Family history of diabetes and the risk of subclinical atherosclerosis.

AIM: This study investigated the influence of a family history of diabetes on the risk of subclinical coronary atherosclerosis according to coronary computed tomography angiography (CCTA) in asymptomatic individuals. METHODS: A total of 6434 consecutive asymptomatic individuals with no prior history of coronary artery disease voluntarily underwent CCTA evaluation as part of a general health examination. Coronary atherosclerotic plaque and significant coronary artery stenosis (degree of stenosis ≥50%) on CCTA were assessed. Logistic regression analysis was used to determine the association between a family history of diabetes and atherosclerotic plaque or significant coronary artery stenosis according to the degree of diabetes (normal, prediabetic and diabetic). RESULTS: Mean age of study participants was 53.7±7.6 years, and 4694 (73.0%) were male. A total of 1593 (24.8%) participants had a family history of diabetes in a first-degree relative. Among the study participants, 1115 (17.3%), 3122 (48.5%) and 2197 (34.1%) were categorized as diabetic, prediabetic and normal, respectively. In diabetic participants, after stepwise adjustments for clinical and laboratory variables, a family history of diabetes was significantly associated with non-calcified plaque (P<0.05 for all), but did not appear to be associated with either calcified or mixed plaques or with significant coronary artery stenosis (P>0.05 for all). In prediabetic and normal participants, a family history of diabetes was not associated with either atherosclerotic plaque or significant coronary artery stenosis (P>0.05 for all). CONCLUSION: In asymptomatic diabetic individuals, a family history of diabetes is consistently associated with non-calcified coronary plaque after adjusting for risk factors.

An open-label, rater-blinded, 8-week trial of bupropion hydrochloride extended-release in patients with major depressive disorder with atypical features.

The present study aimed at investigating the effectiveness and tolerability of -bupropion hydrochloride extended release (XL) in major depressive disorder (MDD) patients with atypical features (AF).51 patients were prescribed bupropion XL for 8 weeks (6 visits: screening, baseline, weeks 1, 2, 4 and 8). The primary efficacy measure was a change of the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) from baseline to endpoint. Secondary efficacy measures included the SIGH-SAD atypical symptoms subscale, Clinical Global Impression-Severity (CGI-S), Sheehan Disability Scale (SDS) and Epworth Sleepiness Questionnaire (ESQ). Response or remission was defined as ≥50% reduction or ≤7 in SIGH-SAD total scores, respectively, at end of treatment.The HAM-D-29 total score reduced by 55.3% from baseline (27.3±6.5) to end of treatment (12.2±6.3) (p<0.001). Atypical symptom subscale scores also reduced by 54.5% from baseline (9.2±3.0) to end of treatment (4.2±2.8) (p<0.001). At the end of treatment, 24.4% (n=10) and 51.2% (n=21) subjects were classified as remitters and responders, respectively. The most frequently reported AEs were headache (13.7%), dry mouth (11.8%), dizziness (9.8%), and dyspepsia (9.8%).Our preliminary study indicates that bupropion XL may be beneficial in the treatment of MDD with atypical features. Adequately powered, randomized, double-blind, placebo-controlled trials are necessary to determine our results.

Hippocampal shape deformation in female patients with unremitting major depressive disorder.

BACKGROUND AND PURPOSE: The hippocampal atrophy of MDD has been known, but the region shape contractions of the hippocampus in MDD were inconsistent. Spheric harmonic shape analysis was applied to the hippocampus in female patients with unremitting MDD to evaluate morphometric changes of the hippocampus. MATERIALS AND METHODS: Shape analysis was performed by using T1-weighted MR imaging in 21 female patients with MDD and 21 age- and sex-matched healthy controls. Manually segmented hippocampi were parameterized, and the point-to-point-based group difference was compared by using the Hotelling T-squared test. The partial correlation analyses were tested between clinical variables and shape changes. RESULTS: Both hippocampal volumes were small in patients with MDD compared with healthy controls, and the right hippocampal volume was negatively correlated with the number of episodes at marginal significance. Regional shape contractions were found in the ambient gyrus, basal hippocampal head, posterior subiculum, and dorsal hippocampus of the left hemisphere. The right hippocampus showed a similar pattern but was less atrophic compared with the left hippocampus. A negative correlation was found between the HDRS and shape deformation in the CA3, ambient gyrus, posterior subiculum, and gyrus fasciolaris of the left hippocampus. CONCLUSIONS: We showed atrophy and regional shape contractions in the hippocampi of patients with MDD, which were more dominant on the left side. The causes of hippocampal damage could be the hypersecretion of glucocorticoids contributing to neuronal death or the failing of adult neurogenesis in the dentate gyrus.

Progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody.

AIMS: To investigate the rate of progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody (GADA) and to determine the factors related to progression to insulin deficiency. METHODS: We retrospectively analysed data on 87 GADA-positive and 87 age- and sex-matched GADA-negative patients with Type 2 diabetes. GADA-positive patients were further subclassified into high-titre (≥ 250 WHO units/ml) (n = 24) and low-titre (< 250 WHO units/ml) (n = 63) subgroups. Cox proportional hazard analysis was used to identify factors associated with progression to insulin deficiency. RESULTS: Over a period of 6 years, two of 87 (2.3%) GADA-negative and 37 of 87 (42.5%) GADA-positive patients had progressed to insulin deficiency. The rate of progression to insulin deficiency was higher in the high-titre than in the low-titre subgroup (75.0 vs. 30.2%). Multivariate analysis in GADA-positive patients showed that high-titre GADA and low BMI at diagnosis were independent factors significantly related to progression to insulin deficiency. CONCLUSIONS: The presence of GADA predicted the progression to insulin deficiency in Korean patients with Type 2 diabetes. In GADA-positive patients, high-titre GADA and low BMI were associated with this progression.

Association of restrictive ventilatory dysfunction with insulin resistance and type 2 diabetes in koreans.

AIMS: To investigate associations of obstructive and restrictive patterns of ventilatory dysfunction with insulin resistance and type 2 diabetes mellitus (DM) in Koreans. METHODS: We cross-sectionally examined clinical, laboratory, and pulmonary function data on 35,456 Korean adults (age 18-93 years, 40% women) recorded during regular health check-ups. Insulin resistance (IR) was determined from fasting serum insulin concentration and homeostasis model assessment (HOMA). RESULTS: Individuals with type 2 DM and those with pre-diabetes (impaired fasting glucose levels) showed a higher prevalence of both restrictive (18% and 11%, respectively, VS. 8%; P<0.01) and obstructive (4.3% and 3.2%, respectively, VS. 2.3%; P<0.01) ventilatory dysfunction than did individuals with normal fasting glucose levels. Compared to subjects with normal ventilatory function, those with restrictive or obstructive ventilatory dysfunction were older, had higher systolic and diastolic blood pressure, and had elevated glucose and HbA1c levels. However, serum triglyceride, fasting insulin, and HOMA-IR were higher only in subjects with restrictive ventilatory dysfunction, and not in those with obstructive ventilatory dysfunction. On logistic regression analysis, the age and gender-adjusted odds ratio (OR) of restrictive ventilatory dysfunction for type 2 DM was 1.59 (95% confidence interval, 1.43-1.78). The increased OR remained significant after controlling for exercise, drinking, and smoking habits, presence of hypertension, body mass index, and waist circumference (OR=1.38 [1.23-1.55]). However, further adjustment for HOMA-IR attenuated the OR (1.11 [0.97-1.26]), making the OR statistically insignificant. In contrast, obstructive ventilatory dysfunction was not independently related to type 2 DM status. CONCLUSION: Restrictive ventilatory dysfunction is independently associated with type 2 DM, probably VIA insulin resistance.

Validation of limited lymphadenectomy for lower-third gastric cancer based on depth of tumour invasion.

BACKGROUND: This study aimed to determine the appropriate extent of lymph node (LN) dissection in gastric cancer by analysing LN metastasis patterns from prospectively collected topographical data on nodal status at Seoul National University Hospital, Korea. METHODS: The metastasis rate for each LN station was analysed according to the depth of tumour invasion in patients with primary lower-third gastric cancer who underwent curative gastrectomy. The Maruyama Index of unresected disease (MI) was calculated using the WinEstimate(®) program with simulation of various extents of LN dissection. RESULTS: LN metastasis in mucosal cancer was rare; 2·6 per cent of patients had a MI of more than 5 with simulation of D1 plus station 7 dissection, whereas 0·9 per cent had a MI above 5 with D1 plus stations 7 and 8a. In submucosal cancer, 3·3 per cent of tumours metastasized to level 2 LN stations outside the range of D1 plus stations 7, 8a and 9. The proportion of patients with a MI above 5 was 9·0 per cent with D1 plus stations 7, 8a and 9 dissection. The nodal metastasis rate was higher at level 1 and 2 for muscularis propria or deeper cancers. CONCLUSION: D1 dissection plus stations 7 and 8a for mucosal cancer, and D2 dissection for cancers of the muscularis propria or deeper seems appropriate. For submucosal cancer, an expanded dissection to the D2 level should be considered to ensure complete removal of metastatic LNs.

