Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients.

Aims: Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied. Methods: PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for "Rabson-Mendenhall syndrome" or "Black acanthosis hirsutism insulin resistance syndrome." Results: A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 µIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations. Conclusion: The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.

A New Ferroptosis-Related Long Non-Coding RNA Risk Model Predicts the Prognosis of Patients With Papillary Thyroid Cancer.

Background: Ferroptosis is a novel form of regulated cell death that involves in cancer progression. However, the role of ferroptosis-related long non-coding RNAs (lncRNAs) in papillary thyroid cancer (PTC) remains to be elucidated. The purpose of this paper was to clarify the prognostic value of ferroptosis-related lncRNAs in PTC. Methods: The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between ferroptosis-related genes (FRGs) and lncRNA was determined using Pearson correlation analysis. Multivariate Cox regression model (P < 0.01) was performed to establish a ferroptosis-related lncRNAs risk model. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, risk curve and nomograms were then performed to assess the accuracy and clinical applicability of prognostic models. The correlations between the prognosis model and clinicopathological variables, immune and m6A were analyzed. Finally, in vitro assays were performed to verify the role of LINC00900, LINC01614 and PARAL1 on the proliferation, migration and invasion in TPC-1 and BCPAP cells, as well as the relationship between three lncRNAs and ferroptosis. Results: A five-ferroptosis-related lncRNAs (PARAL1, LINC00900, DPH6-DT, LINC01614, LPP-AS2) risk model was constructed. Based on the risk score, samples were divided into the high- and low-risk groups. Patients in the low-risk group had better prognosis than those in high-risk group. Compared to traditional clinicopathological features, risk score was more accurate in predicting prognosis in patients with PTC. Additionally, the difference of immune cell, function and checkpoints was observed between two groups. Moreover, experiments showed that LINC00900 promoted the proliferation, migration and invasion in TPC-1 and BCPAP cells, while LINC01614 and PARAL1 revealed opposite effects, all of which were related to ferroptosis. Conclusions: In summary, we identified a five-ferroptosis-related lncRNAs risk model to predict the prognosis of PTC. Furthermore, our study also revealed that LINC00900 functioned as a tumor suppressor lncRNA, LINC01614 and PARAL1 as an oncogenic lncRNA in PTC.

The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review.

Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.

Rational Design of Cu Vacancies and Antisite Defects for Boosting the Thermoelectric Properties of CuGaTe2-Based Compounds.

CuGaTe2-based compounds show great promise in the application for high-temperature thermoelectric power generation; however, its wide bandgap feature poses a great challenge for enhancing thermoelectric performance via structural defects modulation and doping the system. Herein, it is discovered that the presence of GaCu antisite defects in the CuGaTe2 compound promotes the formation of Cu vacancies, and vice versa, which tends to form the charge-neutral structure defects combination with one GaCu antisite defect and two Cu vacancies. The accumulation of Cu vacancies in the structure of the (Cu2Te)x(Ga2Te3)1-x compounds evolves into twins and stacking faults. This in conjunction with GaCu antisite defects intensify the point defects phonon scattering, yielding a dramatic reduction on lattice thermal conductivity from 6.95 W m-1 K-1 for the pristine CuGaTe2 sample to 2.98 W m-1 K-1 for the (Cu2Te)0.45(Ga2Te3)0.55 sample at room temperature. Furthermore, the high concentration of charge-neutral defects combination narrows the band gap and increases the carrier concentration, leading to an improved power factor of 1.58 mW/mK2 at 600 K for the (Cu2Te)0.49(Ga2Te3)0.51 sample, which is 41% higher than for the pristine CuGaTe2 sample. Consequently, the highest ZT value of 0.82 is achieved at 915 K for Cu0.015(Cu2Te)0.48(Ga2Te3)0.52, which represents an enhancement of about 22% over that of the pristine CuGaTe2 compound.

Transition experiences of patients with post stroke dysphagia and family caregivers: A longitudinal, qualitative study.

