KLIF: An Optimized Spiking Neuron Unit for Tuning Surrogate Gradient Function.

Spiking neural networks (SNNs) have garnered significant attention owing to their adeptness in processing temporal information, low power consumption, and enhanced biological plausibility. Despite these advantages, the development of efficient and high-performing learning algorithms for SNNs remains a formidable challenge. Techniques such as artificial neural network (ANN)-to-SNN conversion can convert ANNs to SNNs with minimal performance loss, but they necessitate prolonged simulations to approximate rate coding accurately. Conversely, the direct training of SNNs using spike-based backpropagation (BP), such as surrogate gradient approximation, is more flexible and widely adopted. Nevertheless, our research revealed that the shape of the surrogate gradient function profoundly influences the training and inference accuracy of SNNs. Importantly, we identified that the shape of the surrogate gradient function significantly affects the final training accuracy. The shape of the surrogate gradient function is typically manually selected before training and remains static throughout the training process. In this article, we introduce a novel k-based leaky integrate-and-fire (KLIF) spiking neural model. KLIF, featuring a learnable parameter, enables the dynamic adjustment of the height and width of the effective surrogate gradient near threshold during training. Our proposed model undergoes evaluation on static CIFAR-10 and CIFAR-100 data sets, as well as neuromorphic CIFAR10-DVS and DVS128-Gesture data sets. Experimental results demonstrate that KLIF outperforms the leaky Integrate-and-Fire (LIF) model across multiple data sets and network architectures. The superior performance of KLIF positions it as a viable replacement for the essential role of LIF in SNNs across diverse tasks.

Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway.

BACKGROUND: Pyroptosis of the renal tubular epithelial cells (RTECs) and interstitial inflammation are central pathological characteristics of acute kidney injury (AKI). Pyroptosis acts as a pro-inflammatory form of programmed cell death and is mainly dependent on activation of the NLRP3 inflammasome. Previous studies revealed that acetyl-CoA synthetase 2 (ACSS2) promotes inflammation during metabolic stress suggesting that ACSS2 might regulate pyroptosis and inflammatory responses of RTECs in AKI. METHODS AND RESULTS: The expression of ACSS2 was found to be significantly increased in the renal epithelial cells of mice with lipopolysaccharide (LPS)-induced AKI. Pharmacological and genetic strategies demonstrated that ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the stimulation of the KLF5/NF-κB pathway in RTECs. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model, and ACSS2-deficient mice displayed impaired NLRP3 activation-mediated pyroptosis and decreased IL-1ß production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and pyroptosis through the downregulation of the KLF5/NF-κB pathway. The KLF5 inhibitor ML264 suppressed NF-κB activity and NLRP3-mediated caspase-1 activation, thus protecting HK-2 cells from LPS-induced pyroptosis. CONCLUSION: Our results suggested that ACSS2 regulates activation of the NLRP3 inflammasome and pyroptosis by inducing the KLF5/NF-κB pathway in RTECs. These results identified ACSS2 as a potential therapeutic target in AKI.

Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.

Effects of roxadustat on thyroid hormone levels and blood lipid metabolism in patients undergoing hemodialysis: a retrospective study.

Background: Roxadustat is commonly used to treat renal anemia. However, the potential effects of roxadustat on metabolism and organs other than the kidneys have recently attracted increased attention. Objective: This study aimed to examine the regulatory effects of roxadustat on thyroid hormones and blood lipid metabolism in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. Methods: Eighty ESKD patients on hemodialysis and taking roxadustat were enrolled. Hemoglobin, thyroid hormones (TSH, FT3, FT4), and blood lipid profiles (TC, LDL-C, TG, HDL-C) were assessed before and after treatment. Changes in these parameters were compared, and relevant causative factors were analyzed. Results: Roxadustat significantly increased Hb, lowered TSH, FT4, TC, and LDL-C levels (all P<0.001). Patients were categorized into three groups based on post-treatment TSH inhibition percentage: Q1(≥70%), Q2(30%-70%), Q3(≤30%). Pre-treatment TSH decreased with reduced TSH inhibition (P<0.05). Post-treatment, TC, LDL-C, TSH, FT3, and FT4 increased with reduced TSH inhibition (all P<0.05).TC and LDL-C significantly decreased post-treatment in Q1 and Q2 (P<0.05). Correlation analysis showed a positive correlation between ΔTSH and pre-treatment TSH levels (r=0.732, P<0.001). The proportion of patients with ≥70% TSH inhibition increased with higher pre-treatment TSH levels (P for trend <0.05). ΔLDL-C and ΔTSH were positively correlated (r=0.278, P<0.05), with ΔTSH identified as an influencing factor in multiple linear regression (ß=0.133, 95% CI [0.042, 0.223], P<0.05). Conclusion: Roxadustat effectively improves anemia in ESKD patients while inhibiting TSH and FT4 secretion and reducing TC and LDL-C levels. Decreases in TSH levels correlate with baseline TSH levels, and lowered blood lipid levels are associated with decreased TSH levels.