Changes in clinicopathological features and survival after gastrectomy for gastric cancer over a 20-year period.

BACKGROUND: The pattern of gastric cancer in the Western world is changing, with an increased proportion of tumours in the upper stomach. The aim of this study was to investigate changes in clinicopathological features and survival of patients with resected gastric cancer at a single institution, in an area of high incidence in the Far East. METHODS: Clinical features and pathological findings were compared in patients with gastric cancer who underwent gastrectomy at Seoul National University Hospital during four consecutive periods (1986-1990, 1991-1995, 1996-2000 and 2001-2006). RESULTS: There were 12 026 patients. The mean age increased from 53·4 years in the first period to 57·4 years in the last (P < 0·001). The proportion of patients aged 70 years or older also increased, reaching 16·1 per cent in the final period. Upper-third cancer increased from 5·3 per cent in the first period to 14·0 per cent in the fourth (P < 0·001). Early gastric cancer (pathological T1) increased continuously over the four time intervals, from 24·8 to 48·9 per cent (P < 0·001). The overall 5-year survival rate increased from 64·0 per cent in the first period to 73·2 per cent at the end (P < 0·001), and this survival improvement was apparent in patients aged 40 years or more. CONCLUSION: The mean age of patients with gastric cancer has increased during the past 20 years. The proportion of early gastric cancer and overall survival have gradually increased, especially in patients aged over 40 years.

Safety of extended endoscopic mucosal resection and endoscopic submucosal dissection following the Japanese Gastric Cancer Association treatment guidelines.

BACKGROUND: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are widely performed. Indications for these procedures have been extended in Korea and Japan. The aim was to evaluate whether these extended indications are safe. METHODS: All patients who had surgery for early gastric cancer at Seoul National University Bundang Hospital between May 2003 and December 2007 were identified from a prospective database. Lymph node status was examined in patients who met extended indications for EMR and had undergone surgical resection. RESULTS: Of patients with mucosal cancers, 129 met extended indications for EMR or ESD and three (2.3 per cent) had lymph node metastasis. Of the 52 submucosal cancers meeting extended indications for EMR or ESD, two (4 per cent) had lymph node metastasis. Differentiated mucosal cancers without ulcer formation did not have lymph node metastasis, irrespective of size. CONCLUSION: Extending the indications for EMR and ESD according to the Japanese Gastric Cancer Association guidelines carries an increased risk of lymph node metastasis. For cancers meeting these criteria, treatment by gastric resection with lymph node dissection should still be considered. A well differentiated mucosal cancer of any size without ulceration may be considered as an extended indication for EMR or ESD.

Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival.

The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III-IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282-0.791, P=0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III-IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.

Laparoscopic hepatectomy for a modified right graft in adult-to-adult living donor liver transplantation.

BACKGROUND: We performed a modified right hepatectomy completely by laparoscopic techniques preserving the middle hepatic vein (MHV) branches in adult-to-adult living donor liver transplantation (LDLT). PATIENTS AND METHODS: Two young women (24 and 25 years old) volunteered to be live donors for their parents who had hepatocellular carcinomas. As the donors expressed concerns about scarring, we performed a laparoscopic procedure using a hand port device. Mobilization of the right liver and the hepatic parenchymal transection were performed under pneumoperitoneum. Parenchymal transection was performed using a laparoscopic ultrasonic aspirator without the Pringle maneuver. During parenchymal transection, major MHV branches >5 mm were preserved using Hem-o-lock clips. The graft was extracted through the hand port site. On the back table, the 3 MHV branches were reconstructed using an artificial vascular graft. The livers were transplanted without complications. RESULTS: The operative times for the donors were 765 and 898 minutes. The donors did not require transfusions or reoperation; they were discharged on postoperative days 10 and 14 with normal liver functions. CONCLUSION: A hepatectomy performed completely by laparoscopic techniques for a right graft with preservation of the MHV branches was technically feasible.

