Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Clinical characteristics of local allergic rhinitis sensitized to house dust mites in Asia.

PURPOSE: Local allergic rhinitis (LAR) is characterized by a localized nasal allergic response without evidence of systemic atopy. LAR is an underdiagnosed entity and is a diagnostic and therapeutic challenge for clinicians. This study aimed to investigate the prevalence and clinical characteristics of patients with LAR to house dust mites (LAR-HDM) in Korea. METHODS: We performed a retrospective chart review of 336 adult patients with rhinitis symptoms who visited the Rhinologic Clinic at Korea University Guro Hospital from October 2019 to April 2021. Using results of the skin prick test, serologic test, and nasal provocation test, patients were classified as allergic rhinitis (AR) to HDM (AR-HDM), AR to other allergens, non-allergic rhinitis (NAR), or LAR-HDM. We excluded patients with AR to other allergens and compared the clinical characteristics of the remaining three groups. Patient demographic data were reviewed, and patients' nasal symptoms, olfactory function, serum total IgE, and severity of accompanying rhinosinusitis were evaluated. RESULTS: In total, 336 patients were examined. AR-HDM was diagnosed in 138 (41.1%) patients, AR to other allergens in 36 (10.7%) patients, NAR in 21 (42.0%) patients, and LAR-HDM in 21 (6.3%) patients. The mean age of patients with LAR-HDM was significantly higher than that of patients with AR-HDM. There were no significant differences in sex, smoking history, asthma, and family history of allergic diseases between the groups. Compared to NAR patients, there were significantly more patients with LAR-HDM who had persistent nasal symptoms. The frequency of nasal itching and sneezing was significantly higher in the LAR-HDM group than in the NAR group. The olfactory function score in the LAR-HDM group was significantly worse than that in the AR-HDM group, and the Lund-Mackay score was significantly higher in the LAR-HDM group than in the other groups. CONCLUSION: Clinical history and nasal symptoms are very similar in LAR-HDM and AR-HDM. Clinicians should take more care to differentiate them. LAR-HDM should also be considered in patients with persistent and severe nasal symptoms without systemic atopy.

Clinical and imaging features of ethmomaxillary sinus compared to Haller's cell.

PURPOSE: Understanding the anatomy of the paranasal sinuses and their variations is essential to achieving safe and effective endoscopic sinus surgery. The ethmomaxillary sinus (EMS) is a relatively under-researched anatomical variation. This study investigated the prevalence, clinical features, and effect of EMS on the maxillary sinus in comparison with Haller's cells. METHODS: Patients who visited the Rhinology Clinic at our hospital for rhinologic symptoms between January 2020 and December 2020. Computed tomography (CT) scans of paranasal sinuses were obtained at 1 mm-section thickness. Using CT scans, we investigated the clinical features of EMS, measured maxillary sinus volume, and analyzed the presence of maxillary sinusitis. RESULTS: EMS was observed in 26 of the 250 patients (10.4%). The male-to-female ratio was equal. The age ranged from 18 to 83 years (mean age, 56.3). Of the patients with EMS, 65.4% were unilateral and 34.6% were bilateral. The prevalence of Haller's cells was similar to that in EMS (10.8%). In the analysis of patients with unilateral EMS, the EMS side was found to have a significantly reduced maxillary sinus volume compared to the opposite side, whereas the difference was not significant in Haller's cells. There was no significant relationship between EMS or Haller's cells and maxillary sinusitis. CONCLUSIONS: EMS can significantly affect maxillary sinus volume. Therefore, surgeons should thoroughly review PNS CT scans before paranasal sinus surgery to determine the presence and features of EMS.

Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.

AIMS/HYPOTHESIS: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. METHODS: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. RESULTS: In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p < 0.001) than the non-progressors (n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p = 0.024). CONCLUSIONS/INTERPRETATION: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-κB pathway and IL-1ß-induced islet inflammation and increases insulin secretion.

