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.

CHL1 promotes insulin secretion and negatively regulates the proliferation of pancreatic ß cells.

Cell adhesion molecule L1-like protein (CHL1) is a member of neural recognition molecules of immunoglobulin superfamily primarily expressing in the nervous system. CHL1 regulates neuronal migration, axonal growth, and dendritic projection. Downregulation of CHL1 has been reported in ß cells of patients with type 2 diabetes (T2DM). However, the detailed role of CHL1 in ß cells has not been characterized. In this study, Real-Time PCR and Western blot were applied to investigate the tissue/cell distribution and expression of CHL1. Gain- or loss-of function studies were conducted in MIN6 cells to determine the effects of CHL1 on cell proliferation, apoptosis, cell cycle, and insulin secretion. Following silencing of CHL1 in MIN6 cells (si-CHL1), insulin secretion and the number of insulin secretary granules <50 nm from the cell membrane decreased in response to 20 mM glucose. Besides, silencing of CHL1 induced cell proliferation, reduced apoptosis, and prolonged S phase and shortened G1 phase of the cell cycle, contrary to overexpressing of CHL1. The inhibitor of ERK1/2MAPK eliminated the effect of CHL1 deficiency on the proliferation of MIN6 cells. In addition, high-fat diet could result in increased islet volume and ß cell proliferation, decreased CHL1 expression and activation of ERK pathway in mice islets. Consequently, CHL1 expression was decreased in islets of high-fat induced mice, which resulted in cell proliferation via ERK pathway and regulation of the cell cycle through p53 pathway. These mechanisms may contribute to pancreatic ß cell compensatory hyperplasia in obesity-induced pre-diabetes.

The role and possible mechanism of long noncoding RNA PVT1 in modulating 3T3-L1 preadipocyte proliferation and differentiation.

Obesity is considered as a high-risk susceptibility state for most metabolic disorders and is directly related to preadipocyte differentiation or adipogenesis. Long noncoding RNAs (lncRNAs) are the key factors which have regulatory functions on various critical physiological and biological processes. PVT1 was identified as an oncogenic lncRNA which could promote angiogenesis in gastric cancer. However, the functions and molecular pathways related to PVT1 in adipogenesis had not been clarified yet. In the current study, the purpose was to identify the effects of lncRNA PVT1 on adipogenesis and the relevant molecular processes. Quantitative real-time polymerase chain reaction (RT-qPCR) was used to quantify PVT1 expression. The mechanism for PVT1 to participate in 3T3-L1 adipogenesis was identified by lentivirus-mediated gain- and loss-of-function tests. The potential association of PVT1 with cell viability was checked by CCK-8 assay and EdU staining. The gene expression for cytokines was determined by quantitative PCR (qPCR) and western blotting. PVT1 expression level was strongly upregulated after 3T3-L1 preadipocytes differentiated. In mice, PVT1 was abundantly expressed in adipose tissue, and the obese mice had higher PVT1 expression in adipose tissue than that of nonobese mice. Predominantly, PVT1 was found inside the nuclei. Overexpressed PVT1 could promote 3T3-L1 adipocyte differentiation as proved, which was the cause for the ability to accelerate lipid accumulation, by upregulating the expression of peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein α, and adipocyte protein 2, while knockdown of PVT1 caused opposite effects. The RNA immunoprecipitation demonstrated the binding relationship between PVT1 and STAT3 suggesting the potential role of STAT3 in 3T3-L1 preadipocyte differentiation. Furthermore, PVT1 could promote fatty acid synthesis but inhibit fatty acid oxidation. PVT1 was positively associated with 3T3-L1 preadipocyte differentiation, which highlighted the potential of PVT1 as a therapeutic target for obesity treatment.

Hepatocytes derived extracellular vesicles from high-fat diet induced obese mice modulate genes expression and proliferation of islet ß cells.

