BACKGROUND:The pathogenesis of diabetic peripheral neuropathy has not yet been clarified,and TAM(Tyro3,Axl,and MerTK)receptor tyrosine kinases can control apoptotic cells and suppress inflammatory responses in the central nervous system. OBJECTIVE:To investigate the difference of Mer receptor tyrosine kinase(MerTK)levels in plasma and sciatic nerve tissue of Sprague-Dawley rats with type 2 diabetes and diabetic peripheral neuropathy,and to study the correlation between MerTK and diabetic peripheral neuropathy. METHODS:Forty male Sprague-Dawley were randomly divided into control group with 15 rats,type 2 diabetes group with 10 rats,and diabetic peripheral neuropathy group with 15 rats.The control group was fed with ordinary diet,while the experimental groups were fed with high-fat and high-sugar diet.After 6 weeks,intraperitoneal injection of streptozotocin at the minimum dose of 35 mg/kg was administered in the two experimental groups.After 14 days,tail vein blood was collected to detect blood glucose.If blood glucose≥16.7 mmol/L,the model of type 2 diabetes was successfully established.Rats in the diabetic peripheral neuropathy group continued to be fed with a high-sugar and high-fat diet for 8 weeks.The sciatic nerve conduction velocity of rats was detected through live isolation under anesthesia.Blood samples were collected from the abdominal aorta,and the sciatic nerve tissue was collected.Histological changes of nerve fibers in each group were observed under a light microscope to confirm the success of diabetic peripheral neuropathy modeling.ELISA was used to detect peripheral blood glucose,blood lipids and serum MerTK levels in rats;hematoxylin-eosin staining was used to observe the histological changes in the sciatic nerve;immunofluorescence,immunohistochemistry and western blot were used to detect the expression of MerTK in the sciatic nerve tissue. RESULTS AND CONCLUSION:The Sprague-Dawley rat models of type 2 diabetes and type 2 diabetes peripheral neuropathy were successfully constructed,and the modeling rate of diabetic peripheral neuropathy was 80%.Compared with the control group,the blood glucose levels of rats in the type 2 diabetes and diabetic peripheral neuropathy groups were significantly higher(P<0.000 1),while the blood glucose level in the diabetic peripheral neuropathy group was higher than that in the type 2 diabetes group;and the sciatic nerve conduction velocity was significantly decreased(P<0.05),which was lower in the diabetic peripheral neuropathy group than the type 2 diabetes group.Histological examination:Compared with the control group,the sciatic nerve nuclei were reduced in the type 2 diabetes group,with some vacuolar degeneration and phagocytosis;in the diabetic peripheral neuropathy group,the cell body was swollen,the nuclear spacing was increased,vacuolar degeneration was observed,and the myelin sheath was partitioned and unsmooth,and lattice-like axons appeared.Serum MerTK levels were significantly higher in the diabetic peripheral neuropathy group than the control group.Expression of MerTK in the sciatic nerve tissue was significantly upregulated in the diabetic peripheral neuropathy group compared with the control group(P<0.05).To conclude,elevated levels of MerTK in plasma and sciatic nerve tissue of rats with diabetic peripheral neuropathy are presumably related to its anti-inflammatory and immunomodulatory effects.

BACKGROUND:Prolyl hydroxylase domain 2(PHD2)inhibitors can regulate bone metabolism and relieve osteoporosis in ovariectomized rats.cpd17 is a small molecule oral PHD2 inhibitor newly developed by China Pharmaceutical University.It is effective in the treatment of renal anemia with few side effects,but its effect on bone formation and bone resorption is still unclear. OBJECTIVE:To investigate the effects of cpd17 on mouse osteogenic precursor cells. METHODS:Osteogenic precursor cells were treated with cpd17.Alkaline phosphatase activity and extracellular matrix mineralization were measured,and the expression levels of osteogenesis-and osteoclastogenesis-related markers,as well as PHD2 and hypoxia-inducible factor 1α,were detected.After inhibition of the hypoxia-inducible factor 1α pathway using LW6(a hypoxia-inducible factor 1α pathway inhibitor),alkaline phosphatase activity and extracellular matrix mineralization were detected again,as well as the expression levels of osteogenesis-and osteoclastogenesis-related markers,PHD2 and hypoxia-inducible factor 1α. RESULTS AND CONCLUSION:cpd17 significantly enhanced alkaline phosphatase activity and extracellular matrix mineralization,up-regulated the expression of osteogenesis-related markers,down-regulated the expression of osteoclastogenesis-related markers,up-regulated the expression of hypoxia-inducible factor 1α,down-regulate the expression of PHD2.However,cpd17's effects were significantly attenuated by LW6.To conclude,the PHD2 inhibitor cpd17 promotes osteogenic differentiation and inhibits osteoclastic differentiation through activation of the hypoxia-inducible factor 1α signaling pathway.

