Unveiling the role of RAC3 in the growth and invasion of cisplatin-resistant bladder cancer cells.

Bladder cancer is one of the most prevalent cancers worldwide, and its morbidity and mortality rates have been increasing over the years. However, how RAC family small GTPase 3 (RAC3) affects the proliferation, migration and invasion of cisplatin-resistant bladder cancer cells remains unclear. Bioinformatics techniques were used to investigate the expression of RAC3 in bladder cancer tissues. Influences of RAC3 in the grade, stage, distant metastasis, and survival rate of bladder cancer were also examined. Analysis of the relationship between RAC3 expression and the immune microenvironment (TIME), genomic mutations, and stemness index. In normal bladder cancer cells (T24, 5637, and BIU-87) and cisplatin-resistant bladder cancer cells (BIU-87-DDP), the expression of RAC3 was detected separately with Western blotting. Plasmid transfection was used to overexpress or silence the expression of RAC3 in bladder cancer cells resistant to cisplatin (BIU-87-DDP). By adding activators and inhibitors, the activities of the JNK/MAPK signalling pathway were altered. Cell viability, invasion, and its level of apoptosis were measured in vitro using CCK-8, transwell, and flow cytometry. The bioinformatics analyses found RAC3 levels were elevated in bladder cancer tissues and were associated with a poor prognosis in bladder cancer. RAC3 in BIU-87-DDP cells expressed a higher level than normal bladder cancer cells. RAC3 overexpression promoted BIU-87-DDP proliferation. The growth of BIU-87-DDP cells slowed after the knockdown of RAC3, and RAC3 may have had an impact on the activation of the JNK/MAPK pathway.

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

AIMS: To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). MATERIALS AND METHODS: Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. RESULTS: Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. CONCLUSIONS: In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Ultra-rapid lispro improved postprandial glucose control compared to insulin lispro in predominantly Chinese patients with type 1 diabetes: A prospective, randomized, double-blind phase 3 study.

AIMS: To investigate the efficacy and safety of ultra-rapid lispro (URLi) versus insulin lispro in predominantly Chinese patients with type 1 diabetes (T1D) in a prospective, randomized, double-blind, treat-to-target, phase 3 study. MATERIALS AND METHODS: Following a lead-in period, during which insulin glargine U-100 or insulin degludec U-100 was optimized, patients were randomly assigned (1:1) to URLi (n = 176) or insulin lispro (n = 178). The primary objective was to test the noninferiority of URLi to insulin lispro in glycaemic control (noninferiority margin = 0.4% for glycated haemoglobin [HbA1c] change from baseline to week 26), with testing for the superiority of URLi to insulin lispro with regard to 1- and 2-hour postprandial glucose (PPG) excursions during a mixed-meal tolerance test and HbA1c change at week 26 as the multiplicity-adjusted objectives. RESULTS: From baseline to week 26, HbA1c decreased by 0.21% and 0.28% with URLi and insulin lispro, respectively, with a least squares mean treatment difference of 0.07% (95% confidence interval -0.11 to 0.24; P = 0.467). URLi demonstrated smaller 1- and 2-hour PPG excursions at week 26 with least squares mean treatment differences of -1.0 mmol/L (-17.8 mg/dL) and -1.4 mmol/L (-25.5 mg/dL), respectively (p < 0.005 for both) versus insulin lispro. The safety profiles of URLi and insulin lispro were similar. CONCLUSIONS: In this study, URLi administered in a basal-bolus regimen demonstrated superiority to insulin lispro in controlling PPG excursions, with noninferiority of HbA1c control in predominantly Chinese patients with T1D.

Gastric emptying in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes and the impact of 4-week insulin pump therapy.