Liver secretes proliferative factors participating compensatory hyperplasia of islets during obesity and insulin resistance. Extracellular vesicles (EVs) mediate intercellular communication by delivering inner factors to recipient cells. This study explored the biological effects of hepatocellular EVs on islet ß cells during obesity. Compared with standard chow diet (CD), hepatocellular EVs derived from high-fat diet (HFD) induced obese mice promoted proliferation of ß cell line-MIN6 cells, but didn't influence their insulin secretion. Microarray analysis found 13 miRNAs with significantly differential expression in hepatocellular EVs between HFD with CD group. Meanwhile, RNA-sequencing detected 80 genes with significantly differential expression in MIN6 cells treated with HFD and CD hepatocellular EVs respectively. Six miRNAs and 11 potential target genes were pre-screened by synthesizing TargetScan prediction and RNA-sequencing results. After miRNA mimic transfection and testing the expressions of target genes and cell vitality, miR-7218-5p was verified to affect MIN6 cell proliferation through targeting CD74 gene. SiRNA transfection and dual luciferase reporter assay further confirmed the binding and regulation of miRNA-7218-5p on CD74. These findings suggest HFD induced obesity could change miRNA profiles in hepatocellular EVs, which modulate expression of multiple genes and proliferation of MIN6 cells and maybe mediate compensatory hyperplasia of islets.

Lipopolysaccharide enhances ADAR2 which drives Hirschsprung's disease by impairing miR-142-3p biogenesis.

Researches over the past decade suggest that lipopolysaccharide is a dominant driver of gastrointestinal motility and could damage the enteric neuron of rat or porcine. However, it remains poorly defined whether LPS participates in Hirschsprung's disease (HSCR). Here, we discovered that LPS increased in HSCR tissues. Furthermore, LPS treatment suppressed the proliferation and differentiation of neural precursor cells (NPCs) or proliferation and migration of human 293T cells. ADAR2 (adenosine deaminase acting on RNA2)-mediated post-transcriptional adenosine-to-inosine RNA editing promotes cancer progression. We show that increased LPS activates ADAR2 and subsequently regulates the A-to-I RNA editing which suppresses the miR-142 expression. RNA sequencing combined with qRT-PCR suggested that ADAR2 restrain cell migration and proliferation via pri-miR-142 editing and STAU1 up-regulation. In conclusion, the findings illustrate that LPS participates in HSCR through the LPS-ADAR2-miR-142-STAU1 axis.

Erratum: LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR: Erratum.

[This corrects the article DOI: 10.7150/ijms.18392.].

Negative feedback circuitry between MIR143HG and RBM24 in Hirschsprung disease.

Hirschsprung disease (HSCR) is a genetic disorder of neural crest development. It is also believed that epigenetic changes plays a role in the progression of this disease. Here we show that the MIR143 host gene (MIR143HG), the precursor of miR-143 and miR-145, decreased cell proliferation and migration and forms a negative feedback loop with RBM24 in HSCR. As RBM24 mRNA is a target of miR-143, upregulation of RBM24 upon an increase in the level of MIR143HG could be attributed to sequestration of miR-143 by MIR143HG (sponge effect). The RBM24 protein was shown to bind to MIR143HG, and subsequently, accelerated its degradation by destabilizing its transcript and facilitating its interaction with Ago2, thus forming a negative feedback between MIR143HG and RBM24. In addition, experiments using siRNA against DROSHA indicated that RBM24 could promote the biogenesis of miR-143. This feedback loop we describe here represents a novel mode of autoregulation, with implications in HSCR pathogenesis.

Mutations of MYH14 are associated to anorectal malformations with recto-perineal fistulas in a small subset of Chinese population.