Early reduction in total cholesterol to high-density lipoprotein cholesterol ratio predicts hydroxychloroquine efficacy in treating IgA nephropathy.

BACKGROUND: Hydroxychloroquine (HCQ) effectively improves lipid levels in patients with autoimmune diseases. This study aimed to examine the effect of HCQ on lipid profiles in patients with immunoglobulin A (IgA) nephropathy (IgAN) and determine whether alterations in lipid profiles can predict the efficacy of HCQ. METHODS: This study retrospectively analyzed 77 patients, and the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) decline rate after 3 months of HCQ treatment was selected as a predictor based on receiver operating curve analysis. Patients were then divided into low and high TC/HDL-C decline rate groups based on the optimal cutoff value. The Cox proportional hazard model and Kaplan-Meier curve were used to evaluate the value of the TC/HDL-C decline rate in predicting the efficacy of HCQ in patients with IgAN. RESULTS: Patients in the high TC/HDL-C decline rate group with ≥50% decrease in proteinuria from baseline experienced a significant improvement during the follow-up. Kaplan-Meier analysis revealed that a high TC/HDL-C decline rate was strongly associated with a higher proteinuria reduction rate in patients with IgAN. Furthermore, multivariate Cox analysis indicated that a higher reduction in the TC/HDL-C ratio (hazard ratio: 2.314; 95% confidence interval: 1.234-4.340; p = 0.009) was an independent predictive indicator for achieving ≥50% reduction in proteinuria with HCQ therapy in IgAN. CONCLUSION: HCQ effectively improves lipid profiles in patients with IgAN, and an early decrease in the TC/HDL-C ratio serves as a predictor of better outcomes in patients treated with HCQ.

Comparison of the Watson formula and bioimpedance spectroscopy for measuring body volume and calculating kt/V in patients with peritoneal dialysis.

CONCLUSION: There were significant differences between Vwat and Vbis and between Kt/Vwat and Kt/Vbis. Kt/Vwat may underestimate small-solute dialysis adequacy in most cases. Kt/Vbis instead of Kt/Vwat could be accounted for in creating individualized dialysis prescriptions if the patient has no obvious clinical symptoms.

Knockdown of AK142426 suppresses M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun.

BACKGROUND: Peritoneal fibrosis is a common complication of peritoneal dialysis, which may lead to ultrafiltration failure and ultimately treatment discontinuation. LncRNAs participate in many biological processes during tumorigenesis. We investigated the role of AK142426 in peritoneal fibrosis. METHODS: The AK142426 level in peritoneal dialysis (PD) fluid was detected by quantitative real-time-PCR assay. The M2 macrophage distribution was determined by flow cytometry. The inflammatory cytokines of TNF-α and TGF-ß1 were measured by ELISA assay. The direct interaction between AK142426 and c-Jun was evaluated by RNA pull-down assay. In addition, the c-Jun and fibrosis related proteins were assessed by western blot analysis. RESULTS: The PD-induced peritoneal fibrosis mouse model was successfully established. More importantly, PD treatment induced M2 macrophage polarization and the inflammation in PD fluid, which might be associated with exosome transmission. Fortunately, AK142426 was observed to be upregulated in PD fluid. Mechanically, knockdown of AK142426 suppressed M2 macrophage polarization and inflammation. Furthermore, AK142426 could upregulate c-Jun through binding c-Jun protein. In rescue experiments, overexpression of c-Jun could partially abolish the inhibitory effect of sh-AK142426 on the activation of M2 macrophages and inflammation. Consistently, knockdown of AK142426 alleviated peritoneal fibrosis in vivo. CONCLUSIONS: This study demonstrated that knockdown of AK142426 suppressed M2 macrophage polarization and inflammation in peritoneal fibrosis via binding to c-Jun, suggesting that AK142426 might be a promising therapeutic target for patients of peritoneal fibrosis.