AIM: To evaluate gastric emptying (GE) and the glycaemic response to a 75-g oral glucose load in newly diagnosed, treatment-naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12-15 months after insulin pump therapy. MATERIALS AND METHODS: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75-g glucose drink containing 150 mg 13C-acetate, to determine the gastric half-emptying time, and underwent assessment of plasma glucose and serum insulin, C-peptide and glucagon-like peptide-1 (GLP-1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re-assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12-15 months, GE was re-measured in 14 of the T2D participants. RESULTS: At baseline, participants with T2D exhibited substantially augmented fasting and post-glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP-1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP-1 secretion was attenuated, fasting and post-glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12-15 months of follow-up. CONCLUSIONS: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short-term insulin pump therapy. The effect on GE is maintained for at least 12 months.

Gastric emptying is slower in women than men with type 2 diabetes and impacts on postprandial glycaemia.

AIM: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). METHODS: In cohort 1, 70 newly diagnosed, treatment-naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75-g glucose drink containing 150 mg 13C-acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi-solid mashed potato meal, labelled with 100 µl 13C-octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). RESULTS: Gastric emptying was slower in female than male subjects in both cohorts (both p < .01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p < .05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p < .001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p < .05). CONCLUSIONS: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume-adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D.

Alterations of outer retinal reflectivity in diabetic patients without clinically detectable retinopathy.

PURPOSE: This study aimed to investigate alterations of outer retinal reflectivity on spectral-domain optical coherence tomography (OCT) in diabetic patients without clinically detectable retinopathy (NDR). METHODS: In this retrospective study, 64 NDR patients and 71 controls were included. Relative reflectivity (RR) of the ellipsoid zone (EZ), photoreceptor outer segment (OS) and inner segment (IS), and outer nuclear layer (ONL) at the foveola and at 500 µm, 1000 µm, and 2000 µm nasal (N), temporal (T), superior (S), and inferior (I) to the foveola was measured by cross-line OCT and ImageJ. Retinal vessel densities (VD) in fovea, parafovea, and perifovea areas were detected by OCT angiography (OCTA). RESULTS: EZ RR in most retinal locations was significantly lower in NDR eyes compared to controls (all P < 0.05), except the foveola. Compared with controls, NDR eyes also displayed lower RR at N2000, T2000, S1000, and I1000 of OS, at S500 and I500 of IS, and at I500 of ONL (all P < 0.05). Negative correlations could be observed between retinal RR and diabetes duration, HbA1c, and best-corrected visual acuity (BCVA) (r = - 0.303 to - 0.452). Compared to controls, EZ, OS, and IS RR of the NDR eyes showed lower correlation coefficients with whole image SCP and DCP VD of parafovea and perifovea regions. CONCLUSION: Outer retinal reflectivity, along with the coefficients between retinal reflectivity and VD, is reduced in NDR patients and is correlated with diabetes duration, HbA1c, and BCVA. The reduction of outer retinal reflectivity may be a potential biomarker of early retinal alterations in diabetic patients.

Decreased glucagon in diabetic peripheral neuropathy patients with long duration type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the association of fasting C-peptide and glucagon with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2DM). METHODS: A comprehensive evaluation was conducted on 797 patients with T2DM to assess the various risk factors affecting DPN. The subjects were categorized into short duration and long duration group according to the duration of diabetes with a threshold of 10 years. Logistic regression analysis was employed to examine the association between DPN and islet function, as well as other parameters. Receiver operating characteristic curve analysis was performed to evaluate the predictive capability of glucagon. RESULTS: The fasting C-peptide levels were significantly lower in the DPN patients with short duration of diabetes, but lost significance in the long duration group. Conversely, a decreased level of glucagon was only observed in DPN patients with long duration of diabetes. For the group with long duration of diabetes, glucagon was the sole risk factor associated with DPN. The receiver operating characteristic curve analysis revealed that glucagon in the long duration group exhibited a moderate area under the curve of 0.706. CONCLUSIONS: The serum glucagon levels in T2DM patients with DPN exhibited bidirectional changes based on the duration of diabetes. Decreased glucagon was associated with DPN in T2DM patients with long duration of diabetes.