Fatty liver is an independent risk factor for the development of Type 2 diabetes in Korean adults.

AIMS: To investigate whether fatty liver per se is an independent risk factor of incident type 2 diabetes mellitus (T2DM) in Koreans. METHODS: We examined the clinical and laboratory data of 5372 non-diabetic participants (3670 men and 1702 women; age 46.8 +/- 8.4 years, range 20-79 years) who underwent voluntary medical check-ups in 2000 and follow-up examinations in 2005. RESULTS: Two hundred and thirty-three participants (4.3%) developed T2DM after 5 years. Univariate analysis showed that the development of diabetes was associated with: male sex; family history of diabetes; smoking; older age; higher body mass index (BMI), systolic and diastolic blood pressure, fasting plasma glucose (FPG), hepatic enzymes, total cholesterol and triglycerides; lower HDL cholesterol; and the presence of fatty liver on ultrasonography at baseline. In multiple logistic regression models, after adjusting for age, sex and alcohol consumption, patients with fatty liver were at significantly higher risk of developing T2DM compared to those without fatty liver [relative risk (RR) 3.92, 95% confidence interval (CI) 2.89-5.31]. After further adjustment for smoking, BMI, triglycerides, HDL cholesterol, FPG, alanine aminotransferase and ultrasonographer, fatty liver remained significantly associated with the development of T2DM (RR 1.51, 95% CI 1.04-2.20). Patients with moderate to severe fatty liver had higher risk ratios than patients with mild fatty liver. Exclusion of frequent drinkers did not attenuate the association. CONCLUSIONS: Fatty liver on ultrasonography is associated with the development of T2DM, independently of classical risk factors, in Korean adults.

Change in prevalence and 6-year incidence of diabetes and impaired fasting glucose in Korean subjects living in a rural area.

AIMS: To determine the change in prevalence, incidence and risk factors associated with diabetes and impaired fasting glucose (IFG) in a rural Korean area. METHODS: Initially a total of 1119 subjects (424 men and 695 women) aged 31-99 years were recruited in 1997. Baseline clinical data and various laboratory values were obtained. Six years later, we visited the same area and measured similar parameters in 814 subjects (316 men and 498 women) of which 558 were original participants and 256 subjects were new. Incidence and risk factors of diabetes were analyzed in 518 subjects. Diabetes and IFG were defined according to American Diabetes Association criteria. RESULTS: Age- and sex-adjusted prevalence of diabetes in 1997 was 6.9%, increasing to 11.7% in 2003. The prevalence of IFG increased alarmingly from 21.9% in 1997 to 38.8% in 2003. The age- and sex-adjusted incidence rate of diabetes was 16.3 per 1000 person-years. Baseline fasting plasma glucose, 2h post-load glucose, abdominal circumference and urinary albumin excretion rate (UAER) acted as independent risk factors for diabetes in a multivariate logistic regression analysis. CONCLUSIONS: The prevalence of diabetes and IFG increased markedly from 1997 to 2003, indicating the need for urgent preventive measures. Fasting and 2h post-load glucose, abdominal circumference and UAER independently predicted the development of diabetes in this rural Korean population.

Brain activation by visual erotic stimuli in healthy middle aged males.

The objective of the present study was to identify brain centers, whose activity changes are related to erotic visual stimuli in healthy, heterosexual, middle aged males. Ten heterosexual, right-handed males with normal sexual function were entered into the present study (mean age 52 years, range 46-55). All potential subjects were screened over 1 h interview, and were encouraged to fill out questionnaires including the Brief Male Sexual Function Inventory. All subjects with a history of sexual arousal disorder or erectile dysfunction were excluded. We performed functional brain magnetic resonance imaging (fMRI) in male volunteers when an alternatively combined erotic and nonerotic film was played for 14 min and 9 s. The major areas of activation associated with sexual arousal to visual stimuli were occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, caudate nucleus. However, hypothalamus and thalamus were not activated. We suggest that the nonactivation of hypothalamus and thalamus in middle aged males may be responsible for the lesser physiological arousal in response to the erotic visual stimuli.

