Roux-en-Y and One-Anastomosis Gastric Bypass Surgery Are Superior to Sleeve Gastrectomy in Lowering Glucose and Cholesterol Levels Independent of Weight Loss: a Propensity-Score Weighting Analysis.

BACKGROUND: The superior effects of gastric bypass surgery in preventing cardiovascular diseases compared with sleeve gastrectomy are well-established. However, whether these effects are independent of weight loss is not known. METHODS: In this retrospective cohort study, we compared the change in cardiometabolic risks of 1073 diabetic patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 265), one-anastomosis gastric bypass (OAGB) (n = 619), and sleeve gastrectomy (SG) (n = 189) with equivalent weight loss from the Min-Shen General Hospital. Propensity score-weighting, multivariate regression, and matching were performed to adjust for baseline differences. RESULTS: After 12 months, OAGB and, to a lesser extent, RYGB exhibited superior effects on glycemic control compared with SG in patients with equivalent weight loss. The effect was significant in patients with mild-to-modest BMI reduction but diminished in patients with severe BMI reduction. RYGB and OAGB had significantly greater effects in lowering total and low-density lipoprotein cholesterol than SG, regardless of weight loss. The results of matching patients with equivalent weight loss yielded similar results. The longer length of bypassed biliopancreatic (BP) limbs was correlated with a greater decrease in glycemic levels, insulin resistance index, lipids, C-reactive protein (CRP) levels, and creatinine levels in patients receiving RYBG. It was correlated with greater decreases in BMI, fasting insulin, insulin resistance index, and C-reactive protein levels in patients receiving OAGB. CONCLUSION: Diabetic patients receiving OAGB and RYGB had lower glucose and cholesterol levels compared with SG independent of weight loss. Our results suggest diabetic patients with cardiovascular risk factors such as hypercholesterolemia to receive bypass surgery.

Genome-Wide Association Studies for Albuminuria of Nondiabetic Taiwanese Population.

INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.

Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice.

Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium-glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin-angiotensin-aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.

Hemoglobin glycation index predicts renal function deterioration in patients with type 2 diabetes and a low risk of chronic kidney disease.

AIMS: Hemoglobin glycation index (HGI) is used to describe the difference between estimated and measured glycated hemoglobin (HbA1c). We aimed to study whether HGI can predict renal function deterioration in patients with type 2 diabetes and a low risk of chronic kidney disease (CKD). METHODS: This retrospective cohort study enrolled 780 patients with type 2 diabetes and a low CKD risk according to the criteria of kidney disease: improving global outcomes. Participants were divided into two subgroups according to the baseline HGI calculated by fasting blood glucose and HbA1c. Multivariate Cox proportional hazard models were used to evaluate the hazard ratios of the study endpoints. Longitudinal data was analyzed using generalized estimating equation (GEE). RESULTS: The participants were followed for a median of 7.3 years. A high HGI predicted rapid renal function decline without or with a resultant eGFR < 60 ml/min/1.73 m2, but not onset of macroalbuminuria. The longitudinal GEE model demonstrated a negative association between HGI and the predicted eGFR changes in both the 1-year and 3-year intervals. CONCLUSIONS: HGI independently predicted renal function deterioration in patients with type 2 diabetes and a low CKD risk. Further investigations are warranted to elucidate its potential clinical impact.

Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Modulates Metastatic Properties in Non-Small-Cell Lung Cancer Cells.

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.

Identification of Novel Biomarkers for Pre-diabetic Diagnosis Using a Combinational Approach.