Gut microbiota involved in myocardial dysfunction induced by sepsis.

Myocardial dysfunction is an important complication of sepsis and an important cause of death in sepsis patients. Sepsis will significantly change the composition of gut microbiota, and the destruction of gut microbiota also creates conditions for the occurrence and progression of sepsis. Gut microbiota is an important player in myocardial injury in sepsis. This review elaborates on the possible mechanisms of gut microbiota affecting myocardial injury in sepsis, including short-chain fatty acids, trimethylamine and trimethylamine oxides, various cytokines, and mitochondrial dysfunction. A better understanding of the mechanism could help improve the treatment of sepsis and get a better prognosis for sepsis patients.

A Noise-Based Novel Strategy for Faster SNN Training.

Spiking neural networks (SNNs) are receiving increasing attention due to their low power consumption and strong bioplausibility. Optimization of SNNs is a challenging task. Two main methods, artificial neural network (ANN)-to-SNN conversion and spike-based backpropagation (BP), both have advantages and limitations. ANN-to-SNN conversion requires a long inference time to approximate the accuracy of ANN, thus diminishing the benefits of SNN. With spike-based BP, training high-precision SNNs typically consumes dozens of times more computational resources and time than their ANN counterparts. In this letter, we propose a novel SNN training approach that combines the benefits of the two methods. We first train a single-step SNN(T = 1) by approximating the neural potential distribution with random noise, then convert the single-step SNN(T = 1) to a multistep SNN(T = N) losslessly. The introduction of gaussian distributed noise leads to a significant gain in accuracy after conversion. The results show that our method considerably reduces the training and inference times of SNNs while maintaining their high accuracy. Compared to the previous two methods, ours can reduce training time by 65% to 75% and achieves more than 100 times faster inference speed. We also argue that the neuron model augmented with noise makes it more bioplausible.

The role of murine M1 macrophages from different sources in unilateral ureteral obstruction.

Introduction: The unilateral ureteral obstruction (UUO) model is the most extensively used model to investigate chronic renal fibrosis. Macrophages play a critical role in the UUO model. We aimed to analyze the phenotype of macrophages from different sources activated in vitro and explore the role of M1 macrophages from various sources in UUO. Material and methods: C57BL/6 mice were randomly allocated to five different groups (n = 5 per group): the sham-operated control group, PBS-treated (UUO + PBS) group, bone marrow-derived M1 macrophage-treated (UUO + BM1) group, peritoneal M1 macrophage-treated (UUO + PM1) group, and splenic M1 macrophage-treated (UUO + SPM1) group. After M1 macrophages were injected into the tail vein of UUO-treated mice, renal fibrosis indexes were determined using HE, Masson staining, and α-SMA. Results: Compared to those in the UUO + PBS group, the pathological changes were much more severe in the UUO + BM1, UUO + PM1, and UUO + SPM1 groups. Compared to that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1 group, the collagen area in the UUO + PM1 group was higher at post-UUO day 5 (p < 0.01). The expression of α-SMA in the UUO + PM1 group was higher than that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1group (p < 0.001). Conclusions: The M1 macrophages cultured in vitro were reinjected into mice and aggravated kidney injury and fibrosis. Compared with BM1 and SPM1, PM1 demonstrated a stronger effect on inducing renal injury and fibrosis.

Suppressing the polarization aberrations by combining reflection and refraction optical groups.

Polarization remote sensing technology expands the dimensions of the target and enriches its basic information over traditional remote sensing methods. During the imaging process, polarization imaging changes the polarization information of the target by the modulation of the optical system, affecting the detection accuracy. We term the modulation of the polarization state of light by an optical system as polarization aberration, and we found that a lens group combined with mirrors is beneficial in suppressing polarization aberrations. This study analyzed the principles of suppression and the polarization aberration of the optical system before and after suppression. Simulation results show that the diattenuation's average value is reduced by 51.1% and the retardance's average value is reduced by 26.3% after suppression. The corrected polarization cross-coupled energy is reduced by 73.18% in the central field of view and by 69.80% in the fringe field of view. Adding a lens group also effectively suppresses traditional aberrations and expands the field of view.

Toll-Like Receptor 4 Is an Early and Sensitive Biomarker to Detect Acute Kidney Injury after Surgery for Type A Aortic Dissection.

