin staining was used to observe the histopathological changes in the hippocampus of rats in each group.Colorimetric assay was used to detect the content of reduced glutathione,ferrous ion(Fe2+),and malondialdehyde in the serum of rats.Prussian blue staining was used to detect the iron deposition in the hippocampal tissue of rats.Transmission electron microscopy was used to observe the ultrastructural changes of mitochondria in rat hippocampal tissues.Western blot assay was used to detect the protein expression levels of Nrf2,HO-1,GPX4,XCT,and ferritin heavy chain 1(FTH1)in rat hippocampal tissues. RESULTS AND CONCLUSION:(1)In comparison to the sham operation,rats in the model group exhibited a significantly prolonged latency period(P<0.05)and a reduced number of platform crossings(P<0.05).Additionally,the hippocampal tissues of these rats displayed loosely organized structure,deeply stained cell nuclei,and solidified or lysed chromatin.Ferri ions aggregated in CA1 region.There were atrophied mitochondria with dissolved cristae and thickened mitochondrial membranes.Fe2+,malondialdehyde,and reduced glutathione levels in rat serum were found to be elevated(P<0.05).A significant reduction in the expression of GPX4,HO-1,XCT,Nrf2,and FTH1 proteins was detected in the hippocampus(P<0.05).(2)Compared to the model group,the average escape latency of the rats was significantly reduced following intervention with Tongmai Kaiqiao Pills and donepezil hydrochloride(P<0.05),with an increased number of platform crossings(P<0.05).Hippocampal neurons showed significant recovery.Notably,iron aggregation in the CA1 region was significantly reduced,and mitochondrial structure and function were improved.There were significant reductions in Fe2+and malondialdehyde levels,while the levels of GPX4,HO-1,XCT,Nrf2,and FTH1 in rat hippocampal tissues,and reduced glutathione in serum were significantly increased(P<0.05).(3)The high-dose Tongmai Kaiqiao Pills exhibited a treatment effect comparable to that of donepezil hydrochloride(P>0.05),with a significant prolongation of water maze escape latency(P<0.05),a reduced number of platform crossings(P<0.05),and insignificant neuronal pathological changes in the CA1 area.However,the combined group showed increased iron deposition,elevated malondialdehyde and Fe2+levels in blood serum(P<0.05),reduced glutathione content(P<0.05),hippocampal tissue mitochondrial atrophy,and reduced expression of Nrf2,XCT,HO-1,GPX4,and FTH1 proteins(P<0.05).Within a certain range,higher doses of Tongmai Kaiqiao Pills demonstrated a more pronounced effect,comparable to the efficacy of high-dose donepezil hydrochloride.(4)It is concluded that Tongmai Kaiqiao Pills have been shown to mitigate histopathological changes in the rat hippocampus and enhance cognitive function in rats with vascular dementia.The mechanism of action is likely associated with the suppression of ferroptosis through the activation of the Nrf2/HO-1/GPX4 signaling pathway.