The herb dwarf lilyturf tuber (Maidong, Ophiopogonis Radix) is widely used in Chinese traditional medicine to manage diabetes and its complications. However, the role of Maidong polysaccharide extract (MPE) in pancreatic ß-cell function is unclear. Here, we investigated whether MPE protects ß-cell function and studied the underlying mechanisms. We treated db/db and high-fat diet (HFD)-induced obese mice with 800 or 400 mg/kg MPE or water for 4 weeks, followed by an oral glucose tolerance test. Pancreas and blood were collected for molecular analyses, and clonal MIN6 ß-cells and primary islets from HFD-induced obese mice and normal chow diet-fed mice were used in additional analyses. In vivo, MPE both increased insulin secretion and reduced blood glucose in the db/db mice but increased only insulin secretion in the HFD-induced obese mice. MPE substantially increased the ß-cell area in both models (3-fold and 2-fold, p < 0.01, for db/db and HFD mice, respectively). We observed reduced nuclear translocation of the p65 subunit of NF-κB in islets of MPE-treated db/db mice, coinciding with enhanced glucose-stimulated insulin secretion (GSIS). In vitro, MPE potentiated GSIS and decreased interleukin 1ß (IL-1ß) secretion in MIN6 ß-cells. Incubation of MIN6 cells with tumor necrosis factor α (TNFα), interferon-γ, and IL-1ß amplified IL-1ß secretion and inhibited GSIS. These effects were partially reversed with MPE or the IκB kinase ß inhibitor PS1145, coinciding with reduced activation of p65 and p-IκB in the NF-κB pathway. We conclude that MPE may have potential for therapeutic development for ß-cell protection.

miR-29b Regulates TGF-ß1-Induced Epithelial-Mesenchymal Transition by Inhibiting Heat Shock Protein 47 Expression in Airway Epithelial Cells.

Tissue remodeling contributes to ongoing inflammation and refractoriness of chronic rhinosinusitis (CRS). During this process, epithelial-mesenchymal transition (EMT) plays an important role in dysregulated remodeling and both microRNA (miR)-29b and heat shock protein 47 (HSP47) may be engaged in the pathophysiology of CRS. This study aimed to determine the role of miR-29b and HSP47 in modulating transforming growth factor (TGF)-ß1-induced EMT and migration in airway epithelial cells. Expression levels of miR-29b, HSP47, E-cadherin, α-smooth muscle actin (α-SMA), vimentin and fibronectin were assessed through real-time PCR, Western blotting, and immunofluorescence staining. Small interfering RNA (siRNA) targeted against miR-29b and HSP47 were transfected to regulate the expression of EMT-related markers. Cell migration was evaluated with wound scratch and transwell migration assay. miR-29b mimic significantly inhibited the expression of HSP47 and TGF-ß1-induced EMT-related markers in A549 cells. However, the miR-29b inhibitor more greatly induced the expression of them. HSP47 knockout suppressed TGF-ß1-induced EMT marker levels. Functional studies indicated that TGF-ß1-induced EMT was regulated by miR-29b and HSP47 in A549 cells. These findings were further verified in primary nasal epithelial cells. miR-29b modulated TGF-ß1-induced EMT-related markers and migration via HSP47 expression modulation in A549 and primary nasal epithelial cells. These results suggested the importance of miR-29b and HSP47 in pathologic tissue remodeling progression in CRS.

Circulating branched-chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register.

AIM: Levels of branched-chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. METHODS: In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular-renal diseases. The study outcome was the first hospitalization for HF. RESULTS: During 29 103 person-years of follow-up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1-10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3-756.3] vs 605.2 [524.8-708.7] µmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per-SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07-1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09-1.41); blood pressure, low-density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14-1.50); HbA1c , waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11-1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11-1.48). The competing risk of death analyses showed similar results. CONCLUSIONS: Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long-term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.

Medical data science in rhinology: Background and implications for clinicians.