Inhibitory Neurons in Nucleus Tractus Solitarius Are Involved in Decrease of Heart Rate Variability and Development of Depression-Like Behaviors in Temporal Lobe Epilepsy.

BACKGROUND: Diminished heart rate variability (HRV) has been observed in epilepsy, especially in epilepsy with depressive disorders. However, the underlying mechanism remains elusive. METHODS: We studied HRV, spontaneous recurrent seizures, and depression-like behaviors in different phases of pilocarpine-induced temporal lobe epilepsy (TLE) in mice. Single-cell RNA sequencing analysis was used to identify various nerve cell subsets in TLE mice with and without depression. Differentially expressed gene (DEG) analysis was performed in epilepsy, depression, and HRV central control-related brain areas. RESULTS: We found decreased HRV parameters in TLE mice, and alterations were positively correlated with the severity of depression-like behaviors. The severity of depression-like behaviors was correlated with the frequency of spontaneous recurrent seizure. Characteristic expression of mitochondria-related genes was significantly elevated in mice with depression in glial cells, and the enrichment analysis of those DEGs showed an enriched GABAergic synapse pathway in the HRV central control-related brain area. Furthermore, inhibitory neurons in the nucleus tractus solitarius, which is an HRV central control-related brain area, were specifically expressed in TLE mice combined with depression compared with those in mice without depression. A significantly enriched long-term depression pathway in DEGs from inhibitory neurons was found. CONCLUSIONS: Our study reported correlations between HRV and epilepsy-depression comorbidity in different phases of TLE. More importantly, we found that HRV central control-related inhibitory neurons are involved in the development of depression in TLE, providing new insights into epilepsy comorbid with depression.

Efficacy and safety of adding once-weekly dulaglutide to basal insulin for inadequately controlled type 2 diabetes in Chinese patients (AWARD-CHN3): A randomized, double-blind, placebo-controlled, phase III trial.

AIM: To determine the efficacy and safety of once-weekly dulaglutide added to basal insulin in Chinese patients with type 2 diabetes mellitus (T2DM) with inadequate glycaemic control. MATERIALS AND METHODS: In the phase III, double-blind AWARD-CHN3 study, Chinese patients with T2DM (N = 291) and glycated haemoglobin (HbA1c) ≥7.0% and ≤11.0% receiving stable doses of basal insulin glargine with metformin and/or acarbose were randomized (1:1) to receive add-on dulaglutide 1.5 mg once weekly or placebo once weekly. The primary endpoint was the superiority of dulaglutide/glargine to placebo/glargine for change from baseline in HbA1c at Week 28. RESULTS: The least squares (LS) mean ± standard error change in HbA1c from baseline to Week 28 was -2.0 ± 0.08% with dulaglutide/glargine and -1.1 ± 0.07% with placebo/glargine (LS mean difference: -1.0%, 95% confidence interval [CI] -1.1 to -0.8; P < 0.001), and more patients receiving dulaglutide/glargine achieved HbA1c levels <7.0% (75.9% vs. 33.8%; P < 0.001 vs. placebo/glargine). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -1.2 kg, 95% CI -1.8 to - 0.6; P < 0.001). Reductions in fasting serum glucose were greater with dulaglutide/glargine than with placebo/glargine (LS mean difference: -0.8 mmol/L, 95% CI -1.1 to - 0.5; P < 0.001). The incidence of hypoglycaemia was similar with dulaglutide/glargine and placebo/glargine (29.2% vs. 31.3%; P = 0.704); no patient in either group had severe hypoglycaemia. The most common treatment-emergent adverse events with dulaglutide/glargine were decreased appetite (22.2%), diarrhoea (13.2%) and nausea (10.4%). CONCLUSIONS: Dulaglutide added to basal insulin was efficacious and well tolerated in Chinese patients with T2DM.

