The association between dental caries and steroid-sensitive nephrotic syndrome in children.

BACKGROUND: Pathogenesis and relapse of steroid-sensitive nephrotic syndrome (SSNS) are primarily associated with infection. Dental caries is the most common chronic progressive oral infection in children. However, clinical studies of SSNS combined with dental caries in children are rare. METHODS: In our retrospective cohort study from January 2021 to June 2022, 145 children with SSNS were included in the baseline analysis and 105 in the follow-up analysis. The follow-up period was 1 year. The primary study endpoints were the relapse-free period and frequently relapsing nephrotic syndrome (FRNS). Secondary endpoints included the number and triggers of relapses and concomitant medications. RESULTS: The median age was 5.5 years, with a caries rate of 60.7%, the mean DMFT/dmft was 3.86, and the caries filling rate was 1.6%. Except for the lower proportion of high household income and high parental education observed in the caries group, no statistical differences were found when comparing the other baseline data with the non-caries group. The caries group had a shorter relapse-free period and a lower 1-year cumulative relapse-free survival rate (HR = 1.90, 95% CI 1.17-3.09, P = 0.009). Univariate regression analysis showed caries associated with FRNS (OR = 2.714, 95% CI 1.021-7.219, P = 0.045), but the correlation no longer remained in the multivariate analysis. Additionally, seven cases of caries-derived pulpal periapical inflammation triggered SSNS relapses. The caries group had more infection triggers and concomitant medication use. CONCLUSION: Dental caries and relapse of SSNS are potentially associated, but careful evaluation is needed.

Diagnostic value of serum CRP, PCT and IL-6 in children with nephrotic syndrome complicated by infection: a single center retrospective study.

OBJECTIVE: The purpose was to look into the diagnostic value of serum CRP, PCT and IL-6 in children with nephrotic syndrome co-infection. METHODS: One hundred and forty-nine children with nephrotic syndrome who met the inclusion and exclusion criteria were included in this study. The children were divided into three groups: bacterial infection group, non-bacterial infection group, and non-infection group. The diagnostic value was analyzed and compared using the ROC curve. RESULTS: There was no statistically significant difference in the Leukocyte counts among three groups. The mean results of serum CRP, PCT and IL-6 were significantly higher in the bacterial infection group compared to those in the non-infection group (p < 0.05). AUC of CRP, PCT, IL-6 in bacterial infection were 0.791, 0.859, 0.783. The following combinations CRP + PCT + IL-6, IL-6 + PCT, CRP + PCT significantly increased the efficiency of bacterial infection diagnosis, the AUCs were 0.881, 0.884, and 0.884, respectively. AUC of PCT in non-bacterial infection was 0.663. The combinations of these three clinical indicators performed no better than PCT in ROC analysis. CONCLUSION: Normal CRP or IL-6 levels do not rule out the diagnosis of bacterial infection in children on long-term glucocorticoid therapy. The appropriate combination of two or three indicators can improve the diagnostic value. IMPACT: This study evaluated the diagnostic value of the serum concentrations of CRP, PCT and IL-6 and assessed whether the value of their combined application is better than when used alone for diagnosing primary nephrotic syndrome complicated by infection. The elevation in leukocyte count cannot be used to diagnose children with nephrotic syndromes on long-term glucocorticoid treatment who have bacterial infections. Normal CRP or IL-6 levels do not rule out the diagnosis of bacterial infection in children on long-term glucocorticoid therapy. The appropriate combination of two or three indicators can improve diagnostic value, sensitivity, and specificity.

External validation of the pediatric International IgA Nephropathy Prediction Tool in a central China cohort.