BACKGROUND: Anorectal malformations (ARMs) are among the most commonly congenital abnormalities of distal hindgut development, ranging from anal stenosis to anal atresia with or without fistulas and persistent cloaca. The etiology remains elusive for most ARM cases and the majority of genetic studies on ARMs were based on a candidate gene approach. MATERIALS AND METHODS: In all eight family members of a non-consanguineous Chinese family, we performed whole-exome sequencing. Subsequently, exome sequencing of MYH14 in 72 unrelated probands with ARMs was performed. The accurate distribution of non-muscle myosin II heavy chain (NMHC II) was investigated by immunohistochemistry in serial sagittal sections of E11.5-13.5 mouse cloacal regions. RESULTS: A homozygous mutation in MYH14 was identified in the two siblings of family 1. Compound heterozygous MYH14 changes were identified in an unrelated individual. Immunohistochemical analysis suggest stronger NMHC IIC localization in the epithelium of the murine embryonic cloaca, urorectal septum and hindgut compared with another two NMHC II isoforms. CONCLUSION: This is the first identification of mutations in MYH14 as a cause of ARMs. The stronger localization of NMHC IIC in E11.5-13.5 mouse cloacal regions further supports the role of MYH14 in anorectal development.

LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR.

Background: Long noncoding RNAs (lncRNAs) have recently emerged as important regulators in a broad spectrum of cellular processes including development and disease. Despite the known engagement of the AFAP1-AS in several human diseases, its biological function in Hirschsprung disease (HSCR) remains elusive. Methods: We used qRT-PCR to detect the relative expression of AFAP1-AS in 64 HSCR bowel tissues and matched normal intestinal tissues. The effects of AFAP1-AS on cell proliferation, migration, cell cycle, apoptosis and cytoskeletal organization were evaluated using CCK-8, transwell assay, flow cytometer analysis and immunofluorescence, in 293T and SH-SY5Y cell lines, respectively. Moreover, the competing endogenous RNA (ceRNA) activity of AFAP1-AS on miR-181a was investigated via luciferase reporter assay and immunoblot analysis. Results: Aberrant inhibition of AFAP1-AS was observed in HSCR tissues. Knockdown of AFAP1-AS in 293T and SH-SY5Y cells suppressed cell proliferation, migration, and induced the loss of cell stress filament integrity, possibly due to AFAP1-AS sequestering miR-181a in HSCR cells. Furthermore, AFAP1-AS could down-regulate RAP1B via its competing endogenous RNA (ceRNA) activity on miR-181a. Conclusions: These findings suggest that aberrant expression of lncRNA AFAP1-AS, a ceRNA of miR-181a, may involve in the onset and progression of HSCR by augmenting the miR-181a target gene, RAP1B.

Downregulated Expression of Long Non-Coding RNA LOC101926975 Impairs both Cell Proliferation and Cell Cycle and Its Clinical Implication in Hirschsprung Disease Patients.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to participate in various diseases. Hirschsprung disease (HSCR) is a common digestive disease in the new born. However, the relationship between lncRNAs and HSCR remains unclarified. METHODS: We used qRT-PCR to detect the relative expression of LOC101926975 in 80 pairs of HSCR bowel tissues and matched normal bowel tissues. CCK-8 assay, transwell assay and flow cytometry were then used to evaluate the function in vitro by knocking down the LOC101926975 in SK-N-BE(2) cells. Receiver operating characteristic (ROC) curve was used to evaluate the potential diagnostic value of LOC101926975. RESULTS: LOC101926975 was significantly downregulated in HSCR tissues with excellent correlation with FGF1. Dysregulation of LOC101926975 suppressed cell proliferation and induced G0/G1 arrest without impact on cell apoptosis or migration. Meanwhile, the AUC of LOC101926975 was 0.900 which presented great diagnostic value. CONCLUSIONS: Our study firstly investigates the potential function of LOC101926975 in HSCR and infers that LOC101926975 can distinguish HSCR from the normal ones.

Activities of daily living and non-exercise physical activity in older adults: findings from the Chinese Longitudinal Healthy Longevity Survey.

