N6-methyladenosine methylation regulator RBM15 promotes the progression of diabetic nephropathy by regulating cell proliferation, inflammation, oxidative stress, and pyroptosis through activating the AGE-RAGE pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world, and m6A modification plays a critical role in the progression of DN. We aimed to find m6A-related genes and their regulatory mechanisms in DN. METHODS: The expression levels of four important m6A-related genes (METTL16, RBM15, IGF2BP1, and ALKBH5) were detected by quantitative real-time PCR (RT-qPCR). RBM15 was chosen and its function was explored. The downstream pathway of RBM15 was screened by transcriptome sequencing. The levels of AGE, inflammation, and oxidative stress were determined with enzyme-linked immunosorbent assay, and the expression of AGE-RAGE pathway-related proteins were detected by Western blot (WB). Cell proliferation was assessed by Cell counting Kit-8 (CCK-8). The levels of pyroptosis-related proteins were evaluated by RT-qPCR or WB. RESULTS: METTL16 and RBM15 were up regulated in the mouse model of DN, in which RBM15 was more significant. Silencing RBM15 recovered cell proliferation, reduced the levels of inflammation factors, and inhibited cell pyroptosis in high glucose-induced HK-2 cells. Transcriptome sequencing suggested that the AGE-RAGE pathway might be downstream of RBM15. RBM15 knockdown reduced AGE level and the expression of AGE-RAGE pathway-related proteins. After silencing RBM15, we found that activating the AGE-RAGE pathway inhibited cell proliferation, increased the levels of inflammation factors, promoted oxidative stress, and induced cell pyroptosis in HK-2 cell model of DN. CONCLUSION: The m6A-related gene RBM15 inhibited cell proliferation, promoted inflammation, oxidative stress, and cell pyroptosis, thereby facilitating the progression of DN through the activation of the AGE-RAGE pathway.

Solitary Interdigital Condyloma Latum in a Female Adolescent: A Case Report of an Unusual Form of Secondary Syphilis.

Condylomata lata are flat-topped, moist papules or plaques usually found in the anogenital area as cutaneous manifestations of secondary syphilis. Here, we present a unique case of a solitary interdigital condyloma latum of secondary syphilis in a 16-year-old female sex worker without other cutaneous findings. Sexual contact history, histopathology, including direct detection of Treponema pallidum, and serological tests were essential for the diagnosis of this case. The patient reached serological cure with two doses of intramuscularly delivered penicillin G benzathine. Owing to the dramatic rise in the incidence of primary and secondary syphilis, medical workers should be aware of the atypical skin manifestations of secondary syphilis in adolescents who are at risk of acquiring sexually transmitted diseases to avoid the progression to late syphilis and further transmission to sexual partners.

Urine Immunoglobin G Greater Than 2.45 mg/L Has a Correlation with the Onset and Progression of Diabetic Kidney Disease: A Retrospective Cohort Study.

AIM: To further assess the correlation between urine immunoglobin G (IgG) greater than 2.45 mg/L and the onset and progression of diabetic kidney disease (DKD). METHODS: One thousand and thirty-five patients with type 2 diabetes mellitus (T2DM) were divided into two groups based on the baseline levels of 24 h urinary albumin excretion (24 h UAE): one group with 24 h UAE < 30 mg/24 h and one with 24 h UAE ≥ 30 mg/24 h. The groups were subdivided using baseline levels of urine IgG (≤2.45 mg/L and >2.45 mg/L; hereafter, the Low and High groups, respectively). We used logistic regression to assess the risk of urine IgG and it exceeding 2.45 mg/L. Kaplan-Meier curves were used to compare the onset and progression time of DKD. The receiver operating characteristic curve was used to test the predictive value of urine IgG exceeding 2.45 mg/L. RESULTS: Urine IgG was an independent risk factor for the onset and progression of DKD. The rate and risk of DKD onset and progression at the end of follow-up increased significantly in the High group. The onset and progression time of DKD was earlier in the High group. Urine IgG exceeding 2.45 mg/L has a certain predictive value for DKD onset. CONCLUSIONS: Urine IgG exceeding 2.45 mg/L has a correlation with the onset and progression of DKD, and it also has a certain predictive value for DKD onset.

Changes of Gut Microbiome in Adolescent Patients with Chronic Spontaneous Urticaria After Omalizumab Treatment.

