IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1via the TLR4 signaling pathway.

BACKGROUND: IgA nephropathy (IgAN) is a major cause of primary glomerulonephritis characterized by mesangial deposits of galactose-deficient IgA1 (Gd-IgA1). Toll-like receptors (TLRs), particularly TLR4 are involved in the pathogenesis of IgAN. The role of gut microbiota on IgAN patients was recently investigated. However, whether gut microbial modifications of Gd-IgA1 through TLR4 play a role in IgAN remains unclear. METHODS: We recruited subjects into four groups, including 48 patients with untreated IgAN, 22 treated IgAN patients (IgANIT), 22 primary membranous nephropathy (MN), and 31 healthy controls (HCs). Fecal samples were collected to analyze changes in gut microbiome. Gd-IgA1 levels, expression of TLR4, B-cell stimulators, and intestinal barrier function were evaluated in all subjects. C57BL/6 mice were treated with a broad-spectrum antibiotic cocktail to deplete the gut microbiota and then gavaged with fecal microbiota transplanted fromclinical subjects of every group. Gd-IgA1 and TLR4 pathway were detected in peripheral blood mononuclear cells (PBMCs) from IgAN and HCs co-incubated with Lipopolysaccharide (LPS) and TLR4 inhibitor. RESULTS: Compared with other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in un-treated IgAN, especially the enrichment of Escherichia -Shigella. Elevated Gd-IgA1 levels were found in un-treated IgAN patients and correlated with gut dysbiosis, TLR4, B-cell stimulators, indexes of intestinal barrier damage, and proinflammatory cytokines. In vivo, mice colonized with gut microbiota from IgAN and IgANIT patients, copied the IgAN phenotype with the activation of TLR4/MyD88/NF-κB pathway, B-cell stimulators in the intestine, and complied with enhanced proinflammatory cytokines. In vitro, LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in the PBMCs from IgAN patients, which resulted in overproduction of Gd-IgA1 and inhibited by TLR4 inhibitor. CONCLUSIONS: Our results illustrated that gut-kidney axis was involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 by TLR4 signaling pathway production and B-cell stimulators.

LPS/TLR4 Pathway Regulates IgA1 Secretion to Induce IgA Nephropathy.

Context: Studies have reported that the incidence and severity of IgA nephropathy (IgAN) are closely related to the imbalance of the intestinal flora. Imbalance of the intestinal flora may cause abnormalities, such as intestinal mucosal immunity or mesenteric B1 lymphocyte subsets. These can lead to an increase in immunoglobulin A (IgA) production and IgA structural changing, which can eventually cause IgA1 deposition in the glomerular mesangial area and nephritis. Objective: The study intended to explore whether the LPS/TLR4 pathway regulates mesenteric B cells, secreting Gd-IgA1 to induce IgA nephropathy. Design: The research team designed an animal study. Setting: The study took place at Department of Nephrology, Minhang Hospital, Fudan University. Animals: The animals were 60 specific pathogen free (SPF) C57BL/6 (B6, H-2b) male mice from that were 6-8 weeks old and weighed 20-25 grams. Intervention: The research team established a mouse model of IgA nephropathy. The team created five groups of mice: (1) the NC group, a normal negative control group without induced nephropathy and with no treatments; (2) the IgA nephropathy (IgAN) group, a positive control group with induced nephropathy and with no treatments; (3) the IgAN+anti-TLR4 group, an intervention group, with induced nephropathy and with a TLR4-antibody (anti-TLR4) treatment; (4) the IgAN+GEC group, an intervention group, with induced nephropathy and with treatment with glutamine enteric-coated capsules (GEC); and (5) the IgAN+anti-TLR4+GEC group, an intervention group, with induced nephropathy and with treatment with anti-TLR4 and GEC. Outcome Measures: The research team collected the blood and urine of all the mice and used an enzyme-linked immunoassay (ELISA) to analyze the levels of blood creatinine, urine protein, and urea nitrogen (BUN). The team also used the ELISA to analyze signal molecules for serum inflammation: interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), cyclooxygenase-2 (COX2), and galactose-deficient IgA1(Gd-IgA1). The team analyzed the distribution and content of IgA+B220+B lymphocytes in the intestinal tissues of all the mice, using tissue immunofluorescence tracking technology, and used hematoxylin-eosin (HE) staining to analyze the pathological damage in the kidney tissue. For analysis of glomerular IgA deposition, the team used a tissue immunofluorescence technique, and for detection of protein expression-toll-like receptor 4 (TLR4), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL)-in mesenteric lymphoid tissues, the team used western blot analysis. Results: For the five groups of mice, the amount or degree of the physiological indicators and inflammatory factors that ELISA detected, the B lymphocytes and IgA sedimentation that immunofluorescence tracing measured, the kidney pathological that HE staining detected, and the expression of immune-related proteins that western blotting measured, all showed a common trend: IgAN group> IgAN+ glomerular endothelial cells (GEC) group> IgAN+anti-TLR4 group> IgAN+anti-TLR4+GEC group> NC group. Conclusions: The TLR4 antibody and GEC for the treatment of the intestinal tract can regulate and repair intestinal function, so that IgAN can also be relieved at the same time. The results supported the hypothesis that a relationship exists between IgAN and the LPS/TLR4 pathway that regulates mesenteric B cells to secrete low-glycosylated poly-IgA1, which provides a new potential therapeutic plan for IgA nephritis.