Reliable protein markers for pre-diabetes in humans are not clinically available. In order to identify novel and reliable protein markers for pre-diabetes in humans, healthy volunteers and patients diagnosed with pre-diabetes and stroke were recruited for blood collection. Blood samples were collected from healthy and pre-diabetic subjects 12 h after fasting. BMI was calculated from body weight and height. Fasting blood glucose (FBG), glycated hemoglobin (HbA1C), triglyceride (TG), total cholesterol, high-density lipoprotein, low-density lipoprotein (LDL), insulin and albumin were assayed by automated clinical laboratory methods. We used a quantitative proteomics approach to identify 1074 proteins from the sera of pre-diabetic and healthy subjects. Among them, 500 proteins were then selected using Mascot analysis scores. Further, 70 out of 500 proteins were selected via volcano plot analysis according to their statistical significance and average relative protein ratio. Eventually, 7 serum proteins were singled out as candidate markers for pre-diabetes due to their diabetic relevance and statistical significance. Immunoblotting data demonstrated that laminin subunit alpha 2 (LAMA2), mixed-lineage leukemia 4 (MLL4), and plexin domain containing 2 (PLXDC2) were expressed in pre-diabetic patients but not healthy volunteers. Receiver operating characteristic curve analysis indicated that the combination of the three proteins has greater diagnostic efficacy than any individual protein. Thus, LAMA2, MLL4 and PLXDC2 are novel and reliable serum protein markers for pre-diabetic diagnosis in humans.

Fibroblast Growth Factor Receptor Inhibitors Reduce Adipogenesis of Orbital Fibroblasts and Enhance Myofibroblastic Differentiation in Graves' Orbitopathy.

Purpose: Orbital fibroblasts are involved in pathogenesis of Graves' orbitopathy (GO). Fibroblast growth factor (FGF) affects fibroblasts of GO. This study aims to investigate the roles of FGF and FGF receptor (FGFR) in GO.Methods: Serum FGF proteins and orbital fibroblast FGFR proteins and mRNAs were measured in GO patients and controls. Orbital fibroblasts of GO were cultured and accessed for changes in proliferation (by nuclei number and MTT), myofibroblastic differentiation (by α-SMA), and adipogenesis (by oil droplets using Oil Red O stain) under FGF1 with or without FGFR inhibitors (FGFRi).Results: Serum FGF1 and FGF2 were increased in GO patients. FGFR1 was the most abundantly expressed FGFR in GO orbital fibroblasts. FGF1 increased GO fibroblast proliferation/adipogenesis and suppressed myofibroblastic differentiation, while FGFRi reversed these effects.Conclusion: FGF signaling may be involved in GO pathogenesis. Manipulation of FGF-FGFR pathway for GO treatment is worthy of further investigation.Registration number on Clinicaltrials.gov: NCT03324022.

The Effects of Bariatric Surgery on Renal, Neurological, and Ophthalmic Complications in Patients with Type 2 Diabetes: the Taiwan Diabesity Study.

BACKGROUND: Bariatric surgery has been shown to improve glycemic control in patients with type 2 diabetes. However, less is known whether it can also reduce diabetic renal, neurological, and ophthalmic complications. METHODS: This prospective multicenter cohort study compared renal, ophthalmic, and neurological complications between 49 patients with obesity/overweight receiving bariatric surgery and 338 patients receiving standard medical treatment after follow-up for 2 years. Patients received neurological examinations including toe tuning fork vibration test, ankle tendon reflex test, 10-g monofilament test, and ophthalmic examinations including visual acuity measurement and fundus examinations. Multiple regressions, propensity score weighting, and matching were employed to adjust for baseline differences. RESULTS: After 2 years of follow-up, patients with type 2 diabetes receiving bariatric surgery had greater reduction in BMI, HbA1c, and urine albumin-creatinine ratio, greater improvement in estimated glomerular filtration rate, and greater increase in tuning fork test score of right and left toes compared with the medical group. However, there is no improvement in 10 g-monofilament test, visual acuity, diabetic non-proliferative retinopathy, and proliferative retinopathy. Similar results were obtained using multiple regression adjustment, propensity-score weighting, or comparing age-, sex-, and BMI-matched subjects. CONCLUSIONS: After 2-year follow-up, patients with obesity/overweight and type 2 diabetes receiving bariatric surgery have increased glomerular filtration rate, reduced albuminuria, and improved tuning folk vibration sensation.

Outcomes after surgery in patients with diabetes who used metformin: a retrospective cohort study based on a real-world database.