Background: Acute kidney injury (AKI) is a relatively common complication after surgery for type A acute aortic dissection (ATAAD) and is associated with a poor prognosis. Preclinical models suggest that toll-like receptor 4 (TLR4) may participate in the pathogenesis of AKI. However, the correlation of serum TLR4 and post-operative AKI has not been studied in ATAAD patients. This study aimed to explore the possibility of using serum TLR4 levels to predict AKI and 30-day mortality in patients undergoing ATAAD surgery. Methods: A prospective, single-center cohort study was conducted and enrolled a total of 64 patients undergoing ATAAD surgery. The level of serum TLR4 was measured and compared before and within 24 hours after the completion of surgery. Results: Thirty-five (54.7%) patients developed AKI, including 7 (10.9%) diagnosed with severe AKI (Kidney Disease Improving Global Outcomes (KDIGO) stage 3). TLR4 levels at 0-hour,1-hour, 3-hour, and 6-hour after intensive care unit (ICU) admission were significantly different between patients with or without AKI. Further analysis showed that the difference was most significant at 0-hour after ICU admission which corresponded to an area under the curve (AUC) of 0.886 (95% confidence interval (CI), 0.800 to 0.973). For severe AKI, the AUC of TLR4 was the highest with 0.923 (0.852 to 0.995) at 1-hour after ICU admission. TLR4 levels before surgery and at 0-hour, 1-hour, as well as 3-hour after ICU admission were significantly different between survivors and non-survivors. Furthermore, we found that the serum level of TLR4 upon ICU admission could be used to predict the 30-day mortality with AUC of 0.805 (0.648 to 0.962). Conclusions: Serum TLR4 levels can be used as a biomarker to predict the occurrence of AKI and 30-day mortality in patients undergoing ATAAD surgery. Clinical Trial Registration Number: ChiCTR2200057197.

Role of IGF-1R in epithelial-mesenchymal transdifferentiation of human peritoneal mesothelial cells.

BACKGROUND: Peritoneal fibrosis (PF) is caused by epithelial-mesenchymal transdifferentiation (EMT) in the peritoneum under high glucose (HG) conditions. The study aimed to explored the role of Insulin-like growth factor 1 receptor (IGF-1R) in the regulation of EMT in human peritoneal mesothelial cells (HPMCs). METHODS: We used HG peritoneal dialysis fluid (PDF) to induce in vivo PF in mice, and treated HPMCs with HG in vitro to stimulate EMT. RESULTS: In the mice, the higher the glucose concentration in the dialysate, the more obvious the peritoneal tissue thickening and the more that collagen was deposited. The in vitro study indicated that the expression of IGF-1R, α-SMA, vimentin was upregulated, while the expression of occludin, ZO-1, and E-cadherin was downregulated in HPMCs under HG and IGF-1R overexpression conditions. Conversely, the expression of IGF-1R, α-SMA, and vimentin was downregulated, while the expression of occludin, ZO-1, and E-cadherin was upregulated in IGF-1R-underexpressed HPMCs under HG conditions. The cell migration abilities were increased, while the cell adhesion abilities were reduced in HPMCs under HG and IGF-1R overexpression conditions. In contrast, cell migration abilities were reduced, while cell adhesion abilities were increased in IGF-1Runderexpressed HPMCs under HG conditions. CONCLUSIONS: Targeting at IGF-1R may provide novel insights into the prevention and treatment of PF.

Angiotensin II type 2 receptor prevents extracellular matrix accumulation in human peritoneal mesothelial cell by ameliorating lipid disorder via LOX-1 suppression.

Evidence suggests that intracellular angiotensin II type 1 receptor (AT1) contributes to peritoneal fibrosis (PF) under high glucose (HG)-based dialysates. It is generally believed that AT2 antagonisticly affects AT1 function. The aim of this study was to explore whether AT2 activation is beneficial for attenuating human peritoneal mesothelial cell (HPMC) injury due to HG. We treated a HPMC line with HG to induce extracellular matrix (ECM) formation. AT2 was increased and blocked using CGP42112A and AT2 siRNA. Lipid deposition was detected, signaling molecules associated with lectin-like oxidized lipoprotein receptor-1 (LOX-1) and ECM proteins were evaluated by real-time PCR and western blot. The results showed that HG led to AT2 inhibition in HPMCs, inhibition of AT2 further aggravated the expression of ECM proteins, including α-smooth muscle actin, fibroblast specific protein-1 and collagen I, while AT2 decreased the expression of ECM proteins, even during HG stimulation. Interestingly, there was a parallel change in lipid accumulation and ECM formation when AT2 was increased or depressed. Moreover, AT2-mediated decreased ECM production was associated with reduced lipid accumulation in HPMCs and depended on the downregulation of LOX-1. Further analysis showed that HG increased oxidized low-density lipoprotein (ox-LDL) deposition in HPMCs concomitant with an enhanced expression of ECM components, whereas blocking LOX-1 reversed ox-LDL deposition even in the presence of HG. This effect was also accompanied by the remission of ECM accumulation. Our results suggested that AT2 prevented ECM formation in HG-stimulated HPMCs by ameliorating lipid via LOX-1 suppression.