Aberrant Gut Microbiome Contributes to Barrier Dysfunction, Inflammation, and Local Immune Responses in IgA Nephropathy.

INTRODUCTION: Numerous research works have shown that serum Gal-deficient (Gd) IgA1 levels are increased in IgA nephropathy (IgAN) patients and these levels are a dangerous risk factor for IgAN. A relationship between the gut microbiota and IgAN has been reported. Whether the gut microbiota participates in the pathogenesis of IgAN was still controversial. METHODS: We evaluated changes in the gut flora and the levels of Gd-IgA1 in IgAN patients and healthy controls (HCs). We investigated the Gd-IgA1 levels in both blood and urine specimens. C57BL/6 mice were given a broad-spectrum antibiotic cocktail to deplete the endogenous gut flora. We established a model of IgAN in pseudosterile mice and investigated the expression of the markers of intestinal permeability, inflammation, and local immune responses. RESULTS: Studies have shown that the levels of certain gut flora differ between IgAN patients and HCs. Moreover, elevated Gd-IgA1 levels were found in both the serum and urine. Interestingly, Coprococcus, Dorea, Bifidobacterium, Blautia, and Lactococcus, selected from 10 candidate biomarkers to predict risk in IgAN patients according to random forest analysis, were inversely associated with urinary Gd-IgA1 levels. Notably, the urine level of Gd-IgA1 could best distinguish IgAN patients from HCs. Additionally, the degree of kidney damage in pseudosterile mice with IgAN was more severe than that in mice with IgAN. Furthermore, the markers of intestinal permeability were significantly elevated in pseudosterile IgAN mice. Moreover, the inflammation responses (TLR4, MyD88, and NF-κB in intestinal and renal tissues; TNF-α and IL-6 in serum) and local immune responses (BAFF and APRIL in intestinal tissue) were upregulated in pseudosterile IgAN mice. CONCLUSIONS: The urine Gd-IgA1 level may be as a biomarker for the early screening of potential IgAN, and gut microbiota dysbiosis was demonstrated in IgAN, which might involve the dysfunction of the mucosal barrier, inflammation, and local immune responses.

Evaluating AI rib fracture detections using follow-up CT scans.