This paper systematically summarizes the practical experience of the 2025 Dingri earthquake emergency medical rescue in Tibet. It analyzes the requirements for earthquake medical rescue under conditions of high-altitude hypoxia, low temperature, and low air pressure. The paper provides a detailed discussion on the strategic layout of earthquake medical rescue at the national level, local government level, and through social participation. It covers the construction of rescue organizational systems, technical systems, material support systems, and information systems. The importance of building rescue teams is emphasized. In high-altitude and cold conditions, rapid response, scientific decision-making, and multi-party collaboration are identified as key elements to enhance rescue efficiency. By optimizing rescue organizational structures, strengthening the development of new equipment, and promoting telemedicine technologies, the precision and effectiveness of medical rescue can be significantly improved, providing important references for future similar disaster rescues.

ObjectiveTo investigate and analyze an outbreak of rotavirus infectious diarrhea in a prison in Chongqing Municipality, to provide a basis for adult rotavirus surveillance and prevention, and to explore the public health problems in special settings. MethodsA retrospective survey was conducted to collect and analyze data on individual cases with diarrheal disease on-site. The clinical characteristics, as well as the temporal, spatial and geographical distribution patterns of the epidemic were described. Multi-pathogen detection tests were conducted both on diarrhea cases and environmental samples, with viral genotyping performed on positive samples. A case-control analysis was performed to identify the causes of the outbreak, and an SEIR model was adopted to predict the outbreak trend and evaluate the effectiveness of interventions. ResultsA total of 65 cases were found among the inmates, with an attack rate of 2.03%. The predominant clinical manifestations included diarrhea (89.23%), watery stool (73.85%), and dehydration (18.46%). The epidemic curve indicated a “human-to-human” transmission pattern, with an average incubation period of 5‒6 days. The attack rates among chefs in the main canteen (80.00%, 8/10) and caterers (28.33%, 17/60) were significantly higher than those of other inmates （P<0.05）. Multi-pathogen polymerase chain reaction (PCR) testing detected positive for group A rotavirus, with the viral genotyping identified as G9P [8] strain. Factors such as unprotected "bare-handed" food distribution among cases with diarrhea (OR=9.512, 95%CI: 4.261‒21.234) and close contact with diarrhea cases (OR=3.656, 95%CI: 1.719‒7.778) were the possible cause of the outbreak. The SEIR model (r₀=5, α=0.3, β₁=0.08, β₂=0.04) was constructed using prison inmates as susceptible population, aiming at fitting the initial transmission trend of the outbreak, and the epidemic rate declined rapidly after intervention measures were implemented (r_t≈0). ConclusionThis rare rotavirus infection diarrhea outbreak among adults in confined settings suggests that the construction of public health prevention and control systems in prison may be overlooked. Cross infection during meal processing and distribution in the canteens of such settings is likely to be the cause of the outbreak. Given the potential neglect of public heath system construction in special settings, it is imperative to enhance the surveillance and monitoring of rotavirus and other intestinal multi-pathogens among adults, as well as the construction of public health prevention and control systems in these special settings.

