Three-dimensional soft tissue changes after reduction malarplasty in female patients.

The aim of this study was to determine the three-dimensional soft tissue changes after reduction malarplasty. Soft tissue changes relative to the amount of movement of the zygomatic bone were studied. Pre- and postoperative cone beam computed tomography images of 21 female patients were superimposed. The anterior-most point of the body osteotomy (point A), arch osteotomy site (point D), and points dividing line A-D into thirds (points B and C) were marked on lateral view images. The vertical distances from the midsagittal line to the centre of the zygomatic bone and the outer prominence of the soft tissue were measured on the coronal view of each image. The proportion of the change in soft tissue to that of the bone before and after surgery was calculated for each point. The relationship between body mass index and the soft tissue change ratio, and the differences in soft tissue changes at each point were analysed. Mean soft tissue changes for points A, B, C, and D were 53.43%, 66.66%, 63.67%, and 57.23%, respectively. The amount of soft tissue change at point B was greater than that at points A and D, which were osteotomy sites. There was no statistical correlation between body mass index and the soft tissue change ratio at each point.

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up.

WHAT IS KNOWN AND OBJECTIVE: Ketamine in a subanaesthetic dose has been shown to produce rapid antidepressant effects. Here, we describe a long-term follow-up case of a Korean patient with severe major depression who received repeated ketamine intravenous therapy (KIT). CASE DESCRIPTION: A 49-year-old woman with a 6-year history of treatment-resistant major depression was given KIT once every 1 or 2 weeks over 10 months, for a total of 36 treatments. Her mood stabilized, and she showed a nearly 50% reduction in the severity of her depressive symptom. WHAT IS NEW AND CONCLUSION: Long-term repeated KIT may be an option for alleviating treatment-resistant and relapsing major depression. Further research and large clinical trials are needed on the optimum KIT protocol, including dose, dosing interval, total number of treatments and when to stop.

Type 2 diabetes as a risk indicator for dental caries in Korean adults: the 2011-2012 Korea national health and nutrition examination survey.

OBJECTIVES: The associations between type 2 diabetes (T2D) and untreated dental caries was examined. This study hypothesized that there would be a positive association between T2D and the prevalence of decayed permanent teeth (DT) in representative Korean adults. METHODS: The information was derived from the Korea National Health and Nutrition Examination Survey conducted in 2011-2012. Sociodemographic and lifestyle variables, anthropometric and biochemical status, metabolic health and glucose tolerance status, oral health behaviors, and dental caries index were evaluated. RESULTS: The number of DT had a positive association with degree of fasting plasma glucose (FPG) level, and glycated hemoglobin (HbA1c) (p-value = 0.045 and 0.007, respectively). The levels of FPG and HbA1c increased with the number of DT (p for trend = 0.009 and 0.004, respectively). The prevalence of untreated caries uncontrolled T2D participants was about 26% higher than those with normal glucose tolerance levels after adjusting for potential confounders including diets and socioeconomic status (OR [95% CI] = 1.26 [1.02, 1.56]). CONCLUSIONS: T2D is an independent risk indicator for untreated caries in Korean adults.

Obesity is inversely related to the risks of dental caries in Korean adults.

OBJECTIVE: This study investigated whether obesity is linked with dental caries. This study hypothesized that obesity may influence the number or prevalence of dental caries in Korean adults. SUBJECTS AND METHODS: Data were derived from Korea National Health and Nutrition Examination Survey performed at 2008-2010. Lifestyle, sociodemographic, and biochemical variables were analyzed. Indices related to obesity, sarcopenia, and metabolic syndrome were investigated. Finally, caries index and oral health behaviors were included for the analysis. RESULTS: The caries index was inversely associated with increasing body mass index (BMI) and body fat quartile (all p-values <.01). Subjects with high waist circumference who met the inclusion criteria of metabolic syndrome were less likely to have decayed tooth (p-value = .0009). Subjects with a BMI of 25 or more showed about 20% less prevalence of dental caries experience than normal individuals with a BMI of 18.5 to 23 glucose (odds ratio [95% confidence intervals] = 0.808 [0.684-0.956]). Similarly, subjects with total body fat in the highest quartile revealed about 20% less prevalence of caries experiences that those with body fat proportion in the lowest quartile (0.84 [0.672,1.049]). CONCLUSIONS: Obesity was inversely associated with occurrence or severity of dental caries in Korean adults.

Immunologic characteristics of human gingival fibroblasts in response to oral bacteria.