Saxagliptin combined with additional oral antihyperglycaemic agents in drug-naive diabetic patients with high glycosylated haemoglobin: A 24-week, multicentre, randomized, open-label, active parallel-controlled group clinical trial in China (SUCCESS).

AIM: To assess the efficacy and safety of a dipeptidyl peptidase-4 (DPP-4) inhibitor combined respectively with three oral antihyperglycaemic agents in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM) with high levels of glycated haemoglobin (HbA1c). MATERIALS AND METHODS: Between 30 December 2014 and 1 November 2017, a 24-week, multicentre, parallel-controlled study was performed on drug-naive T2DM patients. In total, 648 patients with 8.0% ≤ HbA1c ≤ 11.0%, aged 18-80 years and body mass index (BMI) 19-40 kg/m2 were randomly assigned 1:1:1 to receive saxagliptin (Saxa) combined with metformin (Met), acarbose (Aca) or gliclazide (Gli) modified release (MR) tablets (Saxa + Met, Saxa + Aca and Saxa + Gli). The primary outcome was the absolute change in HbA1c from baseline; secondary outcome was the percentage of patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: Each treatment arm contained 216 patients; overall, 583 completed the 24-week trial. At 24 weeks, the mean (95% confidence interval) change in HbA1c from baseline in Saxa + Met, Saxa + Aca and Saxa + Gli were, respectively: -2.9% [-3.1, -2.8]; -2.6% [-2.8, -2.5]; and -2.8% [-2.9, -2.6] (overall p = .04, Saxa + Aca vs. Saxa + Met, p = .010, Saxa + Gli vs. Saxa + Met, p = 0.18). At 24 weeks, 84.9%, 74.7% and 80.3% of participants were at HbA1c <7.0% (overall p = .05); and 72.6%, 59.8% and 63.3% were HbA1c ≤6.5% (overall p = 0.10). The rates of minor or symptomatic hypoglycaemia were very low. CONCLUSIONS: Initial treatment with a DPP-4 inhibitor combined with Metform, alpha-glycosidase inhibitor or sulphonylurea was safe and effective for patients with newly diagnosed T2DM and high HbA1c. DPP-4 inhibitor combined with Met showed the best efficacy for this population.

Diabetes remission in drug-naïve patients with type 2 diabetes after dorzagliatin treatment: A prospective cohort study.

AIM: To investigate the post-treatment effect of dorzagliatin in drug-naïve patients with type 2 diabetes (T2D) regarding the achievement of stable glycaemic control and drug-free diabetes remission. MATERIALS AND METHODS: Patients who completed dorzagliatin treatment in the SEED trial and achieved stable glycaemic control were enrolled in this 52-week study without any antidiabetic medication. The primary endpoint was the diabetes remission probability at week 52 using the Kaplan-Meier method. The potential factors that contribute to stable glycaemic control and diabetes remission based on the characteristics of patients before and after treatment with dorzagliatin were analysed. A post hoc sensitivity analysis of diabetes remission probability using the American Diabetes Association (ADA) definition was conducted. RESULTS: The Kaplan-Meier remission probability was 65.2% (95% CI: 52.0%, 75.6%) at week 52. Based on the ADA definition, the remission probability was 52.0% (95% CI: 31.2%, 69.2%) at week 12. The significant improvements in the insulin secretion index ΔC30/ΔG30 (41.46 ± 77.68, P = .0238), disposition index (1.22 ± 1.65, P = .0030), and steady-state variables of HOMA2-ß (11.49 ± 14.58, P < .0001) and HOMA2-IR (-0.16 ± 0.36, P = .0130) during the SEED trial were important factors in achieving drug-free remission. A significant improvement in time in range (TIR), a measure of glucose homeostasis, in the SEED trial from 60% to more than 80% (estimated treatment difference, 23.8%; 95% CI: 7.3%, 40.2%; P = .0084) was observed. CONCLUSIONS: In drug-naïve patients with T2D, dorzagliatin treatment leads to stable glycaemic control and drug-free diabetes remission. Improvements in ß-cell function and TIR in these patients are important contributors to diabetes remission.