PURPOSE: This study compares the results of Artificial Intelligence (AI) diagnosis of rib fractures using initial CT and follow-up CT as the final diagnostic criteria, and studies AI-assisted diagnosis in improving the detection rate of rib fractures. METHODS: A retrospective study was conducted on 113 patients who underwent initial and follow-up CT scans due to trauma. The initial and follow-up CT were used as diagnostic criteria, respectively. All images were transmitted to the AI software (V2.1.0, Huiying Medical Technology Co., Beijing, China) for rib fracture detection. The radiologist group (Group 1), AI group (Group 2), and Radiologist with AI group (Group 3) reviewed CT images at an interval of one month, recorded and compared the differences in the sensitivity and specificity for diagnosing rib fractures. RESULTS: 589 and 712 rib fractures were diagnosed by the initial and follow-up CT, respectively. The initial CT diagnosis failed to detect 127 rib fractures, resulting in a missed rate of 17.84%. In addition, four normal ribs were mistakenly identified as being fractured. The follow-up CT was regarded as the diagnostic standard for rib fractures. The sensitivity and specificity were 82.16% and 99.80% for Group 1, 79.35% and 84.90% for Group 2, and 91.57% and 99.70% for Group 3. The sensitivity of Group 3 was higher than that of Group 1 and Group 2 (p < 0.05). The specificity was lower for Group 2 compared with Group 1 and Group 3 (p < 0.05). CONCLUSION: AI-assisted diagnosis improved the detection rate of rib fractures, the follow-up CT should be used for the diagnosis standard of rib fractures, and AI misdiagnoses can be greatly reduced when a radiologist reviews the diagnosis.

Identification of Hub Gene and Transcription Factor Related to Chronic Allograft Nephropathy Based on WGCNA Analysis.

INTRODUCTION: Kidney transplantation (KT) has surpassed dialysis as the optimal therapy for end-stage kidney disease. Yet, most patients could suffer from a slow but continuous deterioration of kidney function leading to graft loss mostly due to chronic allograft nephropathy (CAN) after KT. The dysregulated gene expression for CAN is still poorly understood. METHODS: To explore the pathogenesis of genomics in CAN, we analyzed the differentially expressed genes (DEGs) of kidney transcriptome between CAN and nonrejecting patients by downloading gene expression microarrays from the Gene Expression Omnibus database. Then, we used weighted gene coexpression network analysis (WGCNA) to analyze the coexpression of DEGs to explore key modules, hub genes, and transcription factors in CAN. Functional enrichment analysis of key modules was performed to explore pathogenesis. ROC curve analysis was used to validate hub genes. RESULTS: As a result, 3 key modules and 15 hub genes were identified by WGCNA analysis. Three key modules had 21 mutual Gene Ontology term enrichment functions. Extracellular structure organization, extracellular matrix organization, and extracellular region were identified as significant functions in CAN. Furthermore, transcription factor 12 was identified as the key transcription factor regulating key modules. All 15 hub genes, Yip1 interacting factor homolog B, membrane trafficking protein, toll like receptor 8, neutrophil cytosolic factor 4, glutathione peroxidase 8, mesenteric estrogen dependent adipogenesis, decorin, serpin family F member 1, integrin subunit beta like 1, SRY-box transcription factor 15, trophinin associated protein, SRY-box transcription factor 1, metallothionein 3, lysosomal protein transmembrane, FERM domain containing kindlin 3, and cathepsin S, had a great diagnostic performance (AUC > 0.7). CONCLUSION: This study updates information and provides a new perspective for understanding the pathogenesis of CAN by bioinformatics means. More research is needed to validate and explore the results we have found to reveal the mechanisms underlying CAN.

Influence of layered skull modeling on the frequency sensitivity and target accuracy in simulations of transcranial current stimulation.

With the development of electrical stimulation technology, especially the emergence of temporally interfering (TI) stimulation, it is necessary to discuss the influence of current frequency on stimulation intensity. Accurate skull modeling is important for transcranial current stimulation (tCS) simulation prediction because of its large role in dispersing current. In this study, we simulated different frequencies of transcranial alternating current stimulation (tACS) and TI stimulation in single-layer and layered skull model, compared the electric field via error parameters such as the relative difference measure and relative magnification factor. Pearson correlation analysis and t-test were used to measure the differences in envelope amplitude. The results showed that the intensity of electric field in the brain generated by per unit of stimulation current will increase with current frequency, and the layered skull model had a better response to frequency. An obvious pattern difference was found between the electric fields of the layered and single-layer skull individualized models. For TI stimulation, the Pearson correlation coefficient between the envelope distribution of the layered skull model and the single-layer skull was only 0.746 in the individualized model, which is clearly lower than the correlation coefficient of 0.999 determined from the spherical model. Higher carrier frequencies seemed to be easier to generate a large enough brain electric field envelope in TI stimulation. In conclusion, we recommend using layered skull models instead of single-layer skull models in tCS (particularly TI stimulation) simulation studies in order to improve the accuracy of the prediction of stimulus intensity and stimulus target.