BACKGROUND: This study aimed to externally validate the pediatric International IgA Nephropathy (IgAN) Prediction Tool updated from the adult IgAN Prediction Tool. METHODS: 439 children with biopsy-confirmed idiopathic IgAN were enrolled in this external validation study. The primary outcome was a 30% decline in eGFR or end-stage kidney disease. We evaluated the discrimination using Harrell's C-index, the receiver operating characteristic (ROC) curve, and Kaplan-Meier curves for four risk groups (< 16th [low risk], ∼16 to < 50th [intermediate risk], ∼50 to < 84th [high risk], and ≥ 84th percentiles [highest risk] of linear predictor). Calibration was assessed using calibration plots. RESULTS: The median follow-up time of the 439 patients was 4.5 (2.7-6.8) years, and 27 patients reached the primary outcome. Compared with the reported cohorts, our cohort was more contemporary, with milder proteinuria at biopsy, and had lower proportions of S1 and T1 lesions. Harrell's C-index and area under the ROC curve at 5 years were < 0.7 for both the models with and without race. The Kaplan-Meier curves of the risk groups were not well separated for the two models, only separated completely between the highest-risk group and the others for the model without race. The two models generally overestimated the risk of the primary outcome, CONCLUSION: The model without race could accurately distinguish the highest-risk patients from patients with low, intermediate, and high risk for kidney progression. Discrimination and calibration for the full model with or without race were unsatisfactory in this contemporary cohort in central China.

Role of abnormal glycosylated IgA1 and interstitial transformation of glomerular endothelial cells in the development and progression of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a common primary renal disease in childhood. METHODS: Twenty blood samples and renal tissue from patients with IgAN, 20 blood samples from healthy children and 10 normal renal tissue were collected. Serum Gd-IgA1 and renal Gd-IgA1, CD31, α-SMA and vimentin were measured. RESULTS: The serum Gd-IgA1 concentration in the IgAN group was significantly higher. Gd-IgA1 was not expressed in normal kidneys, which was positive in the IgAN group. Gd-IgA1 levels in serum and renal tissue were not related. The expression of CD31 decreased significantly in IgAN group, while the expression of α-SMA and vimentin increased significantly. There was no significant correlation between the renal concentration of Gd-IgA1 and CD31, α-SMA and vimentin. CONCLUSION: The increased Gd-IgA1 in the serum and kidney may promote the pathogenesis of IgAN. The serum Gd-IgA1 cannot predict the extent of its deposition in the kidney. Endothelial mesenchymal transition (EndMT) may be involved in the pathogenesis of renal fibrosis in IgAN.

Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review.

BACKGROUND: Millions of COVID-19 pediatric survivors are facing the risk of long COVID after recovery from acute COVID-19. The primary objective of this study was to systematically review the available literature and determine the pooled prevalence of, and risk factors for long COVID among the pediatric survivors. METHODS: Studies that assessed the prevalence of, or risk factors associated with long COVID among pediatric COVID-19 survivors were systematically searched in PubMed, Embase, and Cochrane Library up to December 11th, 2022. Random effects model was performed to estimate the pooled prevalence of long COVID among pediatric COVID-19 patients. Subgroup analyses and meta-regression on the estimated prevalence of long COVID were performed by stratification with follow-up duration, mean age, sex ratio, percentage of multisystem inflammatory syndrome, hospitalization rate at baseline, and percentage of severe illness. RESULTS: Based on 40 studies with 12,424 individuals, the pooled prevalence of any long COVID was 23.36 % ([95 % CI 15.27-32.53]). The generalized symptom (19.57 %, [95 % CI 9.85-31.52]) was reported most commonly, followed by respiratory (14.76 %, [95 % CI 7.22-24.27]), neurologic (13.51 %, [95 % CI 6.52-22.40]), and psychiatric (12.30 %, [95% CI 5.38-21.37]). Dyspnea (22.75 %, [95% CI 9.38-39.54]), fatigue (20.22 %, [95% CI 9.19-34.09]), and headache (15.88 %, [95 % CI 6.85-27.57]) were most widely reported specific symptoms. The prevalence of any symptom during 3-6, 6-12, and> 12 months were 26.41 % ([95 % CI 14.33-40.59]), 20.64 % ([95 % CI 17.06-24.46]), and 14.89 % ([95 % CI 6.09-26.51]), respectively. Individuals with aged over ten years, multisystem inflammatory syndrome, or had severe clinical symptoms exhibited higher prevalence of long COVID in multi-systems. Factors such as older age, female, poor physical or mental health, or had severe infection or more symptoms were more likely to have long COVID in pediatric survivors. CONCLUSIONS: Nearly one quarter of pediatric survivors suffered multisystem long COVID, even at 1 year after infection. Ongoing monitoring, comprehensive prevention and intervention is warranted for pediatric survivors, especially for individuals with high risk factors.

The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-κB1 p105 to p50.

