Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

ObjectiveTo evaluate the clinical efficacy and safety of Tongluo Mingmu capsules in the treatment of diabetic retinopathy with blood stasis， collateral obstruction， and Qi and Yin deficiency syndrome. MethodA randomized， double-blind， positive-control， and multi-center clinical trial design method was used. 416 patients with diabetic retinopathy with blood stasis， collateral obstruction， and Qi and Yin deficiency syndrome in four test centers were included （the ratio of the treatment group to the control group was 3∶1）. On the basis of standardized hypoglycemic treatment， the treatment group was given both four Tongluo Mingmu capsules and two Calcium Dobesilate capsule agents three times a day， while the control group were given both two Calcium Dobesilate capsules and four Tongluo Mingmu capsule agents three times a day. The course of treatment was 12 weeks. The curative effect of Tongluo Mingmu capsules was evaluated by comparing the comprehensive curative effect of diabetic retinopathy， traditional Chinese medicine（TCM） syndrome score， corrected visual acuity， fundus changes， fundus fluorescence angiography， and other curative effect indexes before and after treatment in the two groups. At the same time， general examination， laboratory examination， and adverse events were performed to evaluate the safety of the drug. ResultThe baseline demographic data and disease characteristics of the treatment group and the control group were balanced and comparable， with the difference not statistically significant. After 12 weeks of treatment， the total effective rate of the comprehensive curative effect of diabetic retinopathy in the treatment group （61.0%， 189/310） was better than that in the control group （44.1%， 45/102）， and the difference was statistically significant （χ²=8.880， P<0.01）. The total effective rate of TCM syndromes in the treatment group （88.4%， 259/293） was better than that in the control group （69.9%， 65/93）， and the difference was statistically significant （χ²=17.927， P<0.01）. The disappearance rate of dry eyes （χ²=8.305）， dull complexion （χ²=4.053）， lassitude （χ²=10.267）， shortness of breath （χ²=8.494）， and dry stool （χ²=8.657） in the treatment group was higher than that in the control group， and the difference between the groups was statistically significant （P<0.05， P<0.01）. In terms of improving corrected visual acuity （χ²=8.382）， fundus changes （χ²=6.026） ， the treatment group was significantly better than the control group （P<0.05）. During the trial， the incidence of adverse events in the treatment group and the control group was 1.3% and 2.9%， respectively. There was no significant difference between the two groups. In addition， there were no serious adverse events and adverse events leading to withdrawal in both groups. ConclusionTongluo Mingmu capsules can improve the comprehensive curative effect of diabetic retinopathy and enhance the efficacy of TCM syndromes， visual acuity， fundus changes， and fundus fluorescein angiography， with great safety. Therefore， it can provide a new alternative therapeutic drug for patients with diabetic retinopathy.

Objective To investigate the effects of exercise on autophagy of the hippocampal neurons and learning and memory abilities in APP/PS1 transgenic Alzheimer's disease(AD)model mice.Methods Four-month-old male APP/PS1 mice were randomly divided into AD model sedentary group(AS)and AD model exercise group(AE).C57BL/6 mice of the same age were used as control group(CS),with 12 mice in each group.Among them,AE group mice underwent regular treadmill exercise at 10 m per minute(the first 10 minutes)and 12 m per minute(the following 50 minutes)for 60 min,0° slope,5 days/week,for 8 weeks.Morris water maze,novel object recognition test,immunohistochemistry,Western blotting,transmission electron microscopy,and Nissl staining were used to detect learning memory abilities,amyloid β-protein(Aβ),human microtubule-associated protein light chain 3B(LC3B),Beclin1,p62 protein expression,autophagy lysosomes and neuron number.Results Eight weeks of exercise intervention could significantly improve the learning and memory abilities of AD model mice in the Morris water maze and novel object recognition test.The expression levels of Aβ plaques and p62 protein in the hippocampus of mice in the AS group increased significantly,while the levels of LC3B,Beclinl,autophagy lysosomes and neurons decreased significantly.Exercise intervention significantly reduced the expression levels of Aβ plaques and p62 protein in the hippocampus of AD model mice,and increased the levels of LC3B,Beclin1,autophagolysosomes and neurons.Conclusion Exercise could effectively improve the damage of neuronal autophagy in the hippocampus of AD model mice and protect the neurons through promoting autophagy lysosomes to degrade pathological Aβ in the hippocampus.These result might underlie the mechanisms for the treadmill exercise-induced improvement of learning and memory abilities.

Objective:To establish a three-dimensional finite element model of the nose, simulate and analyze the deformation of nasal tissue caused by different focal points, traction directions, and modes, provide the theoretical basis for the effectiveness of physical traction therapy, and guide the clinical selection of more efficient physical traction therapy methods.Methods:A finite element model of the nose was established by ANSYS Workbench 19.2 software based on image data obtained from CT scans of a 29-year-old male volunteer with normal nasal appearance in Peking University Third Hospital. Two focal points, the nasal tip, and the nasal columella, were selected, and three force directions, parallel to the forward, forward and down 30°, forward and down 60°, were applied. The deformation caused by different traction conditions on the skin, lining, and soft bone parts, as well as the four anatomical landmarks of the nasal tip, nasal root, the midpoint of the nasal columella, and the nasal base, were compared. The deformation produced by 10 minutes of continuous pulling and 10 times 1-minute pulse pulling were compared under the same pulling conditions. The deformations generated by two types of pulling modes within a 24-hour cycle: a single 1-hour cycle and 6 intermittent 10-minute cycles, were compared.Results:All traction conditions resulted in deformation of the nasal model, with the maximum deformation of the nasal tissue obtained by pulling forward and downward at 60° (4.632 9 mm) which was greater than other traction conditions (0.825 0-3.105 0 mm). The maximum deformation value was located near the nasion of the model’s skin layer. The deformation obtained by 10 minutes of continuous pulling (0.176 6 mm) was slightly greater than that obtained by 10 times of 1-minute pulse pulling (0.176 5 mm). Within 24 hours, the final deformation of multiple intermittent pulling modes (0.019 0 mm) was greater than that of a single pulling mode (0.004 3 mm).Conclusion:Physical traction can effectively deform the skin and soft tissue of the nose, and the most efficient operation is to continuously pinch the tip of the nose for a short period and apply tension parallel to the back of the nose downwards, repeating every a few hours.