Effect of Selective Thrombus Aspiration on Serum Lipoprotein-Associated Phospholipase A2 in Patients with ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention with High Thrombus Burden.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a potential therapeutic target in acute coronary syndromes. Although recent evidence does not support the routine use of manual thrombus aspiration (TA) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), the use of TA is associated with a significant improvement in myocardial reperfusion, especially in patients with high thrombus burden (HTB). We hypothesized that TA would reduce the serum Lp-PLA2 levels in STEMI patients undergoing PPCI with HTB. METHODS AND RESULTS: Our study cohort included 320 consecutive STEMI patients undergoing PPCI with HTB who were randomly assigned to receive either TA before PPCI (TA group, n = 160) or PPCI alone (standard PPCI group, n = 160). The baseline characteristics of study participants were well-matched. After 30 ± 2 days, serum Lp-PLA2 levels decreased by 53.9% in the TA group (152.9 ± 58.1 ng/mL) and decreased by 31.2% in the standard PPCI group (84.2 ± 86.6 ng/mL, p < 0.001). The TA group had a significantly lower prevalence of balloon predilatation, number of stents used, total stent length and corrected thrombolysis in myocardial infarction frame count, and a higher percentage of myocardial blush grade ≥ 2 compared with the standard PPCI group (all p < 0.001). No significant difference between the groups was observed in 30 ± 2 days for major adverse cardiovascular and cerebrovascular events (p = 0.702). CONCLUSIONS: After 30 ± 2 days of treatment, TA may significantly reduce serum levels of Lp-PLA2 in STEMI patients undergoing PPCI with HTB.

[Activation of intestinal mucosal TLR4/NF-κB pathway is associated with renal damage in mice with pseudo-sterile IgA nephropathy].

Objective To investigate the effect of intestinal mucosal Toll-like receptor 4/nuclear factor κB (TLR4/NF-κB) signaling pathway on renal damage in pseudo-sterile IgA nephropathy (IgAN) mice. Methods C57BL/6 mice were randomly divided into experimental group (pseudosterile mouse model group), control group (IgAN mouse model group), pseudosterile mouse blank group, and normal mouse blank group. Pseudosterile mice were established by intragastric administration of quadruple antibiotics once a day for 14 days. The pseudosterile IgAN mouse model was set up by combination of oral bovine serum albumin (BSA) administration and staphylococcal enterotoxin B (SEB) injection. The pathological changes of renal tissue were observed by immunofluorescence staining and PAS staining, and the intestinal mucosa barrier damage indicators lipopolysaccharide(LPS), soluble intercellular adhesion molecule 1(sICAM-1) and D-lactate(D-LAC) were analyzed by ELISA. Biochemical analysis was used to test 24 hour urine protein, serum creatinine and blood urea nitrogen. The mRNA and protein levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor κB (NF-κB) were detected by reverse transcription PCR and Western blot analysis. Results The kidney damage of pseudosterile IgAN mice was more severe than that of IgAN mice, and the expressions of intestinal mucosal barrier damage markers (LPS, sICAM-1 and D-LAC) were significantly increased in pseudosterile IgAN mice. In addition, the expressions of TLR4, MyD88, and NF-κB level were all up-regulated in the intestinal tissues of IgAN pseudosterile mice. Conclusion Intestinal flora disturbance leads to intestinal mucosal barrier damage and induces activation of TLR4 signaling pathway to mediate renal injury in IgAN.

CT-based radiomics signature for differentiating pyelocaliceal upper urinary tract urothelial carcinoma from infiltrative renal cell carcinoma.