Purpose: Omalizumab is a humanized anti-immunoglobulin (Ig) E monoclonal antibody that is effective in treating some patients with chronic spontaneous urticaria (CSU) who do not respond to antihistamines. Gut microbiome plays a role in the pathogenesis of allergies and autoimmune diseases. Here, we investigated differences in the gut microbiome of adolescent CSU patients before and after omalizumab treatment, which has not been previously reported. Patients and Methods: Ten adolescent CSU patients were given 300 mg omalizumab subcutaneously in three treatments at 4-week intervals. Urticaria Activity Score (UAS7) was applied to evaluate the efficacy of each omalizumab treatment during follow-up. Fecal samples were collected before and 12 weeks after the first treatment. Total DNA of the gut microbiota in all fecal samples were extracted. The 16S rRNA gene-targeted sequencing technology was used for the analysis of the diversity and distribution of gut microbiome, followed by bioinformatics analysis. Results: UAS7 scores decreased significantly after each treatment compared with the baseline (all P < 0.0001). There were five well-controlled responders and five non-responders after three treatment sessions of omalizumab. The dominant bacteria phyla in all fecal samples were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Alpha diversity analysis showed no significant difference before and after treatment (P > 0.05), whereas beta diversity analysis revealed a significant difference in the bacterial abundance before and after treatment (P < 0.01). The relative abundance of Alphaproteobacteria and Betaproteobacteria at the class level and Burkholderia, Rhodococcus, and Sphingomonas at the genus level decreased significantly after treatment (linear discriminant analysis > 4, P < 0.05). The functional prediction results showed that the dioxin and xylene degradation pathways were more abundant before treatment. Conclusion: Omalizumab is effective in treating CSU and the abundance of Alphaproteobacteria and Betaproteobacteria was reduced after treatment, which may help improve the treatment outcomes in adolescent CSU patients.

Establishment and validation of the cut-off values of estimated glomerular filtration rate and urinary albumin-to-creatinine ratio for diabetic kidney disease: A multi-center, prospective cohort study.

Objective: We aimed to study the cut-off values of estimated glomerular filtration rate (eGFR) and the urinary albumin creatinine ratio (UACR) in the normal range for diabetic kidney disease (DKD). Methods: In this study, we conducted a retrospective, observational cohort study included 374 type 2 diabetic patients who had baseline eGFR ≥60 mL/min/1.73 m2 and UACR <30 mg/g with up to 6 years of follow-up. The results were further validated in a multi-center, prospective cohort study. Results: In the development cohort, baseline eGFR (AUC: 0.90, cut-off value: 84.8 mL/min/1.73 m2, sensitivity: 0.80, specificity: 0.85) or UACR (AUC: 0.74, cut-off value: 15.5mg/g, sensitivity: 0.69, specificity: 0.63) was the most effective single predictor for DKD. Moreover, compared with eGFR or UACR alone, the prediction model consisted of all of the independent risk factors did not improve the predictive performance (P >0.05). The discrimination of eGFR at the cut-off value of 84.80 mL/min/1.73 m2 or UACR at 15.5mg/g with the largest Youden's index was further confirmed in the validation cohort. The decrease rate of eGFR was faster in patients with UACR ≥15.5mg/g (P <0.05). Furthermore, the decrease rate of eGFR or increase rate of UACR and the incidence and severity of cardiovascular disease (CVD) were higher in patients with eGFR ≤84.8 mL/min/1.73 m2 or UACR ≥15.5mg/g (P <0.05). Conclusions: In conclusion, eGFR ≤84.8mL/min/1.73 m2 or UACR ≥15.5mg/g in the normal range may be an effective cut-off value for DKD and may increase the incidence and severity for CVD in type 2 diabetic patients.

Novel compound heterozygous mutation of SLC12A3 in Gitelman syndrome co-existent with hyperthyroidism: A case report and literature review.

BACKGROUND: Gitelman syndrome (GS) is a rare inherited autosomal recessive tubulopathy, characterized clinically by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis, and is caused by an inactivating mutation in SLC12A3. GS is prone to misdiagnosis when occurring simultaneously with hyperthyroidism. It is important to consider the possibility of other diseases when hyperthyroidism is combined with hypokalemia, which is difficult to correct. CASE SUMMARY: A female patient with hyperthyroidism complicated with limb weakness was diagnosed with thyrotoxic hypokalemic periodic paralysis for 4 mo. However, the patient's serum potassium level remained low despite sufficient potassium replacement and remission of hyperthyroidism. GS was confirmed by whole exome and Sanger sequencing. Gene sequencing revealed compound heterozygous mutations of c.488C>T (p.Thr163Met), c.2612G>A (p.Arg871His), and c.1171_1178dupGCCACCAT (p.Ile393fs) in SLC12A3. Protein molecular modeling was performed to predict the effects of the identified missense mutations. All three mutations cause changes in protein structure and may result in abnormal protein function. All previously reported cases of GS coexisting with autoimmune thyroid disease are reviewed. CONCLUSION: We have identified a novel compound heterozygous mutation in SLC12A3. The present study provides new genetic evidence for GS.