BACKGROUND AND OBJECTIVE: There is ample evidence that gingival fibroblasts (GFs) participate in the immune response to oral bacteria and serve as immune-regulatory cells. The objective of this study was to investigate the innate immune response of GFs to oral bacteria. MATERIAL AND METHODS: Human GFs were cocultured with relatively less-pathogenic (Leptotrichia wadei, Fusobacterium nucleatum and Campylobacter gracilis) and pathogenic red-complex bacteria. The expression of mRNA for antimicrobial peptides [AMPs; namely human beta defensins (HBDs)], chemokines with antimicrobial activity [chemokine C-X-C motif (CXCL)10, CXCL11 and chemokine C-C motif ligand 20 (CCL20)] and proinflammatory mediators [interleukin (IL)6 and IL8] and the levels of CXCL11, CCL20, IL-6 and IL-8 accumulated in supernatants were analyzed using real-time PCR and ELISA, respectively. The proteolytic activities of CXCL11, CCL20, IL-6 and IL-8 produced by six species of bacteria were also determined. RESULTS: The relatively less-pathogenic bacteria strongly up-regulated the expression of antimicrobial chemokines and proinflammatory mediators, whereas the red-complex bacteria stimulated low levels, or often suppressed, expression of these factors. Regarding the regulation of AMPs, the inhibition of HBD3, HBD106 and HBD107 mRNAs by Porphyromonas gingivalis was noticeable; however, differences between the two bacterial groups were not conspicuous. Differential degradation of proteins by the six bacterial species was observed: P. gingivalis and Treponema denticola degraded proteins well, whereas the other species degraded proteins to a relatively lower degree. CONCLUSION: The invasion of red-complex bacteria into gingival connective tissue can suppress the immune response of GFs and can be a source of persistent infection in connective tissue.

Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway.

The current study was carried out to define the involvement of Peroxiredoxin (Prx) II in progression of hepatocellular carcinoma (HCC) and the underlying molecular mechanism(s). Expression and function of Prx II in HCC was determined using H-ras(G12V)-transformed HCC cells (H-ras(G12V)-HCC cells) and the tumor livers from H-ras(G12V)-transgenic (Tg) mice and HCC patients. Prx II was upregulated in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg mouse tumor livers, the expression pattern of which highly similar to that of forkhead Box M1 (FoxM1). Moreover, either knockdown of FoxM1 or site-directed mutagenesis of FoxM1-binding site of Prx II promoter significantly reduced Prx II levels in H-ras(G12V)-HCC cells, indicating FoxM1 as a direct transcription factor of Prx II in HCC. Interestingly, the null mutation of Prx II markedly decreased the number and size of tumors in H-ras(G12V)-Tg livers. Consistent with this, knockdown of Prx II in H-ras(G12V)-HCC cells reduced the expression of cyclin D1, cell proliferation, anchorage-independent growth and tumor formation in athymic nude mice, whereas overexpression of Prx II increased or aggravated the tumor phenotypes. Importantly, the expression of Prx II was correlated with that of FoxM1 in HCC patients. The activation of extracellular signal-related kinase (ERK) pathway and the expression of FoxM1 and cyclin D1 were highly dependent on Prx II in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg livers. Prx II is FoxM1-dependently-expressed antioxidant in HCC and function as an enhancer of Ras(G12V) oncogenic potential in hepatic tumorigenesis through activation of ERK/FoxM1/cyclin D1 cascade.

Effect of decompression on cystic lesions of the mandible: 3-dimensional volumetric analysis.

Decompression is effective in reducing both the size of cystic lesions on jaws and the associated morbidity of resection. However, quantitative measurement of reduced volume after decompression among different cystic diseases has not been fully investigated. We have retrospectively investigated the difference in reduction in volume among keratocystic odontogenic tumours (n=17), unicystic ameloblastomas (n=10), and dentigerous cysts (n=10) of the posterior mandible using 3-dimensional computed tomography (CT). Various other influential factors such as age, sex, the presence of impacted teeth, and the number of drains were also recorded. There was no significant difference in the speed of shrinkage among the 3 groups, but there was a significant correlation (p<0.01) between the initial detected volume of the lesion and the absolute speed of shrinkage in each type of cyst. Initial volume was also significantly associated (p<0.01) with reduction of total volume in each type of cyst. Age may correlate negatively with the rate of reduction in dentigerous cysts, which means that the older the patient is, the less the reduction. Treatment seemed to last longer as the speed of shrinkage lessened in the keratocystic tumours and dentigerous cysts (p<0.05) as multiple regression has shown. The relative speed of shrinkage of unicystic ameloblastomas seemed to be slower when an impacted tooth was involved in the lesion (p=0.019). However, the sample size was too small to make any definite statistical statement. These results suggest that the rate of reduction of volume was related to the original size of the lesion. Despite the need for a second operation and longer duration of treatment compared with excision alone, decompression is a valuable way of reducing the size of large cystic lesions, with low morbidity and recurrence rate. There was no difference in the rate of reduction according to the underlying histopathological picture.

Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells.

Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib-resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5'-triphosphate and mitochondrial Ca(2+) concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2-methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making.

Transport of organic cationic drugs: effect of ion-pair formation with bile salts on the biliary excretion and pharmacokinetics.

More than 40% of clinically used drugs are organic cations (OCs), which are positively charged at a physiologic pH, and recent reports have established that these drugs are substrates of membrane transporters. The transport of OCs via membrane transporters may play important roles in gastrointestinal absorption, distribution to target sites, and biliary and/or renal elimination of various OC drugs. Almost 40 years ago, a molecular weight (Mw) threshold of 200 was reported to exist in rats for monoquaternary ammonium (mono QA) compounds to be substantially (e.g., >10% of iv dose) excreted to bile. It is well known that some OCs interact with appropriate endogenous organic anions in the body (e.g., bile salts) to form lipophilic ion-pair complexes. The ion-pair formation may influence the affinity or binding of OCs to membrane transporters that are relevant to biliary excretion. In that sense, the association of the ion-pair formation with the existence of the Mw threshold appears to be worthy of examination. It assumes the ion-pair formation of high Mw mono QA compounds (i.e., >200) in the presence of bile salts in the liver, followed by accelerated transport of the ion-pair complexes via relevant bile canalicular transporter(s). In this article, therefore, the transport of OC drugs will be reviewed with a special focus on the ion-pair formation hypothesis. Such information will deepen the understanding of the pharmacokinetics of OC drugs as well as the physiological roles of endogenous bile salts in the detoxification or phase II metabolism of high Mw QA drugs.

A case of a giant mucocoele of the appendiceal stump presented with a palpable mass in the right thigh: pre-operative diagnosis based on characteristic multidetector CT findings.

The pre-operative diagnosis of a mucocoele of the appendiceal stump (MAS) may be difficult owing to rarity and non-specific clinical presentation. However, a pre-operative diagnosis of a MAS is important to prevent widespread dissemination by inadvertent spillage of mucous contents. We describe a case of a MAS presenting with a palpable mass in the right thigh in which a pre-operative diagnosis was made by characteristic multidetector CT (MDCT) findings.

Comparison of endoscopic ultrasonography and conventional endoscopy for prediction of depth of tumor invasion in early gastric cancer.

BACKGROUND AND STUDY AIMS: This study aimed to compare the diagnostic accuracy of endoscopic ultrasonography (EUS) with that of conventional endoscopy for staging depth of invasion (T staging) in early gastric cancer. PATIENTS AND METHODS: A total of 955 patients with suspected early gastric cancer were prospectively registered. EUS staging was carried out prospectively by a single endoscopist using either miniprobe or radial EUS depending on the endoscopic appearance of the tumor. Conventional endoscopy staging was performed retrospectively by consensus between two endoscopists who were blinded to the EUS staging. Conventional endoscopy staging was conducted on the basis of endoscopic features such as surface nodularity and fold convergence. Patients underwent either surgical (n = 586) or endoscopic resection (n = 369) with curative intent. The staging accuracy of each test was compared with the pathological staging of the resected specimen. RESULTS: The presence of a T1m tumor was histologically confirmed in 644 cases (67.4 %) and that of a T1sm tumor in 311 cases (32.6 %). The overall accuracy of EUS staging was 67.4 % (644 / 955) and that of conventional endoscopy staging was 73.7 % (704 / 955) ( P < 0.001). The accuracy of miniprobe EUS was significantly higher than that of radial EUS (79.5 % vs. 59.6 %, P < 0.001), but did not differ significantly from that of conventional endoscopy (79.0 %). CONCLUSIONS: EUS does not substantially impact on pretreatment T staging of patients with early gastric cancer compared with conventional endoscopy. Therefore, EUS may not be necessary routinely, and conventional endoscopy may be sufficient for determining the optimal therapeutic strategy, especially in relation to endoscopic resection for early gastric cancer.