Objectives: To develop a CT-based radiomics model and a combined model for preoperatively discriminating infiltrative renal cell carcinoma (RCC) and pyelocaliceal upper urinary tract urothelial carcinoma (UTUC), which invades the renal parenchyma. Materials and methods: Eighty patients (37 pathologically proven infiltrative RCCs and 43 pathologically proven pyelocaliceal UTUCs) were retrospectively enrolled and randomly divided into a training set (n = 56) and a testing set (n = 24) at a ratio of 7:3. Traditional CT imaging characteristics in the portal venous phase were collected by two radiologists (SPH and ZXL, who have 4 and 30 years of experience in abdominal radiology, respectively). Patient demographics and traditional CT imaging characteristics were used to construct the clinical model. The radiomics score was calculated based on the radiomics features extracted from the portal venous CT images and the random forest (RF) algorithm to construct the radiomics model. The combined model was constructed using the radiomics score and significant clinical factors according to the multivariate logistic regression. The diagnostic efficacy of the models was evaluated using receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC). Results: The RF score based on the eight validated features extracted from the portal venous CT images was used to build the radiomics model. Painless hematuria as an independent risk factor was used to build the clinical model. The combined model was constructed using the RF score and the selected clinical factor. Both the radiomics model and combined model showed higher efficacy in differentiating infiltrative RCC and pyelocaliceal UTUC in the training and testing cohorts with AUC values of 0.95 and 0.90, respectively, for the radiomics model and 0.99 and 0.90, respectively, for the combined model. The decision curves of the combined model as well as the radiomics model indicated an overall net benefit over the clinical model. Both the radiomics model and the combined model achieved a notable reduction in false-positive and false-negativerates, resulting in significantly higher accuracy compared to the visual assessments in both the training and testing cohorts. Conclusion: The radiomics model and combined model had the potential to accurately differentiate infiltrative RCC and pyelocaliceal UTUC, which invades the renal parenchyma, and provide a new potentially non-invasive method to guide surgery strategies.

Gut Microbiota Correlates With Clinical Responsiveness to Erythropoietin in Hemodialysis Patients With Anemia.

The main treatment for renal anemia in end-stage renal disease (ESRD) patients on hemodialysis is erythropoiesis (EPO). EPO hyporesponsiveness (EH) in dialysis patients is a common clinical problem, which is poorly understood. Recent searches reported that gut microbiota was closely related to the occurrence and development of ESRD. This study aims to explore the changes in gut microbiota between ESRD patients with different responsiveness to EPO treatment. We compared the gut microbiota from 44 poor-response (PR) and 48 good-response (GR) hemodialysis patients treated with EPO using 16S rDNA sequencing analysis. The results showed that PR patients displayed a characteristic composition of the gut microbiome that clearly differed from that of GR patients. Nine genera (Neisseria, Streptococcus, Porphyromonas, Fusobacterium, Prevotella_7, Rothia, Leptotrichia, Prevotella, Actinomyces) we identified by Lasso regression and ROC curves could excellently predict EH. In contrast, five genera (Faecalibacterium, Citrobacter, Bifidobacterium, Escherichia-Shigella, Bacteroides) identified by the same means presented a protective effect against EH. Analyzing the correlation between these biomarkers and clinical indicators, we found that gut microbiota may affect response to EPO through nutritional status and parathyroid function. These findings suggest that gut microbiota is altered in hemodialysis patients with EH, giving new clues to the pathogenesis of renal anemia.

Gut Dysbiosis and Intestinal Barrier Dysfunction Promotes IgA Nephropathy by Increasing the Production of Gd-IgA1.