Liver-directed gene therapy of diabetic rats using an HVJ-E vector containing EBV plasmids expressing insulin and GLUT 2 transporter.

Insulin gene therapy in clinical medicine is currently hampered by the inability to regulate insulin secretion in a physiological manner, the inefficiency with which the gene is delivered, and the short duration of gene expression. To address these issues, we injected the liver of streptozotocin-induced diabetic rats with hemagglutinating virus of Japan-envelope (HVJ-E) vectors containing Epstein-Barr virus (EBV) plasmids encoding the genes for insulin and the GLUT 2 transporter. Efficient delivery of the genes was achieved with the HVJ-E vector, and the use of the EBV replicon vector led to prolonged hepatic gene expression. Blood glucose levels were normalized for at least 3 weeks as a result of the gene therapy. Cotransfection of GLUT 2 with insulin permitted the diabetic rats to regulate their blood glucose levels upon exogenous glucose loading in a physiologically appropriate manner and improved postprandial glucose levels. Moreover, cotransfection with insulin and GLUT 2 genes led to in vitro glucose-stimulated insulin secretion that involved the closure of K(ATP) channels. The present study represents a new way to efficiently deliver insulin gene in vivo that is regulated by ambient glucose level with prolonged gene expression. This may provide a basis to overcome limitations of insulin gene therapy in humans.

Sentinel node biopsy for cT1 and cT2a gastric cancer.

AIMS: To evaluate the feasibility and accuracy of sentinel node (SN) biopsy for gastric cancer. PATIENTS AND METHODS: One hundred patients with gastric cancer diagnosed as cT1 (n=80) or cT2a (n=20) were enrolled. Indocyanine green-stained SNs were analysed by hematoxylin and eosin staining (n=100) and by cytokeratin immunohistochemistry (n=50). RESULTS: SNs were identified in 94 of the 100 patients and the mean number of SNs was 4.4 (range, 1-12). Of these 94 patients, 14 patients had lymph node metastases. Two patients with T1 and one patient with T2 had metastases in non-SNs alone by hematoxylin and eosin staining (diagnostic accuracy =97.3% in T1 and 95.0% in T2). All three patients with a false negative result had a tumour, which was more than 4 cm in size and signet ring cell histology. In two of them, the tumour was located at lesser curvature. By immunohistochemical staining, three patients with T1 and one patient with T2 were found to have lymph node micrometastases in non-SNs alone among 45 patients (diagnostic accuracy =92.1% in T1, 85.7% in T2). CONCLUSION: SN biopsy using indocyanine green can be performed rapidly and easily with a high detection rate and accuracy in patients with T1 gastric cancer. However, it should be performed with caution for large tumours with a signet ring cell histology located at lesser curvature due to the possibility of a false negative result.

Intraoperative gastroscopy for gastric surgery.

BACKGROUND: Few reports are available on the use of intraoperative gastroscopy for gastric surgery. METHODS: The details of 33 patients (25 early gastric cancers and eight gastric submucosal tumors) who underwent intraoperative gastroscopy from June 2003 to June 2004 were analyzed. The type of operation or resection margin was determined by evaluating both sides of the stomach simultaneously by combined operative and gastroscopic methods. RESULTS: Preoperative endoscopic clipping was done preferentially for early gastric cancer. However, when precise localization was needed, intraoperative gastroscopy was used. Curative gastric resection was possible in 25 early gastric cancer patients after accurate lesion localization. Laparoscopic wedge resections of submucosal tumors were performed in seven patients without stenosis by combined laparoscopic and gastroscopic methods. CONCLUSIONS: Intraoperative gastroscopy can be used effectively during gastric surgery for early gastric cancer or submucosal tumors and can be regarded as a modern stethoscope to gastric surgeons.

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats.

AIMS/HYPOTHESIS: Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia. MATERIALS AND METHODS: Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague-Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominant-negative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia. RESULTS: Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and alpha2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses. CONCLUSIONS/INTERPRETATION: Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counter-regulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.

Predictors of operative morbidity and mortality in gastric cancer surgery.