OBJECTIVES: Studies have shown that good cognitive function can moderate the relationship between non-exercise physical activity (NEPA) and activities of daily living (ADLs) disability to some extent, and this study mainly explores the relationship between ADL and NEPA and cognitive function in Chinese older adults. SETTING AND PARTICIPANTS: Data came from a nationally representative sample of 2471 Chinese old adults (aged 65+) from the 2011, 2014 and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. PRIMARY AND SECONDARY OUTCOME MEASURES: A cross-lagged panel model combined with mediation analysis was used to determine the relationship between ADL and NEPA and the mediating effect of cognitive function on the ascertained ADL-NEPA relationship. RESULTS: The more frequently people over the age of 65 in China participate in NEPA, the lower the risk of ADL disability. Cognitive function partially mediated this expected relationship, accounting for 9.09% of the total NEPA effect on ADL. CONCLUSION: Participating in more NEPA could reduce the risk of ADL disability, and participating in NEPA may reduce the risk of ADL disability through cognitive function to some extent.

Impact of Fixed Combination of Metformin and Pioglitazone on Insulin Resistance of Patients with Type 2 Diabetes: Results of a Randomized Open-Label Study.

Aim: To compare the effect of metformin, a fixed combination of metformin and pioglitazone, or dapagliflozin on insulin resistance in patients with newly diagnosed type 2 diabetes. Methods: In this 6-week randomized open-label trial, 58 patients were randomly assigned to insulin with metformin, a fixed combination of metformin and pioglitazone, or dapagliflozin for 4 weeks. Hyperinsulinemic euglycemic clamp tests and FreeStyle Libre Pro Sensor were used to evaluate the insulin sensitivity represented by glucose-infusion rate (M value) and glycemic control, respectively. The main outcome was changes in insulin resistance compared with baseline. Results: The baseline characteristics were well matched among the three groups. When compared to baseline, insulin sensitivity after treatment was significantly improved. Further study revealed that the fixed combination of metformin and pioglitazone provided superior M-value improvement compared with metformin, but not different from dapagliflozin. Moreover, a greater reduction in insulin dose was observed in the fixed combination of metformin and pioglitazone group than the metformin or dapagliflozin group. However, there were no significant differences in the parameters of glycemic control within the groups. Conclusion: In patients with newly diagnosed type 2 diabetes, a fixed combination of metformin and pioglitazone provided greater improvement in insulin resistance than metformin alone and similar changes in insulin resistance to dapagliflozin.

CDCA4 interacts with IGF2BP1 to regulate lung adenocarcinoma proliferation via the PI3K/AKT pathway.

BACKGROUND: Lung adenocarcinomas (LUAD) remain the leading cause of death in many countries. In this study, we investigated the role of division cycle-associated 4 (CDCA4) in the carcinogenesis of LUADs. METHODS: Real-time fluorescent quantitative polymerase chain reaction and western blot were performed to detect the messenger RNA and protein levels of CDCA4 in cells. Cell counting kit 8, real-time cell analysis, clone formation, EdU assays, and cell-cycle assays were used to preliminarily investigate the proliferation and cell-cycle-related functions of CDCA4 in lung adenocarcinoma. Immunoprecipitation assays were used to identify possible targets of CDCA4. A xenograft model was used to examine how CDCA4 knockdown affects LUAD cells growth in vivo. RESULTS: We found that the expression of CDCA4 was upregulated in LUAD cell lines. When CDCA4 was knocked out, the ability of LUAD cells to proliferate was dramatically reduced, and the cell cycle was stalled in the S phase. Meanwhile, boosting the CDCA4 expression had the opposite effect. The critical protein levels of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway were subsequently examined. The findings demonstrated that elevated CDCA4 lowered the phosphate and tensin homolog expression and increased the p-PI3K and p-AKT levels. Moreover, we demonstrated that CDCA4 favorably regulated IGF2BP1, a downstream target. The downregulation of the IGF2BP1 expression could reverse the proliferation promotion effect induced by the CDCA4 overexpression. CONCLUSIONS: CDCA4 can operate as an oncogenic factor to control the growth of lung adenocarcinoma via the PI3K/AKT pathway.