BACKGROUND: An important challenge of big data is using complex information networks to provide useful clinical information. Recently, machine learning, and particularly deep learning, has enabled rapid advances in clinical practice. The application of artificial intelligence (AI) and machine learning (ML) in rhinology is an increasingly relevant topic. PURPOSE: We review the literature and provide a detailed overview of the recent advances in AI and ML as applied to rhinology. Also, we discuss both the significant benefits of this work as well as the challenges in the implementation and acceptance of these methods for clinical purposes. METHODS: We aimed to identify and explain published studies on the use of AI and ML in rhinology based on PubMed, Scopus, and Google searches. The search string "nasal OR respiratory AND artificial intelligence OR machine learning" was used. Most of the studies covered areas of paranasal sinuses radiology, including allergic rhinitis, chronic rhinitis, computed tomography scans, and nasal cytology. RESULTS: Cluster analysis and convolutional neural networks (CNNs) were mainly used in studies related to rhinology. AI is increasingly affecting healthcare research, and ML technology has been used in studies of chronic rhinitis and allergic rhinitis, providing some exciting new research modalities. CONCLUSION: AI is especially useful when there is no conclusive evidence to aid decision making. ML can help doctors make clinical decisions, but it does not entirely replace doctors. However, when critically evaluating studies using this technique, rhinologists must take into account the limitations of its applications and use.

Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes.

Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio [OR] 6.9; 95% confidence interval [CI]: 5.6-8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057--0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.

Interactive effects of testosterone and the androgen receptor CAG repeat length polymorphism on cardiovascular-renal events and mortality in men with diabetes.

AIM: Current evidence relating testosterone to cardiovascular disease and mortality is inconclusive. Cellular effects of testosterone are mediated by androgen receptor and longer receptor gene CAG repeat length correlates with reduced transcriptional activity. We investigated the independent and interactive association of total testosterone and CAG repeat length with incident cardiovascular disease (CVD), chronic kidney disease (CKD) and mortality in Chinese men with type 2 diabetes. MATERIALS AND METHODS: From March 2008 and February 2009, 474 men with diabetes underwent structured clinical assessment including genotyping for CAG repeat length. Patients were followed for new-onset CVD, CKD defined by estimated glomerular filtration rate <60 mL/min/1.73m2 , and death until 31 May 2015. RESULTS: In this cohort (mean age: 58.6 years, disease duration: 15.4 years), CAG repeat number ranged from 11 to 32 with median of 23, and 9.3% had low testosterone. Over follow-up of 5.8 years, 49 (10.3%) men had CVD, 139 (29.3%) had CKD, and 43 (9.1%) died. In multivariate Cox regression adjusted for age, duration of diabetes, and cardiometabolic risk factors, both total testosterone and interaction term of total testosterone × CAG repeat were associated with all-cause death with respective hazard ratios 1.63 (P = 0.002) and 0.98 (P = 0.004). Total testosterone and CAG repeat were not related to incident CVD or CKD. CONCLUSIONS: Among men with type 2 diabetes, high total testosterone was associated with increased mortality in the presence of shorter CAG repeat length but decreased mortality in those with long CAG repeats.

Glucocorticoids ameliorate periostin-induced tissue remodeling in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Periostin plays an important role in the development of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). Glucocorticoids (GCs) are anti-inflammatory drugs used to treat CRS, but the mechanism for inhibiting periostin-induced tissue remodeling is still unclear. We sought to investigate the expression of periostin, α-SMA, and extracellular matrix (ECM) components in sinonasal tissues and to evaluate the inhibitory mechanism of GCs in nasal fibroblasts and mucosa. METHODS: We measured the expression of periostin, α-SMA and ECM components in sinonasal tissues. Correlation of CRS severity and periostin was evaluated by the Lund-Mackey score. Fibroblasts and ex vivo culture of the inferior turbinate were used to investigate the effects of GCs on periostin-induced alterations using real-time PCR, western blot, and immunostaining. Wound healing, transwell invasion, and collagen gel contraction were performed to evaluate migration and collagen contraction. RESULTS: Periostin was highly expressed in eosinophilic CRSwNP and correlated with the Lund-Mackay score. In nasal fibroblasts, periostin increased tissue remodeling involved protein. GCs suppressed the alterations of periostin. In addition, periostin induced activation of Src/AKT/mTOR, which was inhibited by GCs. GCs also inhibited periostin-induced migration, invasion, and collagen gel contraction. CONCLUSION: We suggest that GCs are therapeutic agents for CRSwNP by inhibiting tissue remodeling through their inhibitory effect on Src/Akt/mTOR signaling pathway. This article is protected by copyright. All rights reserved.