BACKGROUND: Stroke patients with dysphagia and family caregivers will experience multiple transitions during the whole process of the disease and various nursing needs will be generated. There is a lack of knowledge about their experiences at different transition stages. Thus, we aimed to explore the transition experiences of patients with post stroke dysphagia and family caregivers from admission to discharge home. METHODS: A semi-structured interview based on Meleis's transition theory was used during hospitalization and telephone follow-up interviews were conducted in the first, third, and sixth month after the diagnosis of dysphagia. Interview transcripts were analyzed using the conventional content analysis method. RESULTS: A total of 17 participants enrolled in the first face-to-face interview, 16 participants took part in the first month's telephone follow-up interview, 14 participants in the third month, and 12 participants in the sixth month. The transition experiences of patients with post stroke dysphagia and family caregivers could be summarized into three themes: (1)transition from onset to admission; (2)transition from discharge to other rehabilitation institutions; and (3)transition from discharge to home. Each theme had identified interrelated subthemes. CONCLUSIONS: The experiences of patients with post stroke dysphagia and family caregivers during transition are a dynamic process with enormous challenges in each phase. Collaboration with health care professionals, follow-up support after discharge, and available community and social support should be integrated into transitional nursing to help patients facilitate their transition.

Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists.

BACKGROUND: Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes. RESULTS: Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non-Asians: (weighted mean difference [WMD], -0.59, 95% CI, -0.73 to -0.45, p < .01) vs (WMD, -0.29, 95% CI, -0.32 to -0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non-Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, -5.12, 95% CI, -5.84 to -4.41, p < .01) compared to non-Asians (WMD, -3.64, 95% CI, -4.38 to -2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non-Asians (p < .01). CONCLUSIONS: Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

Study on Fracture Characteristics of Layered Sandstone under Asymmetric Loading.

In engineering practice, layered rock masses often display obvious anisotropy while deforming and failing, and the failure mode directly impacts the engineering construction stability. In this study, the fracture failure load, fracture toughness, crack deflection angle, and failure mode of a layered rock mass under different fracture modes were analyzed by utilizing improved asymmetric semi-circular disc specimens. According to the constitutive model of transversely isotropic materials, the maximum tensile stress (MTS), maximum energy release rate (MERR), and maximum strain energy density (MSED) calculation formulas were modified, and the calculation formulas of the three prediction criteria under anisotropic materials were derived. The calculation results were compared with the experimental results. The results show that the fracture toughness and crack deflection angle were significantly affected by the weak bedding plane. As a result of applying the MTS criterion, the results are closer to the experimental results, providing a solid foundation for engineering deformation, failure, and fracture analyses.

Bushen Huoxue formula protects against renal fibrosis and pyroptosis in chronic kidney disease by inhibiting ROS/NLRP3-mediated inflammasome activation.

BACKGROUND: Renal fibrosis contributes to chronic renal failure and a decline in the quality of life. Bushen Huoxue (BSHX) formula is a Traditional Chinese Medicine used to treat chronic renal failure. However, its mechanisms of action remain unclear. METHODS AND RESULTS: In this study, a rat model of renal fibrosis was constructed by 5/6 nephrectomy in vivo, and histopathological changes were analyzed using hematoxylin-eosin and Masson's trichrome staining. Angiotensin II (Ang II) was used to establish an in vitro renal fibrosis cell model in vitro. Pyroptosis was measured using flow cytometry. Related markers of fibrosis and NOD-like receptor protein 3 (NLRP3) inflammasome activation were measured using western blotting and enzyme-linked immunosorbent assay. Treatment with BSHX (0.25, 0.5, and 1 g/kg) significantly inhibited renal fibrosis and damage in 5/6 nephrectomized rats and simultaneously reduced oxidative stress and NLRP3 inflammasome activation. Similarly, BSHX treatment reduced the levels of hydroxyproline, transforming growth factor-ß, matrix metalloproteinase 2, and matrix metalloproteinase 9 and inactivated the Smad2/3 signaling pathway in Ang II-treated HK-2 cells. Our data also showed that treatment with BSHX reduced NLRP3 inflammasome activation and pyroptosis in Ang II-treated HK-2 cells. Moreover, fibrosis and pyroptosis in HK-2 cells induced by NLRP3 overexpression were reduced by treatment with BSHX. CONCLUSIONS: BSHX significantly reduced renal fibrosis and pyroptosis, and its mechanism was mainly associated with the inhibition of reactive oxygen species (ROS)/NLRP3-mediated inflammasome activation.

C/EBPß-Lin28a positive feedback loop triggered by C/EBPß hypomethylation enhances the proliferation and migration of vascular smooth muscle cells in restenosis.

BACKGROUND: The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins ß (C/EBPß) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPß-Lin28a axis in restenosis. METHODS: Restenosis and atherosclerosis rat models of type 2 diabetes (n  =  20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPß between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPß on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student's t-test and one-way analysis of variance were used for statistical analysis. RESULTS: C/EBPß expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitroC/EBPß overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPß knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPß could directly bind to Lin28a promoter. Increased C/EBPß expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPß and Lin28a expression accompanied by C/EBPß hypomethylation. Additionally, Lin28a overexpression reduced C/EBPß methylation via recruiting TET1 and enhanced C/EBPß-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells. CONCLUSION: Our findings suggest that the C/EBPß-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.