Immunotherapy, targeted therapy, and their cross talks in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a challenging malignancy with limited treatment options beyond surgery and chemotherapy. Recent advancements in targeted therapies and immunotherapy, including PD-1 and PD-L1 monoclonal antibodies, have shown promise, but their efficacy has not met expectations. Biomarker testing and personalized medicine based on genetic mutations and other biomarkers represent the future direction for HCC treatment. To address these challenges and opportunities, this comprehensive review discusses the progress made in targeted therapies and immunotherapies for HCC, focusing on dissecting the rationales, opportunities, and challenges for combining these modalities. The liver's unique physiology and the presence of fibrosis in many HCC patients pose additional challenges to drug delivery and efficacy. Ongoing efforts in biomarker development and combination therapy design, especially in the context of immunotherapies, hold promise for improving outcomes in advanced HCC. Through exploring the advancements in biomarkers and targeted therapies, this review provides insights into the challenges and opportunities in the field and proposes strategies for rational combination therapy design.

Therapeutic Strategies for Resectable Stage-IIIA N2 Non-Small Cell Lung Cancer Patients: A Network Meta-Analysis.

Background: The National Comprehensive Cancer Network (NCCN) guidelines did not give an explicit comparison of the efficacy between surgery and radiotherapy in treating Stage-III N2 non-small cell lung cancer (NSCLC) patients, leaving a paucity for clinical reference. Through this study, we try to locate the optimum treatment strategy including surgical type for these patients. Methods: A systematic literature search was performed from PubMed, Cochrane Library, Embase, and Google Scholars. The endpoints were overall survival (OS), mean OS, and progression-free survival (PFS). The treatments comprised radiotherapy, lobectomy, and pneumonectomy. Network meta-analysis was carried out for calculating the odds ratio (OR) for binary variants. All the analyses implemented Stata 17.0 MP. Results: Eight clinical trials reporting 1756 patients met the inclusion criteria. Radiotherapy and surgery were equivalent in improving patients' OS (OR = 0.842, 95% confidence interval [CI]: [0.645, 1.099]). The mean OS of patients were similar in terms of radiotherapy, lobectomy, and pneumonectomy. Besides, radiotherapy and surgery had equivalent effects in improving PFS (OR = 0.896, 95% CI: [0.718, 1.117]). Conclusions: Since lobectomy and pneumonectomy following neoadjuvant treatments had equivalent efficacy in prolonging OS for patients with stage-IIIA N2 NSCLC compared with definitive radiotherapy, young patients with favorable performance status (0) should try surgery to pursue better prognosis while elderly patients with unfavorable PS or radiosensitive pathology types should accept definitive radiotherapy. More high-quality clinical trials are needed to support our findings.

Increased Glycemic Variability Evaluated by Continuous Glucose Monitoring is Associated with Osteoporosis in Type 2 Diabetic Patients.

Background: Subjects with type 2 diabetes mellitus (T2DM) are susceptible to osteoporosis. This study was conducted to evaluate the association between glycemic variability evaluated by continuous glucose monitoring (CGM) and osteoporosis in type 2 diabetic patient. Methods: A total of 362 type 2 diabetic subjects who underwent bone mineral density (BMD) measurement and were monitored by a CGM system from Jan 2019 to May 2020 were enrolled in this cross-sectional study. Glycemic variability was calculated with the Easy GV software, including 24-hour mean blood glucose (24-h MBG), the standard deviation of 24-h MBG (SDBG), coefficient of variation (CV), mean amplitude of glycemic excursions (MAGE), and time in range between 3.9 and 10.0 mmol/L (TIR). Other potential influence factors for osteoporosis were also examined. Results: Based on the T-scores of BMD measurement, there were 190 patients with normal bone mass, 132 patients with osteopenia and 40 patients with osteoporosis. T2DM patients with osteoporosis showed a higher 24-h MBG, SDBG, CV, and MAGE, but a lower TIR (all p < 0.05). Multivariate logistic regression analysis revealed that age, female gender, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), serum uric acid (SUA) and MAGE independently contribute to osteoporosis, and corresponding odds ratio [95% confidence interval (CI)] was 1.129 (1.072-1.190), 4.215 (1.613-11.012), 0.801 (0.712-0.901), 2.743 (1.385-5.431), 0.993 (0.988-0.999), and 1.380 (1.026-1.857), respectively. Further receiver operating characteristic analysis with Youden index indicated that the area under the curve and its 95% CI were 0.673 and 0.604-0.742, with the optimal cut-off value of MAGE predicting osteoporosis being 4.31 mmol/L. Conclusion: In addition to conventional influence factors including age, female gender, BMI, LDL-C and SUA, increased glycemic variability assessed by MAGE is associated with osteoporosis in type 2 diabetic patients.