Chemical Chaperone of Endoplasmic Reticulum Stress Inhibits Epithelial-Mesenchymal Transition Induced by TGF-ß1 in Airway Epithelium via the c-Src Pathway.

Epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells to assume a mesenchymal cell phenotype. EMT is considered as a therapeutic target for several persistent inflammatory airway diseases related to tissue remodeling. Herein, we investigated the role of endoplasmic reticulum (ER) stress and c-Src in TGF-ß1-induced EMT. A549 cells, primary nasal epithelial cells (PNECs), and inferior nasal turbinate organ cultures were exposed to 4-phenylbutylic acid (4PBA) or PP2 and then stimulated with TGF-ß1. We found that E-cadherin, vimentin, fibronectin, and α-SMA expression was increased in nasal polyps compared to inferior turbinates. TGF-ß1 increased the expression of EMT markers such as E-cadherin, fibronectin, vimentin, and α-SMA and ER stress markers (XBP-1s and GRP78), an effect that was blocked by PBA or PP2 treatment. 4-PBA and PP2 also blocked the effect of TGF-ß1 on migration of A549 cells and suppressed TGF-ß1-induced expression of EMT markers in PNECs and organ cultures of inferior turbinate. In conclusion, we demonstrated that 4PBA inhibits TGF-ß1-induced EMT via the c-Src pathway in A549 cells, PNECs, and inferior turbinate organ cultures. These results suggest an important role for ER stress and a diverse role for TGF-ß1 in upper airway chronic inflammatory disease such as CRS.

Efficacy of hyaluronic acid and hydroxyethyl starch in preventing adhesion following endoscopic sinus surgery.

Adhesion is a major complication of endoscopic sinus surgery that may lead to recurrence of chronic rhinosinusitis, necessitating revision surgery. The purpose of this study was to evaluate the effect of hyaluronic acid and hydroxyethyl starch (HA-HES) relative to hyaluronic acid and carboxymethylcellulose (HA-CMC) with regard to anti-adhesion effect. In this multi-center, prospective, single-blind, randomized controlled study, 77 consecutive patients who underwent bilateral endoscopic sinus surgery were enrolled between March 2014 and March 2015. HA-HES and HA-CMC were applied to randomly assigned ethmoidectomized cavities after the removal of middle meatal packing. At the 1st, 2nd and 4th weeks after surgery, the presence and grades of adhesion, edema, and infection were, respectively, examined via endoscopy by a blinded assessor. The incidence and grades of adhesion at the 2-week follow-up were significantly less in the HA-CMC group than in the HA-HES group (p < 0.05). However, with the exception of week 2, there were no significant differences in the incidence or grades of adhesion, edema, and infection between the two groups. When the primary endpoint-the presence of adhesion at the 4-week follow-up-was compared between two groups, the incidence of adhesion in HA-HES group at the 4-week follow-up was 32% and in HA-CMC was 41.3%, indicating that HA-HES was not inferior to HA-CMC in terms of anti-adhesive effect. No severe adverse reactions were noted during the study period. In conclusion, HA-HES is a safe substitutional anti-adhesion agent that has equivalent effect as HA-CMC after endoscopic sinus surgery.

Genetic and clinical variables identify predictors for chronic kidney disease in type 2 diabetes.