BACKGROUND: Aberrant RNA editing of adenosine-to-inosine (A-to-I) has been linked to multiple human cancers, but its role in intrahepatic cholangiocarcinoma (iCCA) remains unknown. We conducted an exome-wide investigation to search for dysregulated RNA editing that drive iCCA pathogenesis. METHODS: An integrative whole-exome and transcriptome sequencing analysis was performed to elucidate the RNA editing landscape in iCCAs. Putative RNA editing sites were validated by Sanger sequencing. In vitro and in vivo experiments were used to assess the effects of an exemplary target gene Kip1 ubiquitination-promoting complex 1 (KPC1) and its editing on iCCA cells growth and metastasis. Crosstalk between KPC1 RNA editing and NF-κB signaling was analyzed by molecular methods. RESULTS: Through integrative omics analyses, we revealed an adenosine deaminases acting on RNA 1A (ADAR1)-mediated over-editing pattern in iCCAs. ADAR1 is frequently amplified and overexpressed in iCCAs and plays oncogenic roles. Notably, we identified a novel ADAR1-mediated A-to-I editing of KPC1 transcript, which results in substitution of methionine with valine at residue 8 (p.M8V). KPC1 p.M8V editing confers loss-of-function phenotypes through blunting the tumor-suppressive role of wild-type KPC1. Mechanistically, KPC1 p.M8V weakens the affinity of KPC1 to its substrate NF-κB1 p105, thereby reducing the ubiquitinating and proteasomal processing of p105 to p50, which in turn enhances the activity of oncogenic NF-κB signaling. CONCLUSIONS: Our findings established that amplification-driven ADAR1 overexpression results in overediting of KPC1 p.M8V in iCCAs, leading to progression via activation of the NF-κB signaling pathway, and suggested ADAR1-KPC1-NF-κB axis as a potential therapeutic target for iCCA.

The relationship between abuse and neglect and adolescent suicidality: A moderated mediation model.

Abuse and neglect can lead to suicide in adolescents; however, the internal mechanisms between abuse and neglect and suicidality remain unclear. We hypothesized that abuse and neglect could affect adolescent suicidality, and that mediating and moderating mechanisms exist between these two variables. We tested the mediating effects of stressful life events (misunderstanding and discrimination by others, poor academic performance, failed exams, interpersonal problems, and school punishment) on suicidal tendencies and moderating effects of resilience among 5,852 adolescents from 37 middle schools in five provinces of North, south, East, west, and central China. We used a questionnaire to collect data and adopted structural equation modeling to verify the correlation, mediating, and moderating effects among the variables. The results showed that stressful life events mediated the relationship between abuse, neglect, and suicide. Furthermore, resilience moderated the direct effect and second half of the mediating effect.

SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer.

BACKGROUND: Secreted phosphoprotein 1 (SPP1) plays a vital role in tumor progression of multiple cancer types However, it still awaits further exploration whether SPP1 is a bystander or an actual player in the modulation of immune infiltration in ovarian cancer. METHODS: In this study, the expression level of SPP1 was identified by Oncomine, GEPIA and TIMER databases, and the result of SPP1 immumohistochemical staining was acquired by The HPA database. The impact of SPP1 expression level on the clinical outcome of ovarian cancer patients were evaluated via Kaplan-Meier Plotter and PrognoScan dataset. Immune infiltration analyses were conducted using TIMER and TISIDB dataset. In addition, Functional enrichment analyses were performed with Metascape and GeneMANIA database. To verify these findings from the public database, the results were validated in a cohort of ovarian cancer patients. RESULTS: SPP1 was found to be overexpressed in ovarian tumor tissues and high SPP1 expression was correlated with shorter survivals. Notably, SPP1 expression was positively correlated with infiltrating levels of CD4 + T cells, CD8 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression level showed strong correlation with diverse immune cells in ovarian cancer. Of note, functional enrichment analysis suggested that SPP1 was strongly correlated with immune response. CONCLUSIONS: These findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in ovarian cancer. TRIAL REGISTRATION: Not applicable.

Factors Influencing Aggressive Adolescent Behavior: An Analysis Using the Decision Tree Method.

