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.     

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.     

Myocardial Depressant Effects of Desflurane: Mechanical and Electrophysiologic Actions In Vitro

Background: The authors determined whether desflurane altered myocardial excitation-contraction coupling and electrophysiologic behavior in the same manner as isoflurane and sevoflurane.

Methods: The effects of desflurane on isometric force in guinea pig ventricular papillary muscles were studied in modified standard and in 26 mm K+ Tyrode solution with 0.1 [mu]m isoproterenol. Desflurane effects on sarcoplasmic reticulum Ca2+ release were also determined by examining its actions on rat papillary muscles, guinea pig papillary muscles in low-Na+ Tyrode solution, and rapid cooling contractures. Normal and slow action potentials were recorded using a conventional microelectrode technique. Ca2+ and K+ currents of guinea pig ventricular myocytes were examined.

Results: Desflurane (5.3% and 11.6%) decreased peak force to approximately 70% and 40% of the baseline, respectively, similar to the effects of equianesthetic isoflurane concentrations. With isoproterenol in 26 mm K+ Tyrode solution, desflurane markedly depressed late peaking force and modestly depressed early peak force. The rested state contractions of rat myocardium or guinea pig myocardium in low-Na+ Tyrode solution were modestly depressed, whereas rapid cooling contractures were virtually abolished after desflurane administration. Desflurane significantly prolonged the action potential duration. Desflurane reduced L-type Ca2+ current and the delayed outward K+ current but did not alter the inward rectifier K+ current.     

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.     

Post-transplantation diabetes is better controlled after conversion from prednisone to deflazacort: a prospective trial in renal transplants

It is well known that long-term use of steroids plays a decisive role in the development of glucose intolerance and diabetes mellitus (DM). Deflazacort, an oxazoline derivative of prednisolone, has been introduced as a potential substitute for conventional steroids in order to ameliorate glucose intolerance. We initiated a randomized study of conversion from prednisone to deflazacort in kidney transplantation (Tx) recipients presenting with pre-Tx or post-Tx DM to ascertain whether or not the switch to deflazacort would ameliorate the diabetic state. Forty-two recipients in the conversion group were compared with 40 patients on prednisone (the control group) in a prospective manner. The dose reduction of insulin or oral blood glucose-lowering agents, the adequacy of glucose control, and the development of side effects were the criteria for evaluating outcome. In the conversion group, patients were switched to deflazacort at a dose ratio of 6 mg deflazacort to 5 mg prednisone. During the mean follow-up period of 13.2 months, neither graft dysfunction nor acute rejection developed in the conversion group. Improvement in blood glucose control in the conversion group was noted. When the conversion group was stratified into pre- or post-Tx DM, promising effects were clearly evident in the post-Tx DM patients. More than 50 % dose reduction of blood glucose-lowering agents was possible in 42.3 % of post-Tx DM patients. In conclusion, it was readily possible to control blood glucose better in post-Tx DM recipients without seriously affecting the immunosuppressive activity after conversion to deflazacort. Received: 20 August 1996 Received after revision: 25 November 1996 Accepted: 6 December 1996     

Perioperative specific management of blood volume loss in craniosynostosis surgery

Accurate assessment and replacement of blood loss and fluid–electrolyte deficit during craniosynostosis repair is difficult owing to patient size and the diversity of surgical technique. Forty-three patients undergoing primary craniosynostosis repair over a 10-year period were studied retrospectively to determine blood loss and fluid deficit and to assess blood transfusion practices during both intraoperative and postoperative periods. Blood loss was calculated on the basis of estimated red cell mass (ERCM) and fluid-electrolyte imbalance was investigated with blood samplings. Blood transfusion was considered appropriate if the postoperative or posttransfusion ERCM was within 12% of the preoperative value. Estimated fluid requirement (EFR) was used in 4 ml kg^–1 h^–1 except for neonates. Intraoperatively, 80% of all patients were appropriately managed with respect to blood transfusion and EFR. Postoperatively only 20% of the patients receiving transfusions were transfused appropriately. In 23.3% of these patients (10/43) unexpected respiratory distress developed immediately after their recovery from the anesthesia. With the measurement of estimated blood volume and allowable blood loss, appropriate transfusion could be achieved for the successful treatment of the primary craniosynostosis. Received: 16 February 1998