Decreased Connectivity in Precuneus of the Ventral Attentional Network in First-Episode, Treatment-Naïve Patients With Major Depressive Disorder: A Network Homogeneity and Independent Component Analysis.

Background and Objective: The ventral attentional network (VAN) can provide quantitative information on cognitive problems in patients with major depressive disorder (MDD). Nevertheless, little is known about network homogeneity (NH) changes in the VAN of these patients. The aim of this study was to examine the NH values in the VAN by independent component analysis (ICA) and compare the NH values between MDD patients and the normal controls (NCs). Methods: Attentional network test and resting-state functional magnetic resonance imaging (rs-fMRI) data were collected from 73 patients, and 70 NCs matched by gender, age, and education years. ICA and NH were employed to evaluate the data. Moreover, the NH values were compared, and Spearman's rank correlation analysis was used to assess the correlations with the executive control reaction time (ECRT). Results: Our results showed that the first-episode, treatment-naive MDD patients had decreased NH in the right precuneus (PCu) and abnormal ECRT compared with NCs. However, no significant correlation was found between the NH values and measured clinical variables. Conclusion: Our results highlight the potential importance of VAN in the pathophysiology of cognitive problems in MDD, thus offering new directions for future research on MDD.

Sex-specific mediating effect of gestational weight gain between pre-pregnancy body mass index and gestational diabetes mellitus.

BACKGROUND: Inappropriate weight gain may increase the risk of gestational diabetes mellitus (GDM). However, the relationship between pre-pregnancy body mass index (BMI), weight gain, and GDM has not been precisely quantified. This study aimed to explore whether gestational weight gain played a mediating role between pre-pregnancy BMI and GDM and whether the mediating effect was sex specific. METHODS: This study established a population-based observational cohort to assess weight gain in pregnant women. Mediation analyses were performed to quantify whether weight gain mediated the association between pre-pregnancy BMI and GDM. RESULTS: A total of 67,777 pregnant women were included in the final analysis, among whom 6751 (10.0%) were diagnosed with GDM. We verified that both pre-pregnancy BMI and weight gain were associated with GDM, and that BMI negatively contributed to weight gain. We also found that weight gain had a significant mediating effect on the relationship between pre-pregnancy BMI and GDM (Za × Zb confidence intervals [CIs] 0.00234-0.00618). Furthermore, the effect was sex-specific, in that it was only significant in overweight women carrying female fetuses (Za × Zb CIs 0.00422-0.01977), but not male fetuses (Za × Zb CIs -0.00085 to 0.01236). CONCLUSIONS: Weight gain during pregnancy had a fetal sex-specific mediating effect between pre-pregnancy BMI and GDM.

The Factors Influencing the Renal Glucose Threshold in Patients with Newly Diagnosed Type 2 Diabetes Mellitus.

OBJECTIVE: This study aims to explore the factors influencing the renal glucose threshold (RTG) in patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study was conducted on 1009 hospitalized patients with T2DM using stratified random sampling. Blood glucose was monitored using a dynamic blood glucose monitor to obtain the mean blood glucose (MBG), which is used to calculate the RTG. The factors influencing the RTG were then analyzed. RESULTS: The mean RTG in patients with newly diagnosed T2DM was 203.58 ± 55.22 mg/dl. The correlation between the RTG and the various variables was analyzed, and the results demonstrated that the RTG was correlated with the patient's age (r = -0.14539, P = 0.0001); MBG (r = -0.35009, P = 0.0001); renal long neck (r = 0.16762, P = 0.0001); homeostatic model assessment for insulin resistance (r = -0.38322, P = 0.0001); homeostatic model assessment for beta-cell function (r = -0.22770, P = 0.0001); and the levels of glycated hemoglobin (HbA1c; r = 0.98994, P = 0.0001), blood urea nitrogen (r = -0.11093, P = 0.0004), creatinine (r = -0.26414, P = 0.0001), uric acid (r = -0.20149, P = 0.0001), total cholesterol (r = 0.13192, P = 0.0001), low-density lipoprotein (r = 0.12466, P = 0.0001), thyroid-stimulating hormone (r = -0.06346, P = 0.0460), beta-2 microglobulin (r = -0.08884, P = 0.0056), and 24-hour urine glucose (r = 0.32115, P = 0.0001). Multiple linear stepwise regression analysis revealed that the HbA1c, 24-hour urine glucose, estimated glomerular filtration rate (eGFR), D-dimer, and body mass index (BMI) should be included in the final model, and HbA1c had the greatest impact on the RTG followed in descending order by the 24-hour urine glucose, eGFR, D-dimer, and BMI (P < 0.05). CONCLUSION: The RTG increases in most patients with newly diagnosed diabetes. The risk factors for the RTG are HbA1c, 24-hour urine glucose, eGFR, D-dimer, and BMI.