Background: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerular disease in adults worldwide. Several studies have reported that galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgAN. Methods: Thirty-five patients with IgAN diagnosed with renal biopsy for the first time served as the experimental group, who were hospitalized in our department. Twenty normal healthy cases in the physical examination center of our hospital served as the control group. Then the levels of Gd-IgA1 in serum and urine, and intestinal mucosal barrier injury indexes [diamine oxidase (DAO), serum soluble intercellular adhesion molecule-1 (sICAM-1), D-lactate (D-LAC), and lipopolysaccharide (LPS)] and inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] in the serum samples were detected. Fecal samples were collected to detect intestinal microbiota using 16 s rDNA sequencing. Then, we assessed possible correlations among clinical and laboratory findings. Results: In patients with IgAN, the levels of Gd-IgA1 both in the serum and urine were higher than that of the healthy control. Furthermore, urine Gd-IgA1 level was positively correlated with the serum creatinine level, 24 h urine protein, and M, S, and T parameters in the Oxford classification. ROC curve analysis showed that urine Gd-IgA1 has a greater diagnostic value (AUC = 0.9714, 95% CI, 0.932-1; P < 0.0001) for IgAN. The best cutoff value for urine Gd-IgA1 was 0.745 ng·l/ml·µmol (sensitivity, 94%; specificity, 95%). The intestinal mucosal barrier damage indexes (DAO, sICAM-1, D-LAC, and LPS) were increased in the patients with IgAN, which were positively correlated with Gd-IgA1 levels (P < 0.05) both in serum and urine. The levels of inflammatory factors in the patients with IgAN were increased. 16 s rDNA analysis showed that the intestinal microbiota in these patients was disordered compared to that observed in the healthy subjects. Actinobacteria, Bifidobacterium, Blautia, Bifidobacteriaceae, and Bifidobacteriales were decreased and Shigella was increased in IgAN. The decreased populations of these flora were negatively and significantly correlated with urine Gd-IgA1 and the levels of DAO, sICAM-1, D-LAC, and LPS. Conclusion: The urine Gd-IgA1 levels may be a non-invasive biological marker for evaluating kidney injury in IgAN. Gut flora dysbiosis and intestinal barrier dysfunction may be involved in Gd-IgA1 expression.

Reno-Protective Effect of Low Protein Diet Supplemented With α-Ketoacid Through Gut Microbiota and Fecal Metabolism in 5/6 Nephrectomized Mice.

Background: Low protein supplemented with α-ketoacid diet (LKD) was recommended to be an essential intervention to delay the progression of chronic kidney disease (CKD) in patients who were not yet on dialysis. Aberrant gut microbiota and metabolism have been reported to be highly associated with CKD. However, the effect of LKD on gut microbiota and related fecal metabolism in CKD remains unclear. Methods: Mice were fed with normal protein diet (NPD group), low protein diet (LPD group), and low protein diet supplemented with α-ketoacid (LKD group) after 5/6 nephrectomy. At the end of the study, blood, kidney tissues, and feces were collected for biochemical analyses, histological, 16S rRNA sequence of gut microbiome, and untargeted fecal metabolomic analyses. Results: Both LKD and LPD alleviate renal failure and fibrosis, and inflammatory statement in 5/6 nephrectomized mice, especially the LKD. In terms of gut microbiome, LKD significantly improved the dysbiosis induced by 5/6Nx, representing increased α-diversity and decreased F/B ratio. Compared with NPD, LKD significantly increased the abundance of g_Parasutterella, s_Parabacteroides_sp_CT06, f_Erysipelotrichaceae, g_Akkermansia, g_Gordonibacter, g_Faecalitalea, and s_Mucispirillum_sp_69, and decreased s_Lachnospiraceae_bacterium_28-4 and g_Lachnoclostridium. Moreover, 5/6Nx and LKD significantly altered fecal metabolome. Then, multi-omics analysis revealed that specific metabolites involved in glycerophospholipid, purine, vitamin B6, sphingolipid, phenylalanine, tyrosine and tryptophan biosynthesis, and microbes associated with LKD were correlated with the amelioration of CKD. Conclusion: LKD had a better effect than LPD on delaying renal failure in 5/6 nephrectomy-induced CKD, which may be due to the regulation of affecting the gut microbiome and fecal metabolic profiles.

Erratum: Influence of colonic dialysis using Chinese medicine on creatinine decomposition by intestinal bacteria in uremia rats.

[This corrects the article on p. 6577 in vol. 11, PMID: 31737209.].

Development of a Non-invasive Deep Brain Stimulator With Precise Positioning and Real-Time Monitoring of Bioimpedance.