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Objective:To conduct the genetic analysis of a family with one patient suffering from juvenile Parkinson's disease(JP)and discuss the clinical manifestations,genetic mutation characteristics,and treatment plans prompted by PRKN gene compound heterozygous mutations,and to enhance the clinicians'awareness of this disease.Methods:The clinical data of one patient with JP caused by PRKN gene mutations was analyzed,the clinical manifestations and genetic mutation features of the patient were summarized,and the related literatures were reviewed.Results:The patient,a 16-year-old male,was admitted to the hospital due to unstable gait,trembling limbs with rigidity in both lower limbs for three years.The examination results revealed a panic gait,clear consciousness,fluent speech,normal muscle strength in limbs,increased"gear-like"muscle tone in both upper limbs,and"lead-pipe"rigidity in both lower limbs;the sensory functions and tendon reflexes were normal.The head,neck,and thoracic magnetic resonance imaging(MRI)results showed no abnormalities.18F-fluorodeoxyglucose(18F-FDG)positron emission tomography/computed tomography(PET/CT)results showed that the head size and shape were normal,the glucose metabolism in the left cerebellum and middle temporal gyrus was slightly decreased,and the glucose metabolism in bilateral thalami,right frontal lobe,parietotemporal lobe,and left medial frontal lobe was increased.The dopamine transporter(DAT)PET/CT results showed that there was no radioactive distribution in the brain cortex and the DAT distribution in the posterior part of both striata was decreased.The whole-exome sequencing results showed the patient had two PRKN gene mutations,such as codons c.8T>A and c.850G>C compound heterozygous mutations,and each mutation was from one parent;the patient's father carried the c.8T>A mutation,the patient's mother carried the c.850G>C mutation,and the patient's sister had the same genetic mutation site as the patient's father.Conclusion:PRKN gene compound heterozygous mutations may be the basis of the disease in this family.Identification of the mutation c.8T>A expands the mutation spectrum of the PRKN gene,and provides the valuable information for the research on the pathogenic genetic mutations of the JP patients.

BACKGROUND:Quercetin plays an important role in the proliferation and differentiation of bone marrow mesenchymal stem cells,but less research has been done on its mechanism of promoting the migration of bone marrow mesenchymal stem cells. OBJECTIVE:To study the effect of quercetin on the migration of human bone marrow mesenchymal stem cells through in vitro experiments,and to explore the regulatory role of CCR1 and CXCR4. METHODS:Human bone marrow mesenchymal stem cells were selected as experimental subjects.CCK8 assay was used to detect the effect of quercetin on the proliferative activity of human bone marrow mesenchymal stem cells.Cell scratch assay and Transwell assay were used to detect the in vitro invasive and migratory abilities of human bone marrow mesenchymal stem cells after quercetin treatment,respectively.The role of quercetin in relation to CCR1 and CXCR4 was demonstrated with the help of molecular docking technology.Western blot assay and real-time fluorescence quantitative PCR were used to detect the migration-related chemokine expression after quercetin treatment. RESULTS AND CONCLUSION:(1)5 and 10 μmol/L quercetin could significantly promote the proliferation of human bone marrow mesenchymal stem cells,and the drug concentration of 10 μmol/L resulted in the highest cell proliferation efficiency.(2)To better explore the dose-effect relationship of quercetin affecting the migration of human bone marrow mesenchymal stem cells,5 and 10 μmol/L quercetin were selected for the subsequent experiments,and ligustrazine was used as the positive control drug,and the experiments were divided into blank control group,5 μmol/L quercetin group,10 μmol/L quercetin group,and 100 μmol/L ligustrazine group.(3)In vitro migration and invasion ability of human bone marrow mesenchymal stem cells were elevated in a concentration-dependent manner after quercetin treatment,and the migration effect of 10 μmol/L quercetin group was better than that of ligustrazine group.(4)The molecular docking results suggested that there was a strong interaction between quercetin and CCR1 and CXCR4.(5)Quercetin could up-regulate the expression of CCR1 and CXCR4 proteins and mRNA.(6)This study confirmed at the cellular level that quercetin could promote the migration of human bone marrow mesenchymal stem cells by targeting CCR1 and CXCR4.