Rhodotorula mucilaginosa A8, a potential helper strain in a vitamin C microbial fermentation process.

In the vitamin C microbial fermentation system, oxidative stress limits the growth and 2-keto-l-gulonic acid (2-KLG, the precursor of vitamin C) production of Ketogulonicigenium vulgare. Most Bacillus strains, as helper strains, have been reported to release key biomolecules to reduce oxidative stress and promote the growth and 2-KLG production of K. vulgare. To understand the specific mechanism by which the helper strain and K. vulgare interact to reduce oxidative stress, a novel helper strain, Rhodotorula mucilaginosa A8, was used to construct a consortium in the co-culture fermentation system. Based on the activities of the antioxidant enzymes and quantitative polymerase chain reaction (qPCR) analysis, R. mucilaginosa A8 could reduce oxidative stress and increase 2-KLG production in K. vulgare by upregulating antioxidant enzyme activities and related gene-expression levels. In addition, the carotenoids of R. mucilaginosa promoted 2-KLG production in K. vulgare. Coculture of R. mucilaginosa with K. vulgare increased the yield of carotenoids. This study suggested that helper strains with the ability to reduce oxidative stress in K. vulgare would likely act as potential helper strains for facilitating 2-KLG biosynthesis. This work could provide a theoretical basis for the search for potential helper strains for vitamin C microbial fermentation and for the construction of synthetic microbial communities to produce valuable products.

Dual-Cation CuAgSe-Based Material: Rapid Mass Transfer in Synthesis and High Thermoelectric Performance Realization.

Understanding mass transfer mechanisms is vital for developing new material synthesis and densification technologies. Ion transport, serving both mass and charge transfer, is essential for the rapid preparation of high-performance fast ionic conductor thermoelectric materials like Zn4Sb3 and Cu2Q (Q = S, Se). In the case of dual-cation fast ion conductor materials like CuAgSe, exploring the relationship between cation transport becomes pertinent. In this study, copper (Cu) and selenium (Se) undergo a reaction in the presence of an electric field (∼15 A), resulting in the formation of the CuSe compound. Subsequent to this initial reaction, a subsequent thermal environment facilitates the interaction among Cu, CuSe, and Ag2Se, culminating in the rapid formation and densification of CuAgSe (with a relative density exceeding 99%) in just 30 s. Evidently, the diffusion of copper ions substantiates a pivotal role in facilitating mass transfer. As a result, CuAg1+xSe samples with different silver contents (x = 0.01, 0.02, 0.03, 0.04 and 0.05) can effectively inhibit cation vacancy, and introduce highly ordered Ag nanotwins to enhance the electrical transport performance. For CuAg1.04Se, a peak ZT value of 1.0 can be achieved at 673 K, which is comparable to the literatures. This work will guide the future electric field-assisted rapid mass transfer of materials.

Guideline for diagnosis and management of congenital dysfibrinogenemia.

INTRODUCTION: Congenital dysfibrinogenemia (CD) is characterized by dysfunction induced by an abnormal fibrinogen molecule structure that results in blood coagulation dysfunction. The clinical manifestations of CD patients are asymptomatic, bleeding and thrombosis. The majority of patient are asymptomatic. However, the single fibrinogen detection method is easy to cause missed diagnosis or misdiagnosis of CD patients. The treatment strategies of CD patients with different clinical manifestations are also different. METHODS: Combing the existing experimental diagnosis technology, literature and our research results, a simple and practical CD diagnostic criteria was proposed. And based on the relevant literature and existing treatment guidelines, more comprehensive treatment recommendations are summarized. RESULTS: In this new criteria, combination Clauss method and PT derived method was proposed to detect fibrinogen and its ratio was used to diagnose for CD. Diagnosis also needs to be combined the clinical manifestations, family investigation and genetic testing. According to different clinical manifestation (bleeding, thrombosis or asymptomatic), treatment methods and strategies are different. The treatment of CD patients should consider the patient's personal and family history of bleeding or thrombosis. Treatment of thrombosis and pregnancy may be more challenging. The risk of bleeding and thrombosis should be evaluated and balanced at all times during clinical treatment. These detailed treatment recommendations can provide reference for patients with different clinical manifestations of CD. CONCLUSIONS: The new CD diagnosis criteria and comprehensive treatment recommendations can effectively improve the diagnosis and treatment of CD.