Type 2 diabetes and chronic kidney disease (CKD) may share common risk factors. Here we used a 3-stage procedure to discover novel predictors of CKD by repeatedly applying a stepwise selection based on the Akaike information criterion to subsamples of a prospective complete-case cohort of 2755 patients. This cohort encompassed 25 clinical variables and 36 genetic variants associated with type 2 diabetes, obesity, or fasting plasma glucose. We compared the performance of the clinical, genetic, and clinico-genomic models and used net reclassification improvement to evaluate the impact of top selected genetic variants to the clinico-genomic model. Associations of selected genetic variants with CKD were validated in 2 independent cohorts followed by meta-analyses. Among the top 6 single-nucleotide polymorphisms selected from clinico-genomic data, three (rs478333 of G6PC2, rs7754840 and rs7756992 of CDKAL1) contributed toward the improvement of prediction performance. The variant rs478333 was associated with rapid decline (over 4% per year) in estimated glomerular filtration rate. In a meta-analysis of 2 replication cohorts, the variants rs478333 and rs7754840 showed significant associations with CKD after adjustment for conventional risk factors. Thus, this novel 3-stage approach to a clinico-genomic data set identified 3 novel genetic predictors of CKD in type 2 diabetes. This method can be applied to similar data sets containing clinical and genetic variables to select predictors for clinical outcomes.

Diesel Exhaust Particles Enhance MUC4 Expression in NCI-H292 Cells and Nasal Epithelial Cells via the p38/CREB Pathway.

BACKGROUND: Diesel exhaust particles (DEPs), the major contributors to air pollution, induce inflammatory responses in the nasal epithelium. Overproduction of airway mucins is an important pathogenic finding in inflammatory airway diseases. OBJECTIVE: The aims of the present study were to determine the effect of DEPs on the expression of the mucin gene MUC4 and to investigate the underlying mechanism of DEP-induced MUC4 expression in NCI-H292 cells and primary nasal epithelial cells (PNECs). METHODS: NCI-H292 cells were stimulated for 24 h with DEPs. Messenger RNA (mRNA) and protein expression of MUC4 was determined by real-time reverse transcription (RT) polymerase chain reaction (PCR) and Western blotting. NCI-H292 cells were exposed to 3 mitogen-activated protein kinase inhibitors (U0126, SB203580, and SP600125) and a CREB (cAMP response element-binding protein) inhibitor prior to stimulation with DEPs, and MUC4 expression was examined by RT-PCR and Western blotting. PNECs were pretreated with a p38 inhibitor and CREB inhibitor prior to stimulation with DEPs, and MUC4 expression was then determined by RT-PCR and/or Western blotting. RESULTS: DEPs significantly increased the expression of MUC4 mRNA and protein. MUC4 mRNA and protein expression was inhibited by pretreatment with p38 and CREB inhibitors in NCI-H292 stimulated with DEPs. p38 and CREB inhibitors also blocked the expression of MUC4 mRNA and protein in DEP-stimulated PNECs. CONCLUSIONS: We demonstrated that DEPs stimulated the expression of MUC4 via the p38/CREB pathway in NCI-H292 cells and PNECs. The results of the present study pave the way for further studies on the role of MUC4 in DEP-induced hypersecretion in airway epithelium.

Additive effects of blood glucose lowering drugs, statins and renin-angiotensin system blockers on all-site cancer risk in patients with type 2 diabetes.

BACKGROUND: Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways. We examined the joint associations of optimal glycemic control (HbA1c <7%), RAS inhibitors and HMGCR inhibitors on cancer incidence in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes, with or without a history of cancer or prior exposure to RAS or HMGCR inhibitors at baseline were observed between 1996 and 2005. All patients underwent a comprehensive assessment at baseline and were followed until the censored date at 2005 or their death. RESULTS: After a median follow-up period of 4.91 years (interquartile range, 2.81 to 6.98), 271 out of 6,103 patients developed all-site cancer. At baseline, patients with incident cancers were older, had longer disease duration of diabetes, higher alcohol and tobacco use, and higher systolic blood pressure and albuminuria, but lower triglyceride levels and estimated glomerular filtration rate (P <0.05). Patients who developed cancers during follow-up were less likely to have started using statins (22.5% versus 38.6%, P <0.001), fibrates (5.9% versus 10.2%, P = 0.02), metformin (63.8% versus 74.5%, P <0.001) or thiazolidinedione (0.7% versus 6.8%, P <0.001) than those who remained cancer-free. After adjusting for co-variables, new treatment with metformin (hazard ratio: 0.39; 95% confidence interval: 0.25, 0.61; P <0.001), thiazolidinedione (0.18; 0.04, 0.72; P = 0.015), sulphonylurea (0.44; 0.27, 0.73; P = 0.014), insulin (0.58; 0.38, 0.89; P = 0.01), statins (0.47; 0.31, 0.70; P <0.001) and RAS inhibitors (0.55; 0.39, 0.78; P <0.001) were associated with reduced cancer risk. Patients with all three risk factors of HbA1c ≥7%, non-use of RAS inhibitors and non-use of statins had four-fold adjusted higher risk of cancer than those without any risk factors (incidence per 1,000-person-years for no risk factors: 3.40 (0.07, 6.72); one risk factor: 6.34 (4.19, 8.50); two risk factors: 8.40 (6.60, 10.20); three risk factors: 13.08 (9.82, 16.34); P <0.001). CONCLUSIONS: Hyperglycemia may promote cancer growth that can be attenuated by optimal glycemic control and inhibition of the RAS and HMGCR pathways.