Mutant DLX 3 disrupts odontoblast polarization and dentin formation.

Tricho-dento-osseous (TDO) syndrome is an autosomal dominant disorder characterized by abnormalities in the thickness and density of bones and teeth. A 4-bp deletion mutation in the Distal-Less 3 (DLX3) gene is etiologic for most cases of TDO. To investigate the in vivo role of mutant DLX3 (MT-DLX3) on dentin development, we generated transgenic (TG) mice expressing MT-DLX3 driven by a mouse 2.3 Col1A1 promoter. Dentin defects were radiographically evident in all teeth and the size of the nonmineralized pulp was enlarged in TG mice, consistent with clinical characteristics in patients with TDO. High-resolution radiography, microcomputed tomography, and SEM revealed a reduced zone of mineralized dentin with anomalies in the number and organization of dentinal tubules in MT-DLX3 TG mice. Histological and immunohistochemical studies demonstrated that the decreased dentin was accompanied by altered odontoblast cytology that included disruption of odontoblast polarization and reduced numbers of odontoblasts. TUNEL assays indicated enhanced odontoblast apoptosis. Expression levels of the apoptotic marker caspase-3 were increased in odontoblasts in TG mice as well as in odontoblastic-like MDPC-23 cells transfected with MT-DLX3 cDNA. Expression of Runx2, Wnt 10A, and TBC1D19 colocalized with DLX3 expression in odontoblasts, and MT-DLX3 significantly reduced expression of all three genes. TBC1D19 functions in cell polarity and decreased TBC1D19 expression may contribute to the observed disruption of odontoblast polarity and apoptosis. These data indicate that MT-DLX3 acts to disrupt odontoblast cytodifferentiation leading to odontoblast apoptosis, and aberrations of dentin tubule formation and dentin matrix production, resulting in decreased dentin and taurodontism. In summary, this TG model demonstrates that MT-DLX3 has differential effects on matrix production and mineralization in dentin and bone and provides a novel tool for the investigation of odontoblast biology.

Decreased urinary secretion of belotecan in folic acid-induced acute renal failure rats due to down-regulation of Oat1 and Bcrp.

The effects of folic acid-induced acute renal failure on the renal excretion of belotecan were investigated in rats after intravenous administration. Both glomeruli and renal tubules were seriously damaged by folic acid-induced acute renal failure. The renal excretion clearance, CLr, of belotecan was significantly decreased by folic acid-induced acute renal failure. Furthermore, glomerular filtration rate and secretion clearance of the drug were dramatically decreased by folic acid-induced acute renal failure. In vivo renal uptake of belotecan was inhibited by p-aminohippurate, whereas renal excretion was inhibited by GF120918, but not by verapamil and bromosulphalein. This indicates that Oat1/3 and Bcrp are involved in the renal uptake and urinary excretion of belotecan, respectively. Both mRNA and protein levels of Oat1, Oat3 and Bcrp were significantly decreased in folic acid-induced acute renal failure rats. Based on the finding that belotecan is a substrate of OAT1 but not of OAT3, the decrease in CLr of belotecan in folic acid-induced acute renal failure could, therefore, mainly be attributed to the down-regulation of Oat1 and Bcrp, in addition to the decrease in glomerular filtration rate.

Comparison of risk factors and clinical responses to proton pump inhibitors in patients with erosive oesophagitis and non-erosive reflux disease.

BACKGROUND: There has been no report on the response to proton pump inhibitor (PPI) therapy and on-demand or the relapse rate of non-erosive reflux disease (NERD) and erosive oesophagitis in Korea. AIM: To compare the risk factors, clinical symptoms and PPI responses between patients with erosive oesophagitis and NERD patients. METHODS: A survey was performed prospectively in the erosive oesophagitis (205 patients) and NERD group (200 patients). Clinical symptoms, risk factors and PPI responses were analysed. On-demand therapy and the relapse rate of GERD symptoms were investigated during a one-year follow-up. RESULTS: BMI > or = 25 (OR 3.0, 95% CI 1.1-8.3), alcohol use (OR 2.9, 95% CI 1.0-8.3), hiatal hernia (OR 5.0, 95% CI 1.2-20) and triglyceride > or =150 mg/dL (OR 4.0, 95% CI 1.7-10) were more common in the erosive oesophagitis group than in the NERD group by multivariate analysis. The ratio of oesophageal to extra-oesophageal symptoms was higher in the erosive oesophagitis group compared with the NERD group (P < 0.001). The PPI response rates at 8 weeks were different (P = 0.02); refractory rates were higher in the NERD group (16.7%) compared with the erosive oesophagitis group (6.0%). However, there was no significant difference between the two groups in on-demand therapy or the relapse rate. CONCLUSION: These results suggest that the underlying pathogenic mechanisms of erosive oesophagitis and NERD are distinct.