Aggression among adolescents is a significant public health concern worldwide. To safeguard adolescents' physical and mental health, controlling the incidence of aggressive behavior and its triggers and drivers is necessary. Different risk factors in each environment drive adolescent aggression. These factors are interconnected, making the environment an ecosystem of aggression. This study aims to analyze the factors that influence adolescents' aggressive behavior and provide a basis for formulating measures to reduce such behavior in the future. This multicenter cross-sectional study was conducted in five middle schools in Lingbao City. The participants were junior high school students aged 11-15 years. Data were analyzed from January to March 2020 using the decision tree analysis method. The aggressive behavior scale, adolescent emotion regulation scale, family intimacy and adaptation scale, parental education participation scale, and a simple parenting style questionnaire were used for the investigation. Of the 581 participants, 25.5% demonstrated a tendency for aggressive behavior, while the remaining did not. The decision tree analysis showed that the incidence of adolescent aggression was the highest (54.8%) when the maternal overprotective score was greater than or equal to 17, the adolescent had low emotional control, and the mother's intelligence score was higher than 30. The decision tree model reflects the influencing factors of adolescent aggressive behavior from multiple levels and provides a reference for formulating effective intervention measures to control such behavior and its influencing factors.

Management and prognosis comparison between incidental and nonincidental intravenous leiomyomatosis: a retrospective single-center real-life experience.

Background: Intravenous leiomyomatosis (IVL) is a rare, difficult-to-treat type of smooth muscle tumor that originates from the uterine myoma. However, its clinical characteristics, management, and prognosis are not clearly understood. Moreover, the 2 different methods used to diagnose IVL-incidental and nonincidental-result in completely different treatments. Methods: We conducted a single-center, retrospective study. Our real-life case series included patients pathologically diagnosed with IVL between July 2011 and December 2020. All patients with IVL were divided into 2 groups: an incidental group and a nonincidental group. Medical records of patients, including clinical characteristics, primary treatment, treatment after recurrence, and prognosis, were reviewed. Results: A total of 39 patients were included in the study, with a median patient age of 47 years. Of the 39 cases, 15 (38.5%) were incidentally diagnosed with only intrapelvic tumors. Among the 24 patients with IVL in the nonincidental group, tumor spread in the inferior vena cava, right heart, and pulmonary artery was identified in 4, 17, and 3 patients, respectively. The most common symptoms were abnormal uterine bleeding in the incidental group and chest distress and dyspnea in the nonincidental group. Among the 15 patients in the incidental group, ovary-preserving surgery was performed in 6 young women (≤40 years old), of whom 3 underwent myomectomy. All 24 patients with IVL in the nonincidental group underwent thrombectomy without uterine or ovary preservation by multidisciplinary surgical treatment. Only 1 patient in each group underwent postoperative adjuvant therapy. During the median follow-up of 36.0 months, recurrence was recorded in 5 (12.8%) cases in the incidental group, with no deaths recorded. Only 1 patient was lost to follow-up. No recurrence was noted in the cases in the nonincidental group. Among the 5 patients who experienced recurrence, 4 received secondary surgical treatment and 1 received hormone therapy. All patients were alive as of this report. Conclusions: Patients with IVL who are diagnosed incidentally have a higher recurrence risk than those who are diagnosed nonincidentally and undergo complete tumor resection. However, patients incidentally diagnosed with IVL can still experience long disease-free survival rates following secondary surgical treatment after recurrence.