EEF1A1 is Involved the Regulating Neuroinflammatory Processes in Parkinson's Disease.

BACKGROUND: Studies have reported that the RNA-binding protein Eukaryotic Elongation Factor 1A1 (EEF1A1) is low expressed in the hippocampal region of Alzheimer's disease (AD). In addition, it is related to PARK2 activity in cells, predicting its importance in neurodegenerative diseases. However, the function of EEF1A1 in Parkinson's disease (PD) is unclear. Our study's primary objective was to knock down EEF1A1 in U251 cells and preliminarily explore the role of EEF1A1 in PD neuroinflammation. METHODS: To inhibit EEF1A1 from being expressed in U251 cells, siRNA was transfected into those cells. Then, RNA-seq sequencing was used to determine the Differentially Expressed Genes (DEGs) resulting from the EEF1A1 knockdown. Additionally, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed to find the biological processes and signaling pathways engaged in the DEGs, as well as to screen for genes associated with neuroinflammatory processes that influence the development of PD. Further Real Time - quantitative Polymerase Chain Reaction (RT-qPCR) validation experiments were performed to confirm the reliability of the sequencing results. Finally, combined with the support of related literature, the molecular mechanism of EEF1A1 in regulating the neuroinflammatory process of PD was initially explored. RESULTS: Analysis using the RNA-seq technique showed that EEF1A1 knockdown could significantly upregulate the expression of IL-6, GDF15, STC1, MT1E, GPNMB, CCL5, MT1X, A2M, and VIP genes at the transcriptional level. These nine highly elevated genes were enriched to signaling pathways linked to inflammatory processes, according to an analysis of GO and KEGG enrichment. CONCLUSIONS: EEF1A1 is involved in the regulating of IL-6, GDF15, STC1, MT1E, GPNMB, CCL5, MT1X, A2M, and VIP genes associated with the neuroinflammatory process of PD. Among them, we found that GDF15, STC1, MT1E, MT1X, GPNMB, VIP, and A2M genes were involved in delaying the neuroinflammatory process of PD, while IL-6 and CCL5 were involved in exacerbating the neuroinflammatory process, implicating that EEF1A1 may participate in the regulation of the PD neuroinflammation.

Selenium nanoparticles improve nickel-induced testosterone synthesis disturbance by down-regulating miR-708-5p/p38 MAPK pathway in Leydig cells.

The present study was designed to investigate the role of miR-708-5p/p38 mitogen-activated protein kinase (MAPK) pathway during the mechanism of selenium nanoparticles (Nano-Se) against nickel (Ni)-induced testosterone synthesis disorder in rat Leydig cells. We conducted all procedures based on in vitro culture of rat primary Leydig cells. After treating Leydig cells with Nano-Se and NiSO4 alone or in combination for 24 h, we determined the cell viability, reactive oxygen species (ROS) levels, testosterone production, and the protein expression of key enzymes involved in testosterone biosynthesis: steroidogenic acute regulatory (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1). The results indicated that Nano-Se antagonized cytotoxicity and eliminated ROS generation induced by NiSO4 , suppressed p38 MAPK protein phosphorylation and reduced miR-708-5p expression. Importantly, we found that Nano-Se upregulated the expression of testosterone synthase and increased testosterone production in Leydig cells. Furthermore, we investigated the effects of p38 MAPK and miR-708-5p using their specific inhibitor during Nano-Se against Ni-induced testosterone synthesis disorder. The results showed that Ni-inhibited testosterone secretion was alleviated by Nano-Se co-treatment with p38 MAPK specific inhibitor SB203580 and miR-708-5p inhibitor, respectively. In conclusion, these findings suggested Nano-Se could inhibit miR-708-5p/p38 MAPK pathway, and up-regulate the key enzymes protein expression for testosterone synthesis, thereby antagonizing Ni-induced disorder of testosterone synthesis in Leydig cells.