Involvement of Mrp2/MRP2 in the species different excretion route of benzylpenicillin between rat and human.

1. The purpose of this study was to investigate the involvement of rat Mrp2 and human MRP2 in benzylpenicillin transport using canalicular liver plasma membrane (cLPM) vesicles isolated from Sprague-Dawley or Easai hyperbilirubinemic (EHBR) rats, and MDCKII cells overexpressing MRP2. 2. The adenosine triphosphate (ATP)-dependent uptake of benzylpenicillin and oestradiol-17beta-D-glucuronide (E(2)17betaG), a representative substrate for Mrp2, into EHBR-cLPM vesicles was decreased relative to that seen with control-cLPM vesicles, which may reflect the absence of Mrp2 in the EHBR. The ATP-dependent uptake of taurocholate, which is not a substrate for Mrp2, was similar in both control and EHBR-cLPM vesicles. The concentration dependence of ATP-dependent benzylpenicillin uptake was reflected in a K(m) of 44.0 microM and a V(max) of 508.4 pmol mg(-1) min(-1). Additional inhibition studies using E(2)17betaG and methotrexate as representative substrates for Mrp2/MRP2 demonstrated the involvement of rat Mrp2, but not human MRP2, in benzylpenicillin efflux. Benzylpenicillin appears not to be a substrate for or inhibitor of other human efflux transporters such as MDR1, MRP1, MRP3, or BCRP. 3. In conclusion, rat Mrp2, but not human MRP2, plays an important role in ATP-dependent benzylpenicillin uptake in the bile canalicular membrane, which may explain why biliary excretion of benzylpenicillin is high in the rat but negligible in humans.

Allopurinol-induced aplastic anemia in a patient with chronic kidney disease.

Aplastic anemia is a rare complication of allopurinol use. We report an unusual case of aplastic anemia associated with allopurinol therapy for hyperuricemia in a patient with chronic kidney disease. A 37-year-old female patient diagnosed with Stage III chronic kidney disease was admitted with pancytopenia. She had a history of taking allopurinol for 5 months. Her bone marrow showed extremely decreased cellularity (< 20%) and there was no malignant cell infiltration. She was free of infections, including parvovirus B19, cytomegalovirus and Epstein-Barr virus. These results suggested a diagnosis of aplastic anemia. Allopurinol was discontinued immediately and treatment with blood transfusions and prednisolone was begun. After 6 months, the bone marrow cellularity improved to approximately 70%. Recently, it was suggested that decreased activity of multidrug resistance P-glycoprotein may play a role in acquired aplastic anemia. So we measured the inhibitory effect of allopurinol and oxypurinol on P-glycoprotein activity. But neither allopurinol nor oxypurinol inhibited P-glycoprotein activity.

Dual-energy X-ray absorptiometry overestimates bone mineral density of the lumbar spine in persons with spinal cord injury.

BACKGROUND: Bone mineral density (BMD) of the lumbar spine (L-spine) has been reported to be normal or increased in persons with chronic spinal cord injury (SCI). OBJECTIVE: To determine BMD of the L-spine by dual-energy X-ray absorptiometry (DXA) and quantitative computerized tomography (qCT) in men with chronic SCI compared with able-bodied controls. DESIGN: Cross-sectional, comparative study. SETTING: Clinical research unit, Veterans Affairs Medical Center, Bronx, NY, USA and Kessler Institute of Rehabilitation, West Orange, NJ, USA. METHODS: Measurements of the L-spine were made in 20 men with SCI and compared with 15 able-bodied controls. The DXA images were acquired on a GE Lunar DPX-IQ. The qCT images of the L-spine were acquired on a Picker Q series computerized tomographic scanner. RESULTS: The mean ages for the SCI and control groups were 44+/-13 vs 42+/-9 years, and the duration of injury of the group with SCI was 14+/-11 years. There were no significant differences between the SCI and control groups for L-spine DXA BMD (1.391+/-0.210 vs 1.315+/-0.178 g/m(2)) or for L-spine DXA T-score (1.471+/-1.794 vs 0.782+/-1.481). L-spine qCT BMD was significantly lower in the SCI compared with the control group (1.296+/-0.416 vs 1.572+/-0.382 g/m(2), P=0.05); the T-score approached significance (-1.838+/-1.366 vs -0.963+/-1.227, P=0.059). Subjects with moderate degenerative joint disease (DJD) had significantly higher T-scores by DXA than those without or with mild DJD. CONCLUSION: Individuals with SCI who have moderate to severe DJD may have bone loss of the L-spine that may be underestimated by DXA, reducing awareness of the risk of fracture.