Hyperinsulinemia contributes to impaired-glucose-tolerance-induced renal injury via mir-7977/SIRT3 signaling.

BACKGROUND: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. METHODS: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. RESULTS: It was found that 12.1% of IGT patients had microalbuminuria, which we termed "IGT-RI." Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-ß-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3'-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. CONCLUSIONS: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.

Analysis of factors related to diabetic retinopathy in patients with newly diagnosed type 2 diabetes: a cross-sectional study.

AIM: To investigate the related factors of diabetic retinopathy (DR) and explore the correlation between smoking and DR in patients with newly diagnosed type 2 diabetes mellitus (T2DM). DESIGN: A single-centre cross-sectional study. SETTING: Tianjin 4th Central Hospital. PARTICIPANTS: Patients with newly diagnosed T2DM who visited the outpatient department of the hospital from December 2018 to April 2019. METHODS: A total of 947 patients were enrolled in the study. They were divided into two groups according to whether they were diagnosed with DR (diabetic retinopathy group, DR group; non-diabetic retinopathy group, NDR group). The smoking index (SI) was calculated to assess smoking status. Factors such as sex, age, hypertension, T2DM diagnosed age, family history of diabetes, drinking history, haemoglobin A1c (HbA1c), body mass index (BMI) and smoking status were compared between the two groups. Logistic regression was used to analyse the relationship between DR and the above factors. RESULTS: There was no statistically significant difference between the two groups in sex, age, hypertension, DM diagnosed age, family history of diabetes, drinking history and HbA1c. BMI was significantly higher in DR patients (27.7±4.2 vs 26.7±4.4, p=0.004). Smoking status was also different between the two groups (χ2=6.350, p=0.042). BMI was shown to be a related factor for DR in patients with newly diagnosed diabetes (OR=0.592, p=0.004). When BMI was ≥28 kg/m2, heavy smoking was significantly associated with DR (OR=2.219, p=0.049), and there was a negative correlation between DR and the age of diagnosis of diabetes ≥60 years (OR=0.289, p=0.009). CONCLUSIONS: Heavy smoking was an important related factor for DR in patients with newly diagnosed diabetes mellitus when BMI was ≥28 kg/m2. Delaying the age of diabetes might prevent the occurrence of DR. To elucidate the correlation, long-term cohort studies with large samples are needed.

Evaluation of urinary biomarkers for prediction of diabetic kidney disease: a propensity score matching analysis.

BACKGROUND: The aim of this study was to evaluate the diagnostic value of six urinary biomarkers for prediction of diabetic kidney disease (DKD). METHODS: The cross-sectional study recruited 1053 hospitalized patients with type 2 diabetes mellitus (T2DM), who were categorized into the diabetes mellitus (DM) with normoalbuminuria (NA) group (n = 753) and DKD group (n = 300) according to 24-h urinary albumin excretion rate (24-h UAE). Data on the levels of six studied urinary biomarkers [transferrin (TF), immunoglobulin G (IgG), retinol-binding protein (RBP), ß-galactosidase (GAL), N-acetyl-beta-glucosaminidase (NAG), and ß2-microglobulin (ß2MG)] were obtained. The propensity score matching (PSM) method was applied to eliminate the influences of confounding variables. RESULTS: Patients with DKD had higher levels of all six urinary biomarkers. All indicators demonstrated significantly increased risk of DKD, except for GAL and ß2MG. Single RBP yielded the greatest area under the curve (AUC) value of 0.920 compared with the other five markers, followed by TF (0.867) and IgG (0.867). However, GAL, NAG, and ß2MG were shown to have a weak prognostic ability. The diagnostic values of the different combinations were not superior to the single RBP. CONCLUSIONS: RBP, TF, and IgG could be used as reliable or good predictors of DKD. The combined use of these biomarkers did not improve DKD detection.