MRI-based Texture Analysis of Infrapatellar Fat Pad to Predict Knee Osteoarthritis Incidence.

Background Infrapatellar fat pad (IPFP) quality has been implicated as a marker for predicting knee osteoarthritis (KOA); however, no valid quantification for subtle IPFP abnormalities has been established. Purpose To investigate whether MRI-based three-dimensional texture analysis of IPFP abnormalities could help predict incident radiographic KOA. Materials and Methods In this prospective nested case-control study, 690 participants whose knees were at risk for KOA were included from the Pivotal Osteoarthritis Initiative MRI Analyses incident osteoarthritis cohort. All knees had a Kellgren-Lawrence grade of 1 or less at baseline. During the 4-year follow-up, case participants were matched 1:1 to control participants, with incident radiographic KOA as the outcome. MRI scans were segmented at the incident time point of KOA (hereafter, P0), 1 year before P0 (hereafter, P-1), and baseline. MRI-based three-dimensional texture analysis was performed to extract IPFP texture features. Least absolute shrinkage and selection operator and multivariable logistic regressions were applied in the development cohort and evaluated in the test cohort. The area under the receiver operating characteristic curve (AUC) was used to evaluate the discriminative value of the clinical score, IPFP texture score, and MRI Osteoarthritis Knee Score. Results Participants were allocated to development (n = 500, 340 women; mean age, 60 years) and test (n = 190, 120 women; mean age, 61 years) cohorts. In both cohorts, IPFP texture scores (AUC ≥0.75 for all) showed greater discrimination than clinical scores (AUC ≤0.69 for all) at baseline, P-1, and P0, with significant differences in pairwise comparisons (P ≤ .002 for all). Greater predictive and concurrent validities of IPFP texture scores (AUC ≥0.75 for all) compared with MRI Osteoarthritis Knee Scores (AUC ≤0.66 for all) were also demonstrated (P < .001 for all). Conclusion MRI-based three-dimensional texture of the infrapatellar fat pad was associated with future development of knee osteoarthritis. ClinicalTrials.gov registration no.: NCT00080171 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Fischer in this issue.

Efficacy and safety of azathioprine, mycophenolate mofetil, and reduced dose of rituximab in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort. METHODS: Patients with aquaporin 4 (AQP4) antibody-positive NMOSD with AZA (n = 167), MMF (n = 131), or RTX (n = 55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events. RESULTS: The median follow-up time of the 353 patients was 30.3 months. The regimen of RTX was 100 mg on Day 1 and 500 mg on Day 2, followed by 500 mg every 6 months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR] = 4.40, 95% confidence interval [CI] = 1.41-13.80, p = 0.011) or MMF (HR = 5.20, 95% CI = 1.60-16.86, p = 0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34-3.66, p = 0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%, p < 0.001). CONCLUSIONS: We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody-positive NMOSD.

Development of organic-diffusive gradients in thin films technique for measuring freely dissolved concentrations of tetracyclines using a commercial SPE packing.