Methods by which to achieve non-invasive deep brain stimulation via temporally interfering with electric fields have been proposed, but the precision of the positioning of the stimulation and the reliability and stability of the outputs require improvement. In this study, a temporally interfering electrical stimulator was developed based on a neuromodulation technique using the interference modulation waveform produced by several high-frequency electrical stimuli to treat neurodegenerative diseases. The device and auxiliary software constitute a non-invasive neuromodulation system. The technical problems related to the multichannel high-precision output of the device were solved by an analog phase accumulator and a special driving circuit to reduce crosstalk. The function of measuring bioimpedance in real time was integrated into the stimulator to improve effectiveness. Finite element simulation and phantom measurements were performed to find the functional relations among the target coordinates, current ratio, and electrode position in the simplified model. Then, an appropriate approach was proposed to find electrode configurations for desired target locations in a detailed and realistic mouse model. A mouse validation experiment was carried out under the guidance of a simulation, and the reliability and positioning accuracy of temporally interfering electric stimulators were verified. Stimulator improvement and precision positioning solutions promise opportunities for further studies of temporally interfering electrical stimulation.

Influence of colonic dialysis using Chinese medicine on creatinine decomposition by intestinal bacteria in uremia rats.

OBJECTIVES: This study aims to investigate influence of colonic dialysis using Chinese medicine on creatinine decomposition by intestinal bacteria in uremia rats. METHODS: Healthy male Sprague Dawley (SD) rats were randomly divided into three groups, including uremic group, sham group and Chinese medicinal group. Uremic model was established in uremic group and Chinese medicinal groupby 5/6 nephrectomy, while sham group did not undergo nephrectomy. All rats were sacrificed at the end of ten weeks. Serum creatinine was examined. Histopathological changes of rat kidney were observed by hematoxylin-eosin staining. The numbers of Bifidobacterium, Lactobacillus and E.coli in the intestinal tract were quantitatively determined by real-time fluorescent quantitative PCR with 16S RNA. RESULTS: Compared with sham group, the number of E.coli in the jejunum increased significantly, while that of Bifidobacterium and Lactobaeillus in the ileum decreased. The number of Bifidobacterium and Lactobaeillus was decreased in the colon whereas that of E.coli increased. CONCLUSION: Our findings revealed that Influence of colonic dialysis using Chinese medicine on creatinine decomposition by intestinal bacteria in uremia rats.

Corticosteroid therapy in IgA nephropathy with minimal proteinuria and high renal pathological score: A single­center cohort study.

Currently, there is no clear evidence that advocates the widespread use of corticosteroids for the treatment of immunoglobulin A nephropathy (IgAN) with minimal proteinuria (<1 g/day). The recent Kidney Disease: Improving Global Outcomes Clinical Practice Guideline recommends supportive corticosteroid treatment. In the present study, 45 IgAN patients with high renal pathological scores and minimal proteinuria were enrolled. The patients were randomly divided into two groups. The treatment group received methylprednisolone tablets in addition to angiotensin­converting­enzyme inhibitor (ACE­I) and/or angiotensin­receptor blocker (ARB) treatment. The control group only received ACE­I and/or ARB treatment. In the treatment group, a single dose of 1 mg/kg (maximum 60 mg/day) methylprednisolone tablets was given daily followed by gradually decreasing dosage. The follow­up time of the patients was 3 years. In addition, the underlying mechanisms were investigated. The results indicated that there was a significant reduction in the amount of urinary proteins in the treatment group compared with the control group. At the end of the follow­up, the endpoint event rate of moderate or severe proteinuria and decrease in estimated glomerular filtration rate (eGFR) in the treatment group was significantly lower than the control group. Furthermore, higher levels of serum cytokines, interleukin (IL)­4, IL­17, transforming growth factor­ß1 and IL­21, were detected in patients with IgAN compared with a group of healthy controls. There was no significant difference in IFN­Î³ expression between the IgAN and healthy control groups. Furthermore, the expression of Janus kinase (Jak)1, Jak3, signal transducer and activator of transcription (STAT)3 and STAT6 was significantly upregulated in patients with IgAN compared with healthy controls. However, the expression levels of STAT5 and chaperone protein, C1GALT1 specific chaperone 1, in IgAN patients were significantly reduced compared with healthy controls. In addition, there was no significant difference in the expression of Jak2, tyrosine kinase 2, STAT1 and STAT4 between the two groups. In conclusion, for IgAN patients with minimal proteinuria and high renal pathological score corticosteroid therapy is likely to be effective. The dysregulation of serum cytokine levels in these patients with IgAN may have a role in the pathogenesis and progression of disease, which is associated with the activation of the JAK/STAT signaling pathway.