Epigallocatechin-3-gallate inhibits collagen production of nasal polyp-derived fibroblasts.

Nasal polyps are chronic inflammatory conditions characterized by myofibroblast differentiation and extracelluar matrix accumulation. The major catechin from green tea is (-)-epigallocatechin-3-gallate (EGCG), which has garnered attention for its potential to prevent oxidative stress-related diseases. The purpose of this study was twofold: (i) to determine the effect of EGCG on fibroblast differentiation into myofibroblasts and extracellular matrix accumulation in transforming growth factor (TGF)-ß1-induced nasal polyp-derived fibroblasts (NPDFs) and (ii) to determine if the antioxidative effect of EGCG on reactive oxygen species (ROS) production in TGF-ß1-induced NPDFs is involved in the aforementioned processes. TGF-ß1-induced NPDFs were treated with or without EGCG. α-smooth muscle actin (α-SMA) and collagen type I mRNA were analyzed by reverse transcription-polymerase chain reaction. α-SMA protein was also detected using immunofluorescent staining. The amount of total soluble collagen was analyzed by Sircol collagen assay. ROS activity was measured by the nitroblue tetrazolium reduction assay and visualized by fluorescent microscopy. EGCG significantly inhibited expressions of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels at concentrations of 10-20 µg/mL. EGCG also inhibited TGF-ß1-induced ROS production at the same concentrations. These results suggest the possibility that EGCG may be effective at inhibiting the development of nasal polyps through an anti-oxidant effect.

A comparative reliability and performance study of different stent designs in terms of mechanical properties: foreshortening, recoil, radial force, and flexibility.

This study seeks to improve the mechanical performance of stents by conducting reliability performance testing and finite element method (FEM)-based simulations for coronary stents. Three commercially available stent designs and our own new design were tested to measure the factors affecting performance, specifically foreshortening, recoil, radial force, and flexibility. The stents used in the present experiments were 3 mm in working diameter and 18 mm of working length. The results of the experiments indicate that the foreshortening of stents A, B, C, and our new design, D, was equivalent to 2.25, 0.67, 0.46, and 0.41%, respectively. The recoil of stents A, B, C, and D was 6.00, 4.35, 3.50, and 4.36%, respectively. Parallel plate radial force measurements were A, 3.72 ± 0.28 N; B, 3.81 ± 0.32 N; C, 4.35 ± 0.18 N; and D, 4.02 ± 0.24 N. Radial forces determined by applying uniform pressure in the circumferential direction were A, 28.749 ± 0.81 N; B, 32.231 ± 1.80 N; C, 34.522 ± 3.06 N; and D, 42.183 ± 2.84 N. The maximum force of crimped stent at 2.2-mm deflection was 1.01 ± 0.08 N, 0.82 ± 0.08 N, 0.92 ± 0.12 N, and 0.68 ± 0.07 N for each of stents A, B, C and D. The results of this study enabled us to identify several factors to enhance the performance of stents. In comparing these stents, we found that our design, stent D, which was designed by a collaborative team from seven universities, performed better than the commercial stents across all parameter of foreshortening, recoil, radial force, and flexibility.