Effects of continuous subcutaneous insulin infusion on the microstructures, mechanical properties and bone mineral compositions of lumbar spines in type 2 diabetic rats.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) for the treatment of type 2 diabetes (T2D) can improve the structure and strength of femur of rats, but the effect of CSII treatment on the lumbar spine of T2D rats is unknown. The purpose of this study is to investigate the effects of CSII on the microstructure, multi-scale mechanical properties and bone mineral composition of the lumbar spine in T2D rats. METHODS: Seventy 6-week-old male Sprague-Dawley (SD) rats were divided into two batches, each including Control, T2D, CSII and Placebo groups, and the duration of insulin treatment was 4-week and 8-week, respectively. At the end of the experiment, the rats were sacrificed to take their lumbar spine. Microstructure, bone mineral composition and nanoscopic-mesoscopic-apparentand-macroscopic mechanical properties were evaluated through micro-computed tomography (micro-CT), Raman spectroscopy, nanoindentation test, nonlinear finite element analysis and compression test. RESULTS: It was found that 4 weeks later, T2D significantly decreased trabecular thickness (Tb.Th), nanoscopic-apparent and partial mesoscopic mechanical parameters of lumbar spine (P < 0.05), and significantly increased bone mineral composition parameters of cortical bone (P < 0.05). It was shown that CSII significantly improved nanoscopic-apparent mechanical parameters (P < 0.05). In addition, 8 weeks later, T2D significantly decreased bone mineral density (BMD), bone volume fraction (BV/TV) and macroscopic mechanical parameters (P < 0.05), and significantly increased bone mineral composition parameters of cancellous bone (P < 0.05). CSII treatment significantly improved partial mesoscopic-macroscopic mechanical parameters and some cortical bone mineral composition parameters (P < 0.05). CONCLUSIONS: CSII treatment can significantly improve the nanoscopic-mesoscopic-apparent-macroscopic mechanical properties of the lumbar spine in T2D rats, as well as the bone structure and bone mineral composition of the lumbar vertebrae, but it will take longer treatment time to restore the normal level. In addition, T2D and CSII treatment affected bone mineral composition of cortical bone earlier than cancellous bone of lumbar spine in rat. Our study can provide evidence for clinical prevention and treatment of T2D-related bone diseases.

Effect of verapamil on bone mass, microstructure and mechanical properties in type 2 diabetes mellitus rats.

BACKGROUND: Verapamil was mainly used to treat hypertension, cardiovascular disease, inflammation and improve blood glucose in patients with diabetes, but its effects on bone mass, microstructure and mechanical properties were unclear. This study described the effects of verapamil on bone mass, microstructure, macro and nano mechanical properties in type 2 diabetic rats. METHODS: Rat models of type 2 diabetes were treated with verapamil at doses of 4, 12, 24 and 48 mg/kg/day by gavage respectively, twice a day. After 12 weeks, all rats were sacrificed under general anesthesia. Blood glucose, blood lipid, renal function and biochemical markers of bone metabolism were obtained by serum analysis, Micro-CT scanning was used to assess the microstructure parameters of cancellous bone of femoral head, three-point bending test was used to measure maximum load and elastic modulus of femoral shaft, and nano-indentation tests were used to measure indentation moduli and hardnesses of longitudinal cortical bone in femoral shaft, longitudinal and transverse cancellous bones in femoral head. RESULTS: Compared with T2DM group, transverse indentation moduli of cancellous bones in VER 24 group, longitudinal and transverse indentation moduli and hardnesses of cancellous bones in VER 48 group were significantly increased (p < 0.05). Furthermore, the effects of verapamil on blood glucoses, microstructures and mechanical properties in type 2 diabetic rats were dependent on drug dose. Starting from verapamil dose of 12 mg/kg/day, with dose increasing, the concentrations of P1NP, BMD, BV/TV, Tb. Th, Tb. N, maximum loads, elastic moduli, indentation moduli and hardnesses of femurs in rats in treatment group increased gradually, the concentrations of CTX-1 decreased gradually, but these parameters did not return to the level of the corresponding parameters of normal rats. Verapamil (48 mg/kg/day) had the best therapeutic effect. CONCLUSION: Verapamil treatment (24, 48 mg/kg/day) significantly affected nano mechanical properties of the femurs, and tended to improve bone microstructures and macro mechanical properties of the femurs, which provided guidance for the selection of verapamil dose in the treatment of type 2 diabetic patients.

A Human-Inspired Soft Finger with Dual-Mode Morphing Enabled by Variable Stiffness Mechanism.