Activation of the RAS contributes to peritoneal fibrosis via dysregulation of low-density lipoprotein receptor.

Peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation in peritoneal mesothelial cells (PMCs) during long-term use of high glucose (HG)-based dialysates. Activation of the renin-angiotensin system (RAS) has been shown to be associated with PF. The aim of this study was to explore the underlying mechanism of the RAS in HG-induced PF. We treated C57BL/6 mice and a human PMC line with HG to induce a PF model and to stimulate ECM accumulation, respectively. RAS activity was blocked using valsartan or angiotensin II (ANGII) type 1 receptor siRNA. The major findings were as follows. First, mice in the HG group exhibited increased collagen deposition and expression of ECM proteins, including α-smooth muscle actin (α-SMA) and collagen type I in the peritoneum. Consistent with the in vivo data, HG upregulated α-SMA expression in human peritoneal mesothelial cells (HPMCs) in a time- and dose-dependent manner. Second, HG stimulation led to RAS activation in HPMCs, and inactivation of RAS decreased the expression of ECM proteins in vivo and in vitro, even during HG stimulation. Finally, RAS-mediated ECM production was associated with lipid accumulation in HPMCs and depended on the dysregulation of the low-density lipoprotein receptor (LDLr) pathway. HG-stimulated HPMCs showed increased coexpression of LDLr and α-SMA, whereas blockade of RAS activity reversed the effect. Furthermore, inhibition of LDLr signaling decreased α-SMA and collagen type I expression in HPMCs when treated with HG and ANG II. In conclusion, increased intracellular RAS activity impaired lipid homeostasis and induced ECM accumulation in HPMCs by disrupting the LDLr pathway, which contributed to PF.

Renal ischemia/reperfusion-induced mitophagy protects against renal dysfunction via Drp1-dependent-pathway.

Autophagy is upregulated under stress conditions to degrade superfluous proteins and recycle damaged organelles including damaged mitochondria. However, the occurrence of mitochondrial autophagy and its contribution remain to be elucidated during renal ischemia/reperfusion injury (IRI). In this study, mitophagosomes and engulfed mitochondria were frequently observed by electron microscopy after renal IRI vs. control. Meanwhile, the increase of lipidated microtubule associated protein light chain 3 (LC3-II) and decrease of mitochondrial proteins were detected by western blot, suggesting the presence of mitophagy. Drp1 translocated to mitochondria and was phosphorylated at S616 in response to IRI. Interestingly, we found that inhibiting drp1 phosphorylation with mdivi-1 significantly suppressed IRI-induced mitophagy without affecting general autophagy. Furthermore, our results showed that downregulation of mitophagy significantly exacerbated cell apoptosis and markedly aggravated kidney dysfunction induced by IRI. Taken together, these data indicate that mitophagy was activated via Drp1-dependent pathway and such mitophagic clearance of damaged mitochondria protects cells from IRI-induced apoptosis.

Maternal and neonatal outcomes after exposure to ADHD medication during pregnancy: A systematic review and meta-analysis.

PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) medications are used by increasing numbers of reproductive-age women. The safety of these medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis was performed to evaluate the adverse maternal and neonatal outcomes associated with exposure to ADHD medication during pregnancy. The PubMed and Embase databases were searched to identify potential studies for inclusion. RESULTS: Eight cohort studies that estimated adverse maternal or neonatal outcomes associated with exposure to ADHD medication during pregnancy were included. Exposure to ADHD medication was associated with an increased risk of neonatal intensive care unit (NICU) admission compared with no exposure at any time (risk ratio (RR) 1.88; 95% confidence interval (CI), 1.7-2.08) and compared with women with exposure either before or after pregnancy (RR 1.38; 95% CI, 1.23-1.54; P < 0.001). Exposure to methylphenidate (MPH) was marginally associated with an increased risk for cardiac malformation (RR 1.27; 95% CI, 0.99-1.63; P = 0.065) compared with no exposure. However, exposure to ADHD medication was not associated with an increased risk for other adverse maternal or neonatal outcomes. This analysis was limited by the small number of studies included and the limited adjustments for the possible confounders in the studies. CONCLUSIONS: Exposure to ADHD medication during pregnancy does not appear to be associated with adverse maternal or neonatal outcomes. Given the few studies included, further larger, prospective studies that control for important confounders are needed to verify our findings.

A modified relief of unilateral ureteral obstruction model.

Objectives: To improve the mouse model of relief for unilateral ureteral obstruction (RUUO) and explore the pathological process of renal fibrosis after the obstruction was relieved. Methods: C57BL/6 mice in model group were randomly divided into RUUO group, improved RUUO group, and UUO group. After leaving Unilateral Ureteral Obstruction (UUO) for 3 days, the obstruction was released by reimplantation way in RUUO group and in reimplantation + catheter way in improved RUUO group. C57BL/6 mice in observation group were randomly divided into 1d RUUO group, 3d RUUO group, 7d RUUO group, and 14d RUUO group. Three days after UUO, the obstruction was released by reimplantation + catheter in four groups. We detected the renal volume, H&E, Masson staining, and immunohistochemistry of kidney pathology on the seventh day after RUUO in model group and on the 1st, 3rd, 7th, and 14th day after RUUO in observation group. Results: Comparing with mice in RUUO group, mice in improved RUUO group had lower renal volume, tubular damage score, and collagen area percentage. After the obstruction was relieved, the renal volume decreased gradually within 2 weeks. The tubular damage score in 7d RUUO group was lower than that in 1d RUUO and 3d RUUO group. However, the tubular damage score in 14d RUUO group was higher than that in 7d RUUO group. The tendency of collagen area percentage and α-SMA IOD value were consistent with the tubular damage score. Conclusions: Using the method of reimplantation + catheter, a reliable mice model of RUUO can be got. After RUUO, the de-obstructed kidneys are still in damage and fibrosis state.

Effect of CXCR4 on Apoptosis in Osteosarcoma Cells via the PI3K/Akt/NF-κß Signaling Pathway.

BACKGROUND/AIMS: Osteosarcoma, the most common primary bone malignancy, arises from primitive transformed cells of mesenchymal origin with the worldwide increasing morbidity and mortality. Previous studies found apoptosis of osteosarcoma cells was essential for an effective manner to improve the progress of osteosarcoma, and CXCR4 has been demonstrated to be relevant with various tumor progress and metastasis. METHODS: The proliferation of cells transfected with CXCR4 shRNA and control shRNA were measured by BrdU assay. Apoptosis was detected by flow cytometry. Apoptotic protein expression levels were detected by Western blot. Caspase activity was detected by Colorimetric Assay Kits using microplate reader. Activation of NF-κß signaling after CXCR4 down-regulation in osteosarcoma cells was examined by constructing NF-κß promoter luciferase reporter plasmid. The expression and activation of NF-κß Signaling relevant protein were analyzed to investigate the relationship between Akt and NF-κß signaling after the down-regulation of CXCR4 in osteosarcoma cells. RESULTS: Down-regulation of CXCR4 significantly reduced the cell proliferation, while remarkably increased the cell apoptosis and apoptotic protein expression levels in osteosarcoma cells. Furthermore, down-regulation of CXCR4 induced cell apoptosis was caspase dependent in osteosarcoma cells. This study also showed CXCR4 down-regulation induced apoptosis through inhibiting PI3K/Akt/NF-κß signaling pathway. In addition, endoplasmic reticulum stress (ERS) activation was involved in cell apoptosis induced down-regulation of CXCR4. Knockdown of partial ERS relevant proteins followed down-regulation of CXCR4 significantly inhibited cell apoptosis and the apoptotic protein expression levels. CONCLUSIONS: Taken together, the results demonstrated that down-regulation of CXCR4 could induce apoptosis of human osteosarcoma cells through inhibiting PI3K/Akt/NF-κß signaling pathway, indicating that CXCR4 could be vital for the clinical therapy of osteosarcoma.