Cardiorenal Benefits of Finerenone in Different Races and Kidney Function in Patients with Chronic Kidney Disease.

BACKGROUND: The mineralocorticoid receptor plays an important pathophysiological role in cardiorenal diseases by causing inflammation and fibrosis. Mineralocorticoid receptor antagonists (MRAs) are well known in treating cardiovascular disease and diverse nephropathies. However, the first-generation MRA (spironolactone) and the second-generation MRA (eplerenone) remain underutilized because of the risk of inducing severe adverse events. As a selective nonsteroidal MRA, finerenone is safer and more effective and improves cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). However, the effect of finerenone on cardiorenal outcomes in patients of different races and kidney function (estimated glomerular filtration rate) is unclear. SUMMARY: In this review, we summarized the impact of finerenone on patients with CKD and T2DM from randomized controlled trials. The synthesis of published data aims to address the questions pertaining to the cardiorenal benefits of finerenone among various racial groups and different levels of kidney function. KEY MESSAGE: Finerenone presents racial differences and effects associated with kidney function in CKD and T2DM patients. Due to the limited data for subgroups, it is prudent to approach the conclusion with caution.

Iron(III) and BF3·OEt2-Promoted O-Transfer Reaction of N-Aryl-α,ß-Unsaturated Nitrones to Prepare Difluoroboron ß-Ketoiminates.

We described an iron(III) and BF3·OEt2-promoted oxygen transfer reaction of N-aryl-α,ß-unsaturated nitrones to prepare various N,O-difluoroboron ß-ketoiminates in good yields ranging from 24% to 87%. Control experiments revealed that the enaminone was the vital intermediate for the formation of N,O-difluoroboron ß-ketoiminates, and iron(III) combined with BF3·OEt2 played as cocatalyst to promote the oxygen transfer reaction through intramolecular cyclization and N-O bond cleavage. More importantly, an estrone-derived N,O-difluoroboron ß-ketoiminate was easily prepared in 40% yield from estrone in four steps.

Factors of Influence on Diabetes Awareness in Older People With Chronic Obstructive Pulmonary Disease Comorbid With Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a common comorbidity in patients with chronic obstructive pulmonary disease (COPD) and has been associated with an increased risk of mortality in this population. PURPOSE: This study was designed to investigate the predictive factors of diabetes awareness (DA), including diabetes knowledge (DK), and diabetes care behaviors (DCB) among older people with both COPD and T2DM. METHODS: This was a cross-sectional descriptive correlation study. One hundred thirty-three older-age patients with COPD comorbid with T2DM receiving treatment at a chest hospital were enrolled as participants. Both DK and DCB were utilized to measure DA. The Diabetes Knowledge Questionnaire was utilized to measure DK, and the Summary of Diabetes Self-Care Activities was used to evaluate DCB. RESULTS: The average glycated hemoglobin (HbA1c) was 7.68% ( SD = 1.55%), with 74 (55.6%) participants having a level > 7%. The average DA was 46.46% ( SD = 13.34%), the average DK was 53.42% ( SD = 18.91%), and the average DCB was 39.50% ( SD = 16.66%). In terms of demographic variables, age, diabetes education, diabetes shared care, and HbA1c were all significantly associated with DA, DK, and DCB (all p s < .05). The overall variance in DA was significantly explained by diabetes education and HbA1c (all p s < .05). The overall variance in DK was significantly explained by age, diabetes education, and HbA1c. The overall variance in DCB was significantly explained by diabetes education and HbA1c (all p s < .05). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Our study findings indicate that older adult patients with COPD comorbid with T2DM are at elevated risks of poor glycemic control and low DA. Healthcare professionals should be aware of these issues and develop appropriate DA plans to prevent poor glycemic control in this population. Providing accurate information on diabetes to older adults with COPD comorbid with T2DM is important to improving their DK and promoting better DCB.

Physical therapy for acute and sub-acute low back pain: A systematic review and expert consensus.