Elevating stiffness without compromising compliance and agility is a key problem for soft finger applications, especially for articulate ones. Inspired by human finger, a multijoint soft finger with dual morphing through active/passive variable rigidity is proposed. The fabricated soft finger weighs 27.4 g. Conductive thermoplastic starch polymers (CTPSs) are embedded in a U-shape-joint pneumatic soft actuator segmentally like biological phalanges. Their stiffness can be independently adjusted utilizing customized thermomechanical property. Yoshimura origami imitating ligaments can passively match deformation and stiffness of the joints. Through electrothemal activation of CTPSs, the finger can realize dual independent articulate morphing: stiffened phalanges (mode 1) for dexterous manipulation and heavy load, softened phalanges (mode 2) for large deformation contact and light load. Comparative experiments of bending angle, output force, and stiffness are carried out between the active and passive stiffness adjustment of mode 1 and mode 2. The results show that the output force and stiffness of the finger adopting mode 1 can be improved more than two times and five times, and its compliance using mode 2 is almost similar, compared with the pure soft one. To further demonstrate performances of dual-mode morphing, a three-fingered gripper is assembled for grasping and manipulating targets with different shapes, sizes, rigidity, and weight, including playing card, unshelled raw egg, grapes, and unscrewing the bottle cap. It can successfully lift a dumbbell weighing 1460 g with a 7.6 load/weight ratio through a two-mode switch.

Impact of body mass index on primary immunoglobulin A nephropathy prognosis: a systematic review and meta-analysis.

PURPOSE: The impacts of body mass index (BMI) on the prognosis of primary IgA nephropathy (IgAN) remain controversial. This systematic review and meta-analysis aimed to solve these issues. METHODS: We searched the PubMed, EMBASE, and Cochrane Library to screen articles investigating the BMI and primary IgAN. BMI was classified according to the World Health Organization as high (≥ 25.0 kg/m2) and low (< 25.0 kg/m2). The baseline renal indexes and the incidences of adverse renal outcomes were focused on. RESULTS: Six studies with a total of 1723 patients were included in this study. High BMI was demonstrated to be associated with increased baseline levels of serum creatinine (weighted mean difference (WMD) 9.54, 95% confidence interval (CI) 0.63-18.45), blood uric acid (WMD 19.85, 95% CI 10.11-29.59) and urine protein (WMD 0.37, 95% CI 0.21-0.53). Patients with high BMI also showed compromised eGFR at diagnosis (WMD - 8.39, 95% CI - 11.62 to - 5.16) with a higher incidence rate of hypertension (odds ratios (OR) 2.59, 95% CI 1.44-4.66) and higher global optical scores (WMD 1.22, 95% CI 0.70-1.74). Regarding the prognosis, high BMI was significantly associated with the incidence of adverse renal outcomes (OR 2.43, 95% CI 1.66-3.55, P < 0.001) and deteriorated eGFR at the last follow-up (WMD - 11.10, 95% CI - 16.96 to - 5.25, P < 0.001), with non-significantly poorer renal disease-free survival (hazard ratio 1.79, 95% CI 0.58-5.50, P = 0.31). CONCLUSION: High BMI was associated with severe onset and poor prognosis of primary IgAN. The management of BMI could be a novel method to promote the therapeutic outcomes of primary IgAN.

A Wide-Range Stiffness-Tunable Soft Actuator Inspired by Deep-Sea Glass Sponges.

Achieving both high compliance and stiffness is a key issue in stiffness-tunable soft robots. A wide-range variable-stiffness method keeping pure soft characteristic is proposed by bioinspired design of deep-sea glass sponges adopting thermoplastic starch. The stiffness-tunable mechanism is designed through force analysis and optimization of its bionic cellular structure. It is fabricated with load-weight ratio exceeding 470. Then, a wide-range stiffness-tunable omnidirectional-bending soft actuator (WOSA) is realized, and the bending stiffness model is established. Comparative experiments of stiffness and deformation are conducted on WOSA and a pure soft actuator (PSA) with the same size. Results show that the WOSA can get 92.3 times initial bending and 70.8 times torsional stiffness variation range, of which the flexibility is even better than PSA. A gripper assembled by three WOSAs is verified through stiffness adjustment that it can grasp different weight fragile, soft items from the unshelled fresh egg, boiled egg yolk to grapes. It can even lift a dumbbell weighting 3.32 kg. Finally, a manipulator demonstrated its potential in future minimally invasive surgical applications due to its wide stiffness range and large deformation capacity.

The role of miR-199b-3p in regulating Nrf2 pathway by dihydromyricetin to alleviate septic acute kidney injury.