In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development.

Distal-less 3 (DLX3) gene mutations are etiologic for Tricho-Dento-Osseous syndrome. To investigate the in vivo impact of mutant DLX3 on bone development, we established transgenic (TG) mice expressing the c.571_574delGGGG DLX-3 gene mutation (MT-DLX3) driven by a mouse 2.3 Col1A1 promoter. Microcomputed tomographic analyses demonstrated markedly increased trabecular bone volume and bone mineral density in femora from TG mice. In ex vivo experiments, TG mice showed enhanced differentiation of bone marrow stromal cells to osteoblasts and increased expression levels of bone formation markers. However, TG mice did not show enhanced dynamic bone formation rates in in vivo fluorochrome double labeling experiments. Osteoclastic differentiation capacities of bone marrow monocytes were reduced in TG mice in the presence of osteoclastogenic factors and the numbers of TRAP(+) osteoclasts on distal metaphyseal trabecular bone surfaces were significantly decreased. TRACP 5b and CTX serum levels were significantly decreased in TG mice, while IFN-gamma levels were significantly increased. These data demonstrate that increased levels of IFN-gamma decrease osteoclast bone resorption activities, contributing to the enhanced trabecular bone volume and mineral density in these TG mice. These data suggest a novel role for this DLX-3 mutation in osteoclast differentiation and bone resorption.

Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes.

1. The authors sought to evaluate the contribution of organic cation transporters (OCTs) to the renal tubular transport of metformin using LLC-PK1 cells as an in vitro model for the renal proximal tubule, and to investigate the effects of three non-synonymous genetic variants of OCT2 on the transport activity of metformin in vitro using an oocyte over-expression system. 2. The basolateral-to-apical transport of metformin was significantly greater than the apical-to-basolateral transport and showed concentration dependency with the kinetic parameters: maximum transport rate (V(max)), 922 pmol min(-1) per 5 x 10(5) cells; Michaelis-Menten constant (K(m)), 393 microM; intrinsic clearance (CL(int)), 2.35 microl min(-1) per 5 x 10(5) cells; and diffusion constant (K(d)), 0.33 microl min(-1) per 5 x 10(5) cells. The basolateral-to-apical transport of metformin was inhibited by phenoxybenzamine, an inhibitor of OCTs, but not by cyclosporine A, MK571, or fumitremorgin C, which are inhibitors of P-glycoprotein, multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP), respectively, suggesting that OCTs play a role in renal tubular secretion of metformin. 3. Metformin uptake was much greater in oocytes expressing OCT2-wild type (OCT2-WT) than OCT1-WT compared with uptake in water-injected oocytes. Uptake was significantly decreased in oocytes expressing OCT2-T199I, -T201M, and -A270S compared with that in OCT2-WT, suggesting that metformin is a better substrate for OCT2 than for OCT1 and that the amino acid-substituted variants of OCT2 cause a functional decrease in metformin uptake. 4. In conclusion, the genetic variants of OCT2 (OCT2-T199I, -T201M, and -A270S) decreased the transport activity of metformin and thus may contribute to the inter-individual variation in metformin disposition as OCT2 plays a pivotal role in renal excretion, the major disposition route of metformin.

Genetic variants of the organic cation transporter 2 influence the disposition of metformin.

Genetic variants of the organic cation transporter 2 (protein, OCT2; gene, SLC22A2) were evaluated for their contribution to the variations in the pharmacokinetics of metformin, especially to its renal elimination. Genetic variants of SLC22A2 (c.596C>T, c.602C>T, and c.808G>T) showed significant differences in metformin pharmacokinetics when compared with the reference genotype, with higher peak plasma concentration (C(max)) and area under the curve (AUC) and lower renal clearance (Cl(renal)), thereby suggesting that a decrease in transport function associated with the SLC22A2 variants results in reduced Cl(renal) of metformin and consequently leads to increased plasma concentrations.