The United States has established a perfect specialist training system for developmental and behavioral pediatrics (DBP), while the DBP specialist training system in China is still in the early stage of development and has been constantly improved. This article analyzes and compares the current status of DBP specialist training system between the United States and China from the aspects of training pattern, eligibility criteria, training plans and contents, assessment and evaluation, and certification. With reference to the training system in the United States, we can further improve the DBP specialist training system in China by perfecting the training system and related documents, constructing reasonable eligibility criteria, establishing a training pattern guided by post competency, improving the DBP assessment and evaluation system based on competency, and enhancing the certification of DBP physicians.

AIM:To explore the effects of CD38 on lysosome reformation and cholesterol efflux in macro-phages.METHODS:Bone marrow-derived macrophages from low-density lipoprotein(LDL)receptor knockout(LDLr-/-)mice were cultured as cell model.Live cell imaging system was applied to evaluate the effect of nicotinic acid adenine di-nucleotide phosphate(NAADP)on lysosome number.ELISA was conducted to measure NAADP level in macrophages.After the cells were treated with nicotinic acid(NA),RT-qPCR was conducted to detect CD38 mRNA expression,and Western blot was conducted to observe CD38 protein expression and phosphorylated transcription factor EB(TFEB)level.Laser scanning confocal microscopy was applied to evaluate the influence of CD38/NAADP signaling on lysosome number and cholesterol egression.RESULTS:NAADP remarkably increased lysosome number(P<0.05),and this effect was significantly inhibited by NAADP antagonist NED-19,Ca2+ chelator BAPTA,and calcineurin inhibitor CsA(P<0.05).CD38 markedly enhanced NAADP synthesis in macrophages(P<0.05).NAADP synthetic substrate NA prominently ele-vated the expression of CD38 mRNA and protein(P<0.05).NA significantly decreased the phosphorylated TFEB level;this effect was also attenuated by NED-19,BAPTA and CsA(P<0.05).Disrupting CD38/NAADP signaling pathway markedly inhibited NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux in macrophages(P<0.05).NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux abolished in LDLr/CD38 DKO macrophages(P<0.05),whereas these effects induced by NA were recovered after CD38 gene rescue.CONCLUSION:CD38 triggers lysosome reformation via TFEB and consequently pro-motes the efflux of lysosomal free cholesterol and cytosol cholesterol ester.

Objective:To explore the efficacy of long intramedullary nails versus short intramedullary nails in the treatment of AO/OTA 31-A3 intertrochanteric fractures.Methods:A retrospective analysis was conducted on 60 patients with AO/OTA 31-A3 intertrochanteric femur fractures treated between March 2019 and August 2022. The patients were randomly divided into two groups (the long nail group and the short nail group). Thirty-four patients were treated with long intramedullary nails, including 16 males and 18 females, aged 68.41±17.84 years old (range 31-96 years). Twenty-six patients were treated with short intramedullary nails, including 13 males and 13 females, aged 72.23±13.97 years old (range 31-90 years). The causes of injury, fracture classification (AO/OTA classification), intraoperative blood loss, operation time, fracture healing time, imaging indexes (fracture reduction quality, postoperative neck trunk angle, and medial support), Harris score of the hip joint at the last follow-up, one-year mortality rates and complications were compared between the two groups.Results:The follow-up time was 24.26±6.67 months in the long nail group and 24.31±5.60 months in the short nail group, and the general information of the two groups were comparable. Between the long nail and short nail group, the intraoperative blood loss was 281.47±235.28 ml vs. 121.92±84.14 ml and the operation time was 110.44±24.63 min vs. 81.15±28.54 min with significant differences ( P<0.05). While the length of hospital stay was 12.35±4.81 d vs. 10.89±4.30 d, the good rate of fracture reduction was 55.9% vs. 61.53%, the fracture healing time was 120.44±16.43 d vs. 128.07±18.33 d, the presence rate of medial support was 67.6% vs. 79.4%, and the excellent rate of Harris score was 65.4% vs. 65.4% with no significant difference between the two groups ( P>0.05). One-year mortality rates was 5.3% vs. 7.1% and complications was 11.7% vs. 15.4% with no significant difference between the two groups ( P>0.05). Conclusion:Both long intramedullary nails and short intramedullary nails are effective in the treatment of AO/OTA 31-A3 intertrochanteric femur fractures. However, surgical time and intraoperative blood loss was less in the short nail group.