INTRODUCTION: Limited information was available regarding the perioperative outcomes in patients with and without use of metformin. This study aims to evaluate the complications and mortality after major surgery in patients with diabetes who use metformin. RESEARCH DESIGN AND METHODS: Using a real-world database of Taiwan's National Health Insurance from 2008 to 2013, we conducted a matched cohort study of 91 356 patients with diabetes aged >20 years who used metformin and later underwent major surgery. Using a propensity score-matching technique adjusted for sociodemographic characteristics, medical condition, surgery type, and anesthesia type, 91 356 controls who underwent surgery but did not use metformin were selected. Logistic regression was used to calculate the ORs with 95% CIs for postoperative complications and 30-day mortality associated with metformin use. RESULTS: Patients who used metformin had a lower risk of postoperative septicemia (OR 0.94, 95% CI 0.90 to 0.98), acute renal failure (OR 0.87, 95% CI 0.79 to 0.96), and 30-day mortality (OR 0.79, 95% CI 0.71 to 0.88) compared with patients who did not use metformin, in both sexes and in every age group. Metformin users who underwent surgery also had a decreased risk of postoperative intensive care unit admission (OR 0.60, 95% CI 0.59 to 0.62) and lower medical expenditures (p<0.0001) than non-use controls. CONCLUSIONS: Among patients with diabetes, those who used metformin and underwent major surgery had a lower risk of complications and mortality compared with non-users. Further randomized clinical trials are needed to show direct evidence of how metformin improves perioperative outcomes.

Naa10p Inhibits Beige Adipocyte-Mediated Thermogenesis through N-α-acetylation of Pgc1α.

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.

Adverse Outcomes after Major Surgeries in Patients with Diabetes: A Multicenter Matched Study.

The impact of diabetes on perioperative outcomes remains incompletely understood. Our purpose is to evaluate post-operative complications and mortality in patients with diabetes. Using the institutional and clinical databases of three university hospitals from 2009⁻2015, we conducted a matched study of 16,539 diabetes patients, aged >20 years, who underwent major surgery. Using a propensity score matching procedure, 16,539 surgical patients without diabetes who underwent surgery were also selected. Logistic regressions were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for post-operative complications and in-hospital mortality associated with diabetes. Patients with diabetes had a higher risk of postoperative septicemia (OR 1.33, 95% CI 1.01⁻1.74), necrotizing fasciitis (OR 3.98, 95% CI 1.12⁻14.2), cellulitis (OR 2.10, 95% CI 1.46⁻3.03), acute pyelonephritis (OR 1.86, 95% CI 1.01⁻3.41), infectious arthritis (OR 3.89, 95% CI 1.19⁻12.7), and in-hospital mortality (OR 1.51, 95% CI 1.07⁻2.13) compared to people without diabetes. Previous admission for diabetes (OR 2.33, 95% CI 1.85⁻2.93), HbA1c >8% (OR 1.96, 95% CI 1.64⁻2.33) and fasting glucose >180 mg/dL (OR 1.90, 95% CI 1.68⁻2.16) were predictors for post-operative adverse events. Diabetes patients who underwent surgery had higher risks of infectious complications and in-hospital mortality compared with patients without diabetes who underwent similar major surgeries.

Sleep Duration and Proteinuria Progression: A Population-Based Cohort Study.

BACKGROUND: Extensive studies have demonstrated that sleep is an important modulator of cardiovascular and metabolic diseases. However, its impact on renal function remains uncertain. METHODS: A total of 26,249 adults aged ≥20 years were recruited through voluntary health examinations in Taiwan. Sleep duration was self-reported by questionnaire. Proteinuria was graded semi-quantitatively by dipstick urine test. The associations of sleep duration with proteinuria and estimated glomerular filtration rate (eGFR) were analyzed. RESULTS: After an average follow-up period of 2.62 years, the crude hazard ratio (HR) for proteinuria progression were 1.92 (95% CI 1.22-3.03), 1.23 (95% CI 1.09-1.39), and 1.18 (95% CI 1.00-1.39) for those with sleep duration < 4, 4-6, and > 8 h compared to those with sleep duration of 6-8 h (the reference group), respectively. The HR remained significant for those with sleep duration < 4 h (adjusted HR 1.65 [95% CI 1.05-2.61]) and 4-6 h (adjusted HR 1.19 [95% CI 1.06-1.35]) after adjustment for age, sex, blood pressure, fasting glucose, body mass index, cholesterols, triglycerides, uric acids, physical activity, smoking, alcohol consumption, income/educational levels, and baseline eGFR. However, eGFR was not significantly different among different sleep duration groups. DISCUSSION: This result indicates short sleep duration is independently associated with the progression of proteinuria.