Circulating NAD+ Metabolism-Derived Genes Unveils Prognostic and Peripheral Immune Infiltration in Amyotrophic Lateral Sclerosis.

Background: Nicotinamide adenine dinucleotide (NAD+) metabolism has drawn more attention on neurodegeneration research; however, the role in Amyotrophic Lateral Sclerosis (ALS) remains to be fully elucidated. Here, the purpose of this study was to investigate whether the circulating NAD+ metabolic-related gene signature could be identified as a reliable biomarker for ALS survival. Methods: A retrospective analysis of whole blood transcriptional profiles and clinical characteristics of 454 ALS patients was conducted in this study. A series of bioinformatics and machine-learning methods were combined to establish NAD+ metabolic-derived risk score (NPRS) to predict overall survival for ALS patients. The associations of clinical characteristic with NPRS were analyzed and compared. Receiver operating characteristic (ROC) and the calibration curve were utilized to assess the efficacy of prognostic model. Besides, the peripheral immune cell infiltration was assessed in different risk subgroups by applying the CIBERSORT algorithm. Results: Abnormal activation of the NAD+ metabolic pathway occurs in the peripheral blood of ALS patients. Four subtypes with distinct prognosis were constructed based on NAD+ metabolism-related gene expression patterns by using the consensus clustering method. A comparison of the expression profiles of genes related to NAD+ metabolism in different subtypes revealed that the synthase of NAD+ was closely associated with prognosis. Seventeen genes were selected to construct prognostic risk signature by LASSO regression. The NPRS exhibited stronger prognostic capacity compared to traditional clinic-pathological parameters. High NPRS was characterized by NAD+ metabolic exuberant with an unfavorable prognosis. The infiltration levels of several immune cells, such as CD4 naive T cells, CD8 T cells, neutrophils and macrophages, are significantly associated with NPRS. Further clinicopathological analysis revealed that NPRS is more appropriate for predicting the prognostic risk of patients with spinal onset. A prognostic nomogram exhibited more accurate survival prediction compared with other clinicopathological features. Conclusions: In conclusion, it was first proposed that the circulating NAD+ metabolism-derived gene signature is a promising biomarker to predict clinical outcomes, and ultimately facilitating the precise management of patients with ALS.

Heart rate-corrected QT interval: A novel diagnostic biomarker for diabetic peripheral neuropathy.