BACKGROUND: The aim of this study was to identify factors that predict morbidity and mortality in gastric cancer surgery. METHODS: Data on 719 consecutive patients who underwent operations for gastric cancer at Seoul National University Hospital between January and December 2002 were reviewed. RESULTS: Overall morbidity and mortality rates were 17.4 per cent (125 patients) and 0.6 per cent (four patients) respectively, and the rates of surgical and non-surgical complications were 14.7 per cent (106 patients) and 3.3 per cent (24 patients). Morbidity rates were higher in patients aged over 50 years (odds ratio (OR) 1.04 (95 per cent confidence interval (c.i.) 1.02 to 1.06)), when the gastric tumour was resected with another organ (36 per cent for combined resection versus 15.4 per cent for gastrectomy only; OR 3.25 (95 per cent c.i. 1.76 to 6.03)) and when gastrojejunostomy was used for reconstruction after subtotal gastrectomy (17.0 per cent for Billroth II versus 9.5 per cent for Billroth I; OR 2.00 (95 per cent c.i. 1.05 to 3.79)). Only three patients (2.8 per cent) with a surgical complication underwent reoperation, two for adhesive obstruction and one for intra-abdominal bleeding. CONCLUSION: Age, combined resection and Billroth II reconstruction after radical subtotal gastrectomy were independently associated with the development of complications after gastric cancer surgery.

The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells.

AIMS/HYPOTHESIS: Increased oxidative stress in vascular smooth muscle cells (VSMCs) has been implicated in the pathogenesis of accelerated atherosclerosis in patients with diabetes mellitus. Uncoupling protein 2 (UCP-2) is an important regulator of intracellular reactive oxygen species (ROS) production. We hypothesised that UCP-2 functions as an inhibitor of the atherosclerotic process in VSMCs. METHODS: Overexpression of human UCP-2 was performed in primary cultured human VSMCs (HVSMCs) via adenovirus-mediated gene transfer. Its effects on ROS production, AP-1 activity, plasminogen activator inhibitor 1 (PAI-1) gene expression, and cellular proliferation and migration were measured in response to high glucose and angiotensin II (Ang II) concentrations, two major factors in the pathogenesis of atherosclerosis in patients with diabetes and hypertension. Mitochondrial membrane potential and NAD(P)H oxidase activity were also measured. RESULTS: High glucose and Ang II caused transient mitochondrial membrane hyperpolarisation. They also significantly stimulated ROS production, NAD(P)H oxidase activity, mitochondrial membrane potential, AP-1 activity, PAI-1 mRNA expression, and proliferation and migration of HVSMCs. Adenovirus-mediated transfer of the UCP-2 gene reversed all of these effects. CONCLUSIONS/INTERPRETATION: The present study demonstrates that UCP-2 can modify atherosclerotic processes in HVSMCs in response to high glucose and Ang II. Our data suggest that agents increasing UCP-2 expression in vascular cells may help prevent the development and progression of atherosclerosis in patients with diabetes and hypertension.

Overexpression of short heterodimer partner recovers impaired glucose-stimulated insulin secretion of pancreatic beta-cells overexpressing UCP2.

The short heterodimer partner (SHP) (NR0B2) is an orphan nuclear receptor whose function in pancreatic beta-cells is unclear. Mitochondrial uncoupling protein (UCP2) in beta-cells is upregulated in obesity-related diabetes, causing impaired glucose-stimulated insulin secretion (GSIS). We investigated whether SHP plays a role in UCP2-induced GSIS impairment. We overexpressed SHP in normal islet cells and in islet cells overexpressing UCP2 by an adenovirus-mediated infection technique. We found that SHP overexpression enhanced GSIS in normal islets, and restored GSIS in UCP2-overexpressing islets. SHP overexpression increased the glucose sensitivity of ATP-sensitive K+ (KATP) channels and enhanced the ATP/ADP ratio. A peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW9662, did not block the SHP effect on GSIS. SHP overexpression also corrected the impaired sensitivity of UCP2-overexpressing beta-cells to methylpyruvate, another energy fuel that bypasses glycolysis and directly enters the Krebs cycle. KATP channel inhibition mediated by dihydroxyacetone, which gives reducing equivalents directly to complex II of the electron transport system, was similar in Ad-Null-, Ad-UCP2- and Ad-UCP2+Ad-SHP-infected cells. The mitochondrial metabolic inhibitor sodium azide totally blocked the effect of SHP overexpression on GSIS. These results suggest that SHP positively regulates GSIS in beta-cells and restores glucose sensitivity in UCP2-overexpressing beta-cells by enhancing mitochondrial glucose metabolism, independent of PPARgamma activation.