OBJECTIVE: To review the effectiveness of different physical therapies for acute and sub-acute low back pain supported by evidence, and create clinical recommendations and expert consensus for physiotherapists on clinical prescriptions. DATA SOURCES: A systematic search was conducted in PubMed and the Cochrane Library for studies published within the previous 15 years. REVIEW METHODS: Systematic review and meta-analysis, randomized controlled trials assessing patients with acute and sub-acute low back pain were included. Two reviewers independently screened relevant studies using the same inclusion criteria. The Physiotherapy Evidence Database and the Assessment of Multiple Systematic Reviews tool were used to grade the quality assessment of randomized controlled trials and systematic reviews, respectively. The final recommendation grades were based on the consensus discussion results of the Delphi of 22 international experts. RESULTS: Twenty-one systematic reviews and 21 randomized controlled trials were included. Spinal manipulative therapy and low-level laser therapy are recommended for acute low back pain. Core stability exercise/motor control, spinal manipulative therapy, and massage can be used to treat sub-acute low back pain. CONCLUSIONS: The consensus statements provided medical staff with appliable recommendations of physical therapy for acute and sub-acute low back pain. This consensus statement will require regular updates after 5-10 years.

High CD133 expression in proximal tubular cells in diabetic kidney disease: good or bad?

BACKGROUND: Proximal tubular cells (PTCs) play a critical role in the progression of diabetic kidney disease (DKD). As one of important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease. However, its role in chronic DKD is unclear. Therefore, we aimed to investigate the expression patterns and elucidate its functional significance of CD133 in DKD. METHODS: Data mining was employed to illustrate the expression and molecular function of CD133 in PTCs in human DKD. Subsequently, rat models representing various stages of DKD progression were established. The expression of CD133 was confirmed in DKD rats, as well as in human PTCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of CD133, utilizing proliferative and injury indicators. After overexpression or knockdown of CD133 in HK-2 cells, the cell proliferation and apoptosis were detected by EdU assay, real-time cell analysis and flow analysis. Additionally, the evaluation of epithelial, progenitor cell, and apoptotic indices was performed through western blot and quantitative RT-PCR analyses. RESULTS: The expression of CD133 was notably elevated in both human and rat PTCs in DKD, and this expression increased as DKD progressed. CD133 was found to be co-expressed with CD24, KIM-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with proliferation. In terms of functionality, the knockdown of CD133 resulted in a significant reduction in proliferation and an increase in apoptosis in HK-2 cells compared to the high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose-induced cell apoptosis, but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided additional evidence to support the correlation between CD133 expression and the progression of DKD. Analysis of single-cell RNA-sequencing data revealed that CD133+ PTCs potentially play a role in the advancement of DKD through multiple mechanisms, including heat damage, cell microtubule stabilization, cell growth inhibition and tumor necrosis factor-mediated signaling pathway. CONCLUSION: Our study demonstrates that the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in DKD and high glucose induced PTC injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of high glucose exposure. However, its sustained increase is associated with the pathological progression of DKD. In conclusion, CD133 exhibits dual roles in the advancement of DKD, necessitating further investigation.

TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.

BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells. METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1ß, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively. RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1ß, IL-18, IL-6, and TNF-α, and promoted the expression of active IL-1ß, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells. CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.

Machine learning decision support model for discharge planning in stroke patients.

BACKGROUND/AIM: Efficient discharge for stroke patients is crucial but challenging. The study aimed to develop early predictive models to explore which patient characteristics and variables significantly influence the discharge planning of patients, based on the data available within 24 h of admission. DESIGN: Prospective observational study. METHODS: A prospective cohort was conducted at a university hospital with 523 patients hospitalised for stroke. We built and trained six different machine learning (ML) models, followed by testing and tuning those models to find the best-suited predictor for discharge disposition, dichotomized into home and non-home. To evaluate the accuracy, reliability and interpretability of the best-performing models, we identified and analysed the features that had the greatest impact on the predictions. RESULTS: In total, 523 patients met the inclusion criteria, with a mean age of 61 years. Of the patients with stroke, 30.01% had non-home discharge. Our model predicting non-home discharge achieved an area under the receiver operating characteristic curve of 0.95 and a precision of 0.776. After threshold was moved, the model had a recall of 0.809. Top 10 variables by importance were National Institutes of Health Stroke Scale (NIHSS) score, family income, Barthel index (BI) score, FRAIL score, fall risk, pressure injury risk, feeding method, depression, age and dysphagia. CONCLUSION: The ML model identified higher NIHSS, BI, and FRAIL, family income, higher fall risk, pressure injury risk, older age, tube feeding, depression and dysphagia as the top 10 strongest risk predictors in identifying patients who required non-home discharge to higher levels of care. Modern ML techniques can support timely and appropriate clinical decision-making. RELEVANCE TO CLINICAL PRACTICE: This study illustrates the characteristics and risk factors of non-home discharge in patients with stroke, potentially contributing to the improvement of the discharge process. REPORTING METHOD: STROBE guidelines.