The pathophysiology of septic acute kidney injury (AKI) is very complex and the fatality is high. Nrf2 is crucial for septic AKI, and dihydromyricetin (DMY) has a protective effect on LPS-induced AKI. We aimed to explore whether DMY could affect Nrf2 pathway by regulating miR-199b-3p and played a protective role in septic AKI. The mouse model was induced by cecal ligation and puncture (CLP) and the cell model was stimulated by LPS. Enzyme-linked immunosorbent assay was conducted to examine MDA, SOD, LDH, GSH, TNF-α, kidney injury molecule 1 (KIM-1), and IL-6 levels. The pathological changes were observed by hematoxylin-eosin staining. The targeted relationship between miR-199b-3p and Nrf2 was verified by a dual-luciferase reporter assay. Levels of SOD, GSH, NQO-1, Nrf2, and HO-1 were decreased, MDA, LDH, TNF-α, IL-6, and KIM-1, and miR-199b-3p were increased in the CLP group and LPS-induced HK-2 cells, while the effect was reversed after DMY treatment. There existed renal tubule cell edema and necrosis, inflammatory cell infiltration in the CLP group, the situation was partially improved by DMY. MiR-199b-3p bound to Nrf2. Nrf2 levels were increased, TNF-α, IL-6, and KIM-1 were decreased after transfected with miR-199b-3p inhibitor, these effects were reversed when co-transfected with si-Nrf2. TNF-α, IL-6, KIM-1, and miR-199b-3p levels were increased; Nrf2, NQO-1, and HO-1 levels were decreased in the LPS + DMY + mimics-miR group. MiR-199b-3p was increased in septic AKI models, DMY might alleviate septic AKI by regulating miR-199b-3p to affect the Nrf2 pathway.

pH and charge reversal-driven nanoplatform for efficient delivery of therapeutics.

Nanomedicine which delivers therapeutics to tumours holds great potential for cancer treatment. However, endosomal trapping and uncontrollable release usually limit the efficiency of nanomedicine. Herein, a smart mesoporous silica based nanoplatform was constructed, in which mesoporous silica nanoparticles (MSNs) serve as the core, capped with pH-induced charge-reversal polymer -PAH-cit- and cationic polyelectrolyte polyethyleneimine (PEI). The oppositely charged polymer can not only act as a gatekeeper for controlled release, but also mediated efficient endosomal escape of the therapeutics. Under the acidic endosomal environment, the hydrolysis of acid-cleavable bonds in PAH-Cit would trigger the charge reversal and endosomal escape of the nanoplatform for efficient drug release. Furthermore, the prepared nanoplatform demonstrated a higher tumor cell proliferation inhibition rate than free theruputics in vitro assays and significantly inhibited tumour growth in the 4T1 tumour model in mice. Therefore, our strategy offers a simple and general nanoplatform to delivery therapeutics to tumours with efficient endosomal escape and controlled release.

Primary Laparoscopic Surgery Does Not Affect the Prognosis of Early-Stage Ovarian Clear Cell Cancer.

PURPOSE: Minimally invasive surgery (MIS) is performed frequently in early-stage ovarian cancer patients, especially in ovarian clear cell carcinoma (OCCC). The aim of this study was to investigate whether primary laparoscopic surgery influences prognosis in patients with early-stage OCCC. PATIENTS AND METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I  OCCC were retrospectively reviewed in two hospitals between April 2010 and August 2020. Clinical data were abstracted, and patients were followed up until February 2021. Patients were divided into open surgery (laparotomy) and laparoscopy groups, and the Kaplan-Meier method was applied to compare progression-free survival (PFS) and overall survival (OS) between the groups. Statistical differences were determined by the Log rank test. RESULTS: Eighty-nine patients were included in the study; 20 (22.5%) and 69 (77.5%) patients underwent laparoscopic and open surgery, respectively. The patients' characteristics were well-balanced except that patients in the laparoscopy group tended to have smaller tumors and lower frequency of omentectomy and lymphadenectomy compared with the open surgery group. The median follow-up duration was 42.6 and 36.5 months in the laparoscopy and open surgery groups, respectively. Nine (10.1%) patients developed recurrence, and 4 (4.5%) died of the disease; all in the open surgery group. The estimated 2-year PFS rates were 100.0% and 90.1%, and the estimated 5-year OS rates were 100.0% and 91.9% in the laparoscopy and open surgery groups, respectively. No significant survival differences were found between the groups. CONCLUSION: Survival was not compromised when primary laparoscopic surgery was performed in early-stage OCCC patients. A well-designed randomized controlled trial is warranted.