The freely dissolved concentrations (FDCs) of pollutants are related to their bioavailability in the environment, and the diffusive gradients in thin films technique (DGT) can obtain the FDC of an analyte. Aiming for the detection of the FDCs of tetracyclines (TCs), we used a polyacrylamide hydrogel comprising acrylamide and acrylaide agarose cross-linker as diffusive and binding gels, and a commercial solid-phase extraction (SPE) packing, namely polymer sorbent (PLS), as an adsorption material in the binding gel for the preparation of the organic-diffusive gradients in thin films (o-DGT) devices. The results showed that the diffusion coefficients of tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC) in the diffusive gels were 1.08 × 10-6, 1.08 × 10-6 and 1.03 × 10-6 cm2/ s at 25 °C, respectively. The binding gel showed excellent performance with adsorption capacities of 534.88-569.42 µg/disc for TC, 527.18-565.98 µg/disc for OTC and 1320.12-1320.86 µg/disc for CTC, respectively. The uptake efficiencies were 94.21-111.12, 71.25-88.44 and 76.10-86.62% for TC, OTC and CTC, respectively, with the TCs concentration of 0.05-10 mg/L. The adsorption kinetics of TCs could be described with a pseudo-second-order model (POSM, R2 >0.97). According to the result of adsorption kinetics, the adsorption rate of TCs in the binding gel was not as fast as that of heavy metals, suggesting that the TCs concentrations at the boundary of binding gels in the o-DGT devices could not decrease to zero. After correction of the boundary concentration, the FDCs accounted for 30.30-56.90, 48.10-64.68 and 16.55-50.16% for TC, OTC and CTC, respectively, while their concentrations ranged from 0.2 to 10.0 mg/L. Our results suggested that SPE packing might be an ideal adsorption material for o-DGT binding gels, and that adsorption kinetics should be corrected when calculating the FDCs of organic pollutants.

Effect of long-term nursing intervention on quality of life and social support of patients with coronary heart disease after percutaneous coronary intervention.

OBJECTIVE: To assess the effect of long-term nursing intervention on the quality of life and social support of patients after percutaneous coronary intervention (PCI). METHODS: A randomised controlled trial was designed. A total of 60 patients with coronary heart disease treated with PCI were randomly divided into the control group and the intervention group. The patients in the control group received routine nursing care, while the patients in the intervention group received long-term nursing intervention. The Simplified Quality of Life Scale-Quality of Life Scale, the Coronary Heart Disease Self-Management Scale, and the Social Support Rating Scale were used to collect and analyse the data. RESULTS: After the intervention, the scores for quality of life, social support and self-management in the intervention group were higher than those in the control group, and the differences were statistically significant (p < 0.05). CONCLUSION: Long-term nursing intervention can improve the quality of life and sense of social support of patients with coronary heart disease after PCI.

Nano-selenium attenuates mitochondrial-associated apoptosis via the PI3K/AKT pathway in nickel-induced hepatotoxicity in vivo and in vitro.

The aim of this study was to investigate the protective effects of Nano-Se against nickel (Ni)-induced hepatotoxicity and the potential mechanism. Hence, we constructed in vivo and in vitro models of Ni-induced hepatotoxicity. Sprague-Dawley (SD) rats were exposed to nickel sulfate (NiSO4 , 5.0 mg/kg, i.p.) with or without Nano-Se (0.5, 1, and 2 mg/kg, oral gavage) co-administration for 14 days, and HepG2 cells were exposed to NiSO4 (1500 µM) with or without Nano-Se (20 µM) for 24 h. Nano-Se obviously prevented Ni-induced hepatotoxicity indicated by ameliorating pathological change and decreasing Ni accumulation in rat livers. Ni induced a significant increase in hepatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH-Px), and malondialdehyde (MDA) level, decreased the glutathione (GSH) content while compared to those in the control group. Nano-Se administration improved the hepatic antioxidant capacity through increase hepatic GSH contents and GSH-Px activity, decrease the activities of SOD, CAT, and MDA level. Nano-Se improved the cell viability, decreased active oxygen (ROS) generation and ameliorated morphological changes of nuclear structures in Ni-treated HepG2 cells. In addition, Nano-Se inhibited the Ni-induced increases of cytochrome c, caspase-9, cleaved caspase-3, increased PI3K and AKT phosphorylation both in vivo and in vitro. Besides, the PI3K inhibitor Y294002 could inhibit the protective effects of Nano-Se on apoptosis. Thus, Nano-Se significantly activates PI3K/AKT signaling to ameliorate apoptosis in Ni-induced hepatotoxicity.

[Analysis of genetic variant in a patient with juvenile meterochromic leukodystrophy].

OBJECTIVE: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product. RESULTS: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein. CONCLUSION: The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.