Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.     

Disease burdens from environmental tobacco smoke in Korean adults

In this study, we estimated the disease burdens attributable to environmental tobacco smoke (ETS) exposure in Korean adults in 2010 and analyzed the trend of that from 2005 to 2010. We obtained information on the study population from the 2010 Cause of Death Statistic and estimated the ETS-attributable fraction using data from the Korean Community Health Survey and the Korean National Health and Nutrition Examination Survey. The numbers of ETS-attributable deaths in female and male non-smokers were estimated to be 4.1 and 69.6?% of the numbers of deaths attributable to current smoke, respectively. The deaths attributable to ETS were larger in female than in male non-smokers (710 vs. 420). The ETS-attributable deaths increased slightly in 2005–2008 but decreased in 2009–2010. The number of potential years of life lost from ETS was 9077.24?years in 2010. If there were no exposure to ETS in adult non-smokers, we would expect to see 1130 fewer deaths (9.9?% of the deaths from current smoke). The results suggest that ETS poses considerable disease burdens for non-smokers, especially women, in Korea.     

The modified outside-in suture: vertical repair of the anterior horn of the meniscus after decompression of a large meniscal cyst

This article describes a modified suture technique designed for the vertical repair of the anterior horn of the meniscus after arthroscopic decompression of a large meniscal cyst. This procedure comprises of three steps: first, the meniscus was pierced vertically using a suture hook and a No. 0 PDS suture. Second, both ends of the No. 0 PDS on the femoral and tibial surfaces of the meniscus were pulled to the outside of the joint capsule using a spinal needle preloaded with suture material. Finally, a skin incision was made adjacent to the suture materials, and both ends were tied. We recommend this technique not only for the vertical repair of the anterior horn of the meniscus after decompression of large meniscal cyst, but also to repair a longitudinal tear of the meniscus.     

Changes in outcome with sphincter preserving surgery for rectal cancer in Korea, 1991-2000.

AIM: To report the clinical and oncological data of patients operated on for rectal cancers 3-5 cm from the AV over a 10 year period, including the Sphincter preservation (SP) rate. METHODS: We reviewed medical records of 304 patients with rectal cancers 3-5 cm from the AV who underwent surgical resection from January 1991 through December 2000. The 10 years were divided into three periods based on the introduction of new surgical techniques, specifically, ultralow anterior resection (ULAR) with double stapling in March 1994 and ULAR with coloanal anastomosis in April 1997. The rates of SP, complications and patient survival during these periods were compared. RESULTS: The SP rate increased significantly over the 10 years, from 16.4% in period I (January 1991-February 1994), to 53.0% in period II (March 1994-March 1997), to 86.5% in period III (April 1997-December 2000) (p<0.001). Over time, the age of the patients increased (p=0.004), the length of the distal resection margin became shorter (p=0.005), and the rate of lymph node metastasis increased (p=0.016). The factors significantly influencing SP were the period (p<0.001) and the distance from the AV (p<0.001). Over time, morbidity did not increase, and overall and disease free survival rates did not decrease. In contrast, the overall survival of N2 cases significantly increased over time (p=0.0492). CONCLUSION: Over 10 years, the SP rate in rectal cancers 3-5 cm from the AV was significantly increased by the introduction of the double stapling and coloanal anastomosis techniques. These surgical methods, however, had no effect on morbidity, disease free survival and overall survival rates.     

Evaluation of left ventricular mechanical dyssynchrony as determined by phase analysis of ECG-gated SPECT myocardial perfusion imaging in patients with left ventricular dysfunction and conduction disturbances

Background  Cardiac resynchronization therapy (CRT) is approved for the treatment of patients with advanced systolic heart failure and evidence of dyssynchrony on electrocardiograms. However, a significant percentage of patients do not demonstrate improvement with CRT. Echocardiographic techniques have been used for more accurate determination of dyssynchrony. Single photon emission computed tomography (SPECT) myocardial perfusion imaging has not previously been used to evaluate cardiac dyssynchrony. The objective of this study is to evaluate mechanical dyssynchrony as described by phase analysis of gated SPECT images in patients with left ventricular dysfunction, conduction delays, and ventricular paced rhythms. Methods and Results  A novel count-based method is used to extract regional systolic wall thickening amplitude and phase from gated SPECT images. Five indices describing the phase dispersion of the onset of mechanical contraction are determined: peak phase, phase SD, bandwidth, skewness, and kurtosis. These indices were determined in consecutive patients with left ventricular dysfunction (n=120), left bundle branch block (n=33), right bundle branch block (n=19), and ventricular paced rhythms (n=23) and were compared with normal control subjects (n=157). Phase SD, bandwidth, skewness, and kurtosis were significantly different between patients with left ventricular dysfunction, left bundle branch block, right bundle branch block, and ventricular paced rhythms and normal control subjects (all P<.001) Peak phase was significantly different between patients with right ventricular paced rhythms and normal control subjects (P=.001). Conclusions  A novel SPECT technique for describing left ventricular mechanical dyssyn-chrony has been developed and may prove useful in the evaluation of patients for CRT. This study was funded in part by a research grant from the Medtronic-Duke Strategic Alliance, of which Dr Borges-Neto is the primary investigator.     

Up-regulation of urinary UPIII mRNA levels in vesicoureteral reflux patients: Potential application as a screening test for vesicoureteral reflux

OBJECTIVES: Vesicoureteral reflux (VUR) is the most common congenital urinary tract anomaly. This disease can pose a major threat to the kidneys as twenty percent of patients with endstage renal disease are reported to have VUR. Although genetic studies for uroplakin III (UPIII) have been reported recently, no study has focused on UPIII gene expression in VUR patients. We describe here the up-regulation of UPIII mRNA in exfoliated urinary cells from primary VUR patients. METHODS: A real-time RT-PCR for UPIII mRNA was performed on exfoliated urothelial cells from 18 primary VUR and 38 control samples. UPIII mRNA copies were calculated for each sample. The statistical differences were assessed by the Mann-Whitney U test. Receiver operator characteristic curves were constructed for analysis of the diagnostic values. RESULTS: UPIII mRNA was found to be up-regulated to a greater extent in VUR than in control exfoliated urinary cells (mean +/- SE: 497.0 +/- 178.5 copies vs. 69.0 +/- 10.0 copies, respectively, P < 0.001). In evaluating the measurement of urinary UPIII mRNA as a screening test for VUR, the sensitivity was 77.8% and the specificity was 76.3% by the best diagnostic cutoff point. CONCLUSIONS: This is the first report demonstrating up-regulation of UPIII in mRNA levels in VUR patients. We submit that the quantitative measurement of urinary UPIII mRNA has a potential of developing into the first non-invasive screening test for VUR.