Study design and recruitment for a prospective controlled study of diabesity: Taiwan Diabesity Study.

BACKGROUND: Strong evidence has shown that metabolic surgery is more effective than medical treatment in the treatment of type 2 diabetic patients. However, no study demonstrated a survival benefit and reduction of diabetes-related end-organ damage. Here, we describe the study design of a large prospective cohort study, the Taiwan Diabesity Study (TDS) which would compare the long-term survival rate and end-organ damage between overweight/obese type 2 diabetic patients receiving metabolic surgery and medical treatment. METHODS: Eligibility criteria include type 2 diabetic patients with duration > 6 months, body mass index (BMI) over 25 kg/m2 and age between 20 and 67 years. Exclusion criteria are serum creatinine over 2.0 mg/dL, C-peptide below 1.0 ng/ml, recent history of cancer, and major diabetic complications. Eligible participants were recruited from six medical centers in Taiwan. The survival rate and diabetes-related end organ damage will be compared between the metabolic surgery group and medical group after follow-up for 10 years. RESULTS: In 3 years, 1016 participants were identified from 38,751 patients. The average BMI of patients was 30.6 (±2.6) kg/m2 and the average hemoglobin A1c was 8.2% (±1.5%) with 18% of them receiving insulin treatment. Among them, 126 patients received metabolic surgery and 890 patients received conventional medical treatment. The metabolic surgery group are younger, have a higher proportion of females, higher BMI and blood lipids as compared to the medical group. CONCLUSION: The TDS recruited 1016 overweight/obese type 2 diabetic patients including 126 patients receiving metabolic surgery and 890 patients receiving medical treatment.

Pro-inflammatory cytokines IL-6 and CCL2 suppress expression of circadian gene Period2 in mammary epithelial cells.

Chronic inflammation is known to contribute to tumor initiation and cancer progression. In breast tissue, the core circadian gene Period (PER)2 plays a critical role in mammary gland development and possesses tumor suppressor function. Interleukin (IL)-6 and C-C motif chemokine ligand (CCL) 2 are among the most abundant cytokines in the inflammatory microenvironment. We found that acute stimulation by IL-6/CCL2 reduced PER2 expression in non-tumorigenic breast epithelial cells. Longer term exposure to IL-6/CCL2 suppressed PER2 to an even lower level. IL-6 activated STAT3/NFκB p50 signaling to recruit HDAC1 to the PER2 promoter. CCL2 activated the PI3K/AKT pathway to promote ELK-1 cytoplasm-to-nucleus translocation, recruit HDAC1 to the proximal PER2 promoter and facilitate DNMT3-EZH2-PER2 promoter association. Ectopic expression of PER2 inhibited IL-6 or CCL2 induced mammosphere forming ability and reduced sphere size indicating that PER2 repression in breast epithelial cells can be crucial to activate tumorigenesis in an inflammatory microenvironment. The diminished expression of PER2 can be observed over a time scale of hours to weeks following IL-6/CCL2 stimulation suggesting that PER2 suppression occurs in the early stage of the interaction between an inflammatory microenvironment and normal breast epithelial cells. These data show new mechanisms by which mammary cells interact with a cancerous microenvironment and provide additional evidence that PER2 expression contributes to breast tumorigenesis.

Asymmetric distribution of hypoxia-inducible factor α regulates dorsoventral axis establishment in the early sea urchin embryo.