Continuous subcutaneous insulin infusion ameliorates bone structures and mechanical properties in type 2 diabetic rats by regulating bone remodeling.

Continuous subcutaneous insulin infusion (CSII) is an intensive insulin therapy for patients with type 2 diabetes mellitus (T2DM) who have poor glycemic control, but its effect on T2DM-related bone disorder is unclear. This study described the possible mechanisms by which CSII affects bone remodeling, structures, and mechanical properties in T2DM rats. Herein, male rats (6-week-old) were assigned randomly to 4-week and 8-week administration groups, each of which included healthy control, T2DM, CSII, and Placebo groups. Then, metabolic markers, bone formation and resorption markers in serum and protein expressions of osteoclastogenesis regulators in tibias were detected. Meanwhile, microstructures, nanostructures, macro-mechanical properties, nano-mechanical properties, and mineral compositions in femurs were evaluated. 4-week later, CSII treatment restored circulatory metabolites, bone formation and resorption markers, and osteoclastogenesis regulators, improved certain bone microstructures, decreased matrix mineralization, and increased fracture toughness in T2DM rats. For 8-week group, CSII treatment restored bone formation and resorption markers, osteoclastogenesis regulators, and bone microstructures, besides improved bone mineral compositions and nanostructures, enhanced bone mechanical properties such as fracture toughness, maximum load, elastic modulus, indentation modulus and hardness. Collectively, 8-week CSII treatment is more conducive to ameliorating bone structures and mechanical properties in T2DM rats by regulating bone remodeling compared with 4-week CSII treatment, thus improving whole bone quality and providing valuable information for clinical prevention and treatment of T2DM-related bone disorders.

Influence of non-enzymatic glycation on the mechanical properties of cortical bone.

Poor bone quality induced by non-enzymatic glycation (NEG) of bone tissue in patients with type 2 diabetes mellitus (T2DM) is regarded as the major factor of bone fragility and affecting bone mechanical properties. A comprehensive and systemic mechanical investigation for evaluating the effect of NEG on bone was still lacking. In order to provide additional information for the bone quality of T2DM, the effects of NEG on mechanical properties of cortical bone were investigated in terms of elastoplasticity, fracture toughness and viscoelasticity. All samples of cortical bone, including the samples of strength test (n = 20), fracture toughness test (n = 40, quasi-static and fall-like conditions with displacement rates of 10-3 mm/s and 10 mm/s, respectively) and stress relaxation test (n = 20), were harvested from bovine tibiae. The samples of each test were equally divided into incubated-control group and ribose-incubated group. All mechanical tests were performed after incubating all samples for 15 days. Post-yield strain (p = 0.014), post-yield energy (p < 0.0001) and damage fraction (p = 0.040) of ribose-incubated group were significantly lower than those of incubated-control group, but secant modulus (p = 0.029) of ribose-incubated group was significantly higher than that of incubated-control group. In quasi-static condition, the plastic contribution Jpl of fracture toughness (p = 0.043) of ribose-incubated group was significantly lower than that of incubated-control group. In fall-like condition, there were no differences in Jpl, elastic contribution Jel and J-integral in both two groups. The quasi-static Jel (p < 0.0001, p < 0.0001) of incubated-control and ribose-incubated groups and J-integral (p = 0.007) of incubated-control group were all significantly higher than those of fall-like condition. In stress relaxation test, initial modulus E0 (p = 0.040) and equilibrium modulus (p = 0.029) of ribose-incubated group were significantly higher than those of incubated-control group. Reductions of relaxation modulus, which were the differences between two adjacent time points within 700 s-3000 s for ribose-incubated group, were significantly lower than those of incubated-control group. NEG could decrease the post-yield properties and quasi-static facture toughness of cortical bone, especially the plastic contribution of quasi-static fracture toughness. It could also decrease the viscoelasticity of cortical bone. The present study confirmed the negative effects of NEG on the mechanical properties of cortical bone in terms of elastoplasticity, fracture toughness and viscoelasticity, but NEG had no significant effect on the fracture toughness of cortical bone at fall-like loading. These results provided more evidence for increased fragility of cortical bone in patients with T2DM.