Objective:To establish a three-dimensional finite element model of the nose, simulate and analyze the deformation of nasal tissue caused by different focal points, traction directions, and modes, provide the theoretical basis for the effectiveness of physical traction therapy, and guide the clinical selection of more efficient physical traction therapy methods.Methods:A finite element model of the nose was established by ANSYS Workbench 19.2 software based on image data obtained from CT scans of a 29-year-old male volunteer with normal nasal appearance in Peking University Third Hospital. Two focal points, the nasal tip, and the nasal columella, were selected, and three force directions, parallel to the forward, forward and down 30°, forward and down 60°, were applied. The deformation caused by different traction conditions on the skin, lining, and soft bone parts, as well as the four anatomical landmarks of the nasal tip, nasal root, the midpoint of the nasal columella, and the nasal base, were compared. The deformation produced by 10 minutes of continuous pulling and 10 times 1-minute pulse pulling were compared under the same pulling conditions. The deformations generated by two types of pulling modes within a 24-hour cycle: a single 1-hour cycle and 6 intermittent 10-minute cycles, were compared.Results:All traction conditions resulted in deformation of the nasal model, with the maximum deformation of the nasal tissue obtained by pulling forward and downward at 60° (4.632 9 mm) which was greater than other traction conditions (0.825 0-3.105 0 mm). The maximum deformation value was located near the nasion of the model’s skin layer. The deformation obtained by 10 minutes of continuous pulling (0.176 6 mm) was slightly greater than that obtained by 10 times of 1-minute pulse pulling (0.176 5 mm). Within 24 hours, the final deformation of multiple intermittent pulling modes (0.019 0 mm) was greater than that of a single pulling mode (0.004 3 mm).Conclusion:Physical traction can effectively deform the skin and soft tissue of the nose, and the most efficient operation is to continuously pinch the tip of the nose for a short period and apply tension parallel to the back of the nose downwards, repeating every a few hours.

Renal fibrosis， the final pathological outcome of end-stage chronic kidney diseases， is associated with inflammation， oxidative stress， epithelial-mesenchymal transdifferentiation （EMT）， and extracellular matrix deposition. It belongs to the categories of edema， ischuria， anuria and vomiting， and consumptive disease in traditional Chinese medicine （TCM）， with the key pathogenesis of Qi deficiency and blood stasis and the primary treatment principle of replenishing Qi and activating blood. Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma mainly contains astragalosides， polysaccharides， calycosin， salvianolic acid， and tanshinone， with the effect of tonifying Qi and activating blood. Studies have shown that this herb pair and its active components can delay the progress of renal fibrosis by regulating multiple signaling pathways. With consideration to the pathogenesis of Qi deficiency and blood stasis， this article reviews the research progress in the mitigation of renal fibrosis by Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma from the aspects of protecting glomerular filtration barrier， inhibiting EMT and mesangial cell proliferation， improving renal hemodynamics， and protecting renal function. Furthermore， the mechanisms were summarized. Specifically， Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma and its effective components can improve mitochondrial function and fatty acid metabolism， alleviate endoplasmic reticulum stress and autophagy disorders， and inhibit immune inflammation and oxidative stress by regulating nuclear factor E₂-related factor 2 （Nrf2）/PTEN-induced kinase 1 （Pink1）， Nrf2/antioxidant response element （ARE）， tumor necrosis factor-α （TNF-α）/nuclear transcription factor-κB （NF-κB）， miR-21/Smad7/transforming growth factor beta （TGF-β）， Wnt/β-catenin， long non-coding RNA-taurine up-regulated gene 1 （lncRNA-TUG1）/tumor necrosis factor receptor-associated factor 5 （TRAF5）， Ras-related C3 botulinum toxin substrate 1 （Rac1）/cell division cycle protein 42 （CDC42）， Ras homolog （Rho）/Rho-associated coiled-coil containing protein kinase （ROCK）， phosphatidylinositol-3-kinase （PI3K）/protein kinase B （Akt）， Janus kinase （JAK）/signal transducer and activator of transcription （STAT）， peroxisome proliferator-activated receptor α （PPARα）/peroxisome proliferator-activated receptor γ coactivator l alpha （PGC-1α）， and p38 mitogen-activated protein kinase （p38 MAPK）. This review aims to provide references for the relevant research， give play to the role of Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma， and provide guidance for the clinical treatment of renal fibrosis.

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.
Male ; Humans ; Prostate-Specific Antigen ; Treatment Outcome ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Immune Checkpoint Inhibitors/therapeutic use* ; Retrospective Studies