Hypoxia signaling is an ancient pathway by which animals can respond to low oxygen. Malfunction of this pathway disturbs hypoxic acclimation and can result in various diseases, including cancers. The role of hypoxia signaling in early embryogenesis remains unclear. Here, we show that in the blastula of the sea urchin Strongylocentrotus purpuratus, hypoxia-inducible factor α (HIFα), the downstream transcription factor of the hypoxia pathway, is localized and transcriptionally active on the future dorsal side. This asymmetric distribution is attributable to its oxygen-sensing ability. Manipulations of the HIFα level entrained the dorsoventral axis, as the side with the higher level of HIFα tends to develop into the dorsal side. Gene expression analyses revealed that HIFα restricts the expression of nodal to the ventral side and activates several genes encoding transcription factors on the dorsal side. We also observed that intrinsic hypoxic signals in the early embryos formed a gradient, which was disrupted under hypoxic conditions. Our results reveal an unprecedented role of the hypoxia pathway in animal development.

Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation.

Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.

Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2.

Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.

Early Myocardial Repolarization Heterogeneity Is Detected by Magnetocardiography in Diabetic Patients with Cardiovascular Risk Factors.

Multi-channel magnetocardiography (MCG) is a sensitive technique to map spatial ventricular repolarization with high resolution and reproducibility. Spatial ventricular repolarization heterogeneity measured by MCG has been shown to accurately detect and localize myocardial ischemia. Here, we explored whether these measurements correlated with cardiovascular risk factors in patients with type 2 diabetes. Two hundreds and seventy-seven type 2 diabetic patients without known coronary artery disease (CAD) and arrhythmia were recruited consecutively from the outpatient clinic of National Taiwan University Hospital. The spatially distributed QTc contour maps were constructed with 64-channel MCG using the superconducting quantum interference device (SQUID) system. Indices of myocardial repolarization heterogeneity including the smoothness index of QTc (SI-QTc) and QTc dispersion were derived and analyzed for association with conventional cardiovascular risk factors. SI-QTc correlated strongly with the QTc dispersion (r = 0.70, p <0.0001). SI-QTc was significantly higher in patients with presence of metabolic syndrome in comparison to those without metabolic syndrome (8.56 vs. 7.96 ms, p = 0.02). In univariate correlation analyses, QTc dispersion was associated with smoking status (average 79.90, 83.83, 86.51, and 86.00 ms for never smokers, ex-smokers, current smokers reporting less than 10 cigarettes daily, and current smoker reporting more than 10 cigarettes daily, respectively, p = 0.03), body weight (r = 0.15, p = 0.01), and hemoglobin A1c (r = 0.12, p = 0.04). In stepwise multivariate regression analyses, QTc dispersion was associated with smoking (p = 0.02), body weight (p = 0.04), total cholesterol levels (p = 0.05), and possibly estimated glomerular filtration rate (p = 0.07). In summary, spatial heterogeneity of myocardial repolarization measured by MCG is positively associated cardiovascular risk factors including adiposity, smoking, and total cholesterol levels.

Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis.

OBJECTIVE: To obtain a pooled risk estimate on the long-term impact of anaemia and related nutritional deficiencies in patients receiving Roux-en-Y gastric bypass (RYGB) surgery. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE and Cochrane databases were searched to identify English reports published before 16 May 2014. ELIGIBILITY CRITERIA: Articles with case numbers >100, follow-up period >12 months, and complete data from both before and after surgery were selected. Outcomes of interest were changes in baseline measurements of proportion of patients with anaemia, by haemoglobin, haematocrit, ferritin, iron, vitamin B12 and folate levels. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed data and selected six prospective and nine retrospective studies with a total of 5909 patients. A random effect model with inverse variance weighting was used to calculate summary estimates of outcomes at 6, 12, 24 and 36 months postoperatively. RESULTS: Proportion of patients with anaemia was 12.2% at baseline, which, respectively, increased to 20.9% and 25.9% at 12 and 24 months follow-up, consistent with decreases in haemoglobin and haematocrit levels. Although the serum iron level did not change substantially after surgery, the frequency of patients with ferritin deficiency increased from 7.9% at baseline to 13.4% and 23.0% at 12 and 24 months, respectively, postoperation. Vitamin B12 deficiency increased from 2.3% at baseline to 6.5% at 12 months after surgery in those subjects receiving RYGB. There was no obvious increase in folate deficiency. CONCLUSIONS: RYGB surgery is associated with an increased risk of anaemia and deficiencies of iron and vitamin B12, but not folate. Ferritin is more sensitive when serum iron level is within normal range.