AIMS/INTRODUCTION: To explore the relationship between heart rate-corrected QT (QTc) interval and diabetic peripheral neuropathy (DPN), and whether QTc interval has diagnostic utility for DPN beyond nerve conduction velocity. MATERIALS AND METHODS: A total of 965 patients with diabetes, including 473 patients with DPN and 492 patients without DPN, underwent standard 12-lead electrocardiography and detailed assessments of peripheral neuropathy. RESULTS: Patients with DPN had longer QTc intervals than those without. Among participants, from the first to fourth quartile of QTc interval, the proportion of patients with DPN appreciably increased and the nerve conduction velocity obviously decreased (P for trend <0.001). The univariate and multivariate analyses showed that prolonged QTc interval was closely associated with increased risk of DPN (univariable odds ratio 1.112, 95% confidence interval 1.097-1.127, P < 0.001; multivariable odds ratio 1.118, 95% confidence interval 1.099-1.137, P < 0.001). Receiver operating characteristic analysis for the diagnosis of DPN showed a greater area under the curve for QTc interval of 0.894 than the median nerve motor conduction velocity of 0.691, median nerve sensory conduction velocity of 0.664 and peroneal nerve motor conduction velocity of 0.692. The optimal cut-off point of QTc interval for DPN was 428.5 ms with sensitivity of 0.715 and specificity of 0.920 (P < 0.001). The combination of QTc interval and nerve conduction testing increased the area under the curve for the diagnosis of DPN (from 0.736 to 0.916; P < 0.001). CONCLUSIONS: QTc interval with 428.5 ms has more reliable diagnostic utility for DPN than nerve conduction velocity, and prolonged QTc interval is closely associated with an increased risk of DPN.

Characterization of Esophageal Microbiota in Patients With Esophagitis and Esophageal Squamous Cell Carcinoma.

Microbial imbalances have been well elucidated in esophageal adenocarcinoma. However, few studies address the microbiota in esophageal squamous cell carcinoma (ESCC) and esophagitis (ES). We aimed to explore the association of esophageal microbiota with these patients. Esophageal tissues were obtained from healthy controls and ES and ESCC patients undergoing upper endoscopy. 16S rRNA gene sequencing was applied to analyze the microbiome. The α and ß diversity differences were tested by Tukey test and partial least squares-discriminant analysis (PLS-DA), respectively. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. A total of 68 individuals were enrolled (control = 21, ES = 15, ESCC = 32). Microbial diversity was significantly different between the ESCC patients and healthy controls by Chao1 index, Shannon index, and PLS-DA. Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria were the five dominant bacterial phyla among the three groups. Megamonas, Collinsella, Roseburia, and Ruminococcus_2 showed a significantly continuous decreasing trend from the control group to the ESCC group at the genus level. When compared with the control group, decreased Fusobacteria at phylum level and Faecalibacterium, Bacteroides, Curvibacter, and Blautia at genus level were detected. ESCC samples also displayed a striking reduction of Bacteroidetes, Faecalibacterium, Bacteroides, and Blautia in comparison with the ES patients. LEfSe analysis indicated a greater abundance of Streptococcus, Actinobacillus, Peptostreptococcus, Fusobacterium, and Prevotella in the ESCC group. Our study suggests a potential association between esophageal microbiome dysbiosis and ESCC and provides insights into potential screening markers for esophageal cancer.

Association of glycemic variability and hypoglycemia with distal symmetrical polyneuropathy in adults with type 1 diabetes.

Previous studies exploring the influence of glycemic variability (GV) on the pathogenesis of distal symmetrical polyneuropathy (DSPN) in type 1 diabetes (T1DM) produced conflicting results. The aim of this study was to assess the relationship between GV and DSPN in T1DM. Adults with T1DM were included in this cross-sectional study and asked to undergo 3-day CGM. GV quantified by coefficient of variation (CV) and mean amplitude of glucose excursions (MAGE) were obtained from CGM. Clinical characteristics and biochemical assessments were collected for analysis. The study comprised 152 T1DM patients (53.9% males) with mean age of 44.2 year. Higher levels of age and duration of diabetes and lower levels of total cholesterol, LDL, fasting C-peptide and postprandial C-peptide were observed in DSPN subjects. DSPN groups displayed a higher blood glucose between 00:00 and 12:59 according to the CGM profile. Higher MAGE and CV were associated with increased risk of DSPN in the fully adjusted model. Meanwhile, a significant association between measurements of hypoglycemia, especially nocturnal hypoglycemia, and DSPN was found after multiple tests. CGM parameters describing the glycemic variability and hypoglycemia were potential risk factors for DSPN in adults with T1DM.