Impact of glycaemic control and CYP3A5 polymorphisms on tacrolimus trough concentrations after adult kidney transplantation.

AIMS: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. RESULTS: Out of 42 patients (CYP3A5 expressers, n = 17, and non-expressers, n = 25), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r = .43, P = .028). Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r = .59, P < .001) and increased HbA1c levels and CYP3A5 non-expressers (r = .62, P < .001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y = 54.6x - 194.6, r = .63, P = .004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y = 54.5x + 20.2, r = .41, P = .036, Bonferroni correction). CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

Suppression of Amyloid-ß Adsorption on Endoplasmic Reticulum Stress-Mimicking Membranes by α-Tocopherol and α-Tocotrienol.

Two forms of hydrophobic vitamin E (VE), α-tocopherol (Toc) and α-tocotrienol (Toc3), have been proposed to be effective against Alzheimer's disease (AD), the etiology of which is thought to involve endoplasmic reticulum (ER) stress. However, previous studies reported conflicting effects of Toc and Toc3 on the risk of AD. We prepared liposomes mimicking the phase separation of the ER membrane (solid-ordered/liquid-disordered phase separation) and studied how VE can influence the interaction between amyloid-ß (Aß) and the ER membrane. We found that Toc could inhibit the formation of the solid-ordered phase more significantly than Toc3. Furthermore, Aß protofibril adsorption on ER stress-mimicking membranes was more strongly suppressed by Toc compared with Toc3. Therefore, we concluded that VE can relieve ER stress by destabilizing the solid-ordered phase of the ER membrane and subsequently reducing the amount of Aß adsorbed on the membrane. Moreover, Toc exerted a stronger effect than Toc3.

Comparison of the Structure-Function Relationship in Glaucoma Using Optical Microangiography in the Peripapillary Retinal Nerve Fiber Layer.

PRCIS: Optical microangiography measurements correlated with functional parameters in glaucoma patients. Optical coherence tomography angiography-derived vessel perfusion density (VPD) better reflected the structure-function relationship than flux index (FI) and retinal nerve fiber layer thickness. PURPOSE: The purpose of this study was to compare the structure-function relationship between peripapillary optical microangiography (OMAG) measurements and standard automated perimetry (SAP) loss by comparison with peripapillary retinal nerve fiber layer (pRNFL) thickness in primary open-angle glaucoma. MATERIALS AND METHODS: One eye from each of 128 patients with early-to-severe glaucoma (including preperimetric glaucoma) and 23 normal participants underwent optic nerve head scanning of the radial peripapillary capillaries and pRNFL scans with OMAG centered on the optic disc and SAP (mean age: 67.8±12.0 y; SAP mean deviation: -5.84±6.6 dB). Regional relationships between VPD, FI, pRNFL thickness, and corresponding SAP sensitivity were compared using linear and fractional polynomial (FP) models. RESULTS: Structure was significantly related to function for all but the nasal pRNFL thickness region. For VPD, the coefficient of determination (R2) using the FP model was significantly stronger than that of the linear model (FP: 0.25 to 0.67, linear: 0.19 to 0.61), while no difference was found for FI in any region (FP: 0.19 to 0.44, linear: 0.15 to 0.42). R2 for VPD was stronger than FI and pRNFL (FP: 0.11 to 0.52, linear: 0.01 to 0.44) in inferior and superior regions, while VPD and FI were not different in temporal and nasal regions. CONCLUSIONS: VPD showed a stronger association with visual field loss than FI or retinal nerve fiber layer thickness except in the temporal region. The FI relationship was weak but more linear around the peripapillary region. The strength of the structure-function relationship may differ depending on the region of OMAG measurements.

Concomitant febuxostat enhances methotrexate-induced hepatotoxicity by inhibiting breast cancer resistance protein.

Methotrexate (MTX) is an antifolate agent used for the treatment of various malignancies and is eliminated by breast cancer resistance protein (BCRP). Because febuxostat (FBX) is known to inhibit BCRP activity, FBX might exacerbate MTX-related adverse effects. In this study, we examined the drug-drug interaction between FBX and MTX in BCRP-expressing membrane vesicles. Moreover, we retrospectively investigated the impact of FBX on MTX-related adverse effects in 38 patients (144 cycles) receiving high-dose MTX therapy (HDMTX). The Food and Drug Administration Adverse Event Reporting System (FAERS) database and human hepatocellular carcinoma cell line HepG2 cells were used to evaluate the effects of FBX on MTX-induced hepatotoxicity. In the membrane vesicle study, FBX significantly inhibited BCRP-mediated transport of MTX. Concomitant FBX significantly increased the incidence of hepatotoxicity, but not of nephrotoxicity and hematological toxicity in patients receiving HDMTX. FAERS database analyses revealed that the reporting odds ratio of FBX for MTX-induced hepatotoxicity was 4.16 (95% CI: 2.89-5.98). Co-incubated FBX significantly decreased the cell viability and increased cytotoxicity in MTX-treated HepG2 cells. These findings suggest that concomitant FBX enhances MTX-induced hepatotoxicity by inhibiting hepatic BCRP. These findings provide important information for the safe management of HDMTX therapy in clinical settings.

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. ©2016 AACR.

Influences of the inner retinal sublayers and analytical areas in macular scans by spectral-domain OCT on the diagnostic ability of early glaucoma.

PURPOSE: We investigated the influences of the inner retinal sublayers and analytical areas in macular scans by spectral-domain optical coherence tomography (OCT) on the diagnostic ability of early glaucoma. METHODS: A total of 64 early (including 24 preperimetric) glaucomatous and 40 normal eyes underwent macular and peripapillary retinal nerve fiber layer (pRNFL) scans (3D-OCT-2000). The area under the receiver operating characteristics (AUC) for glaucoma diagnosis was determined from the average thickness of the total 100 grids (6 × 6 mm), central 44 grids (3.6 × 4.8 mm), and peripheral 56 grids (outside of the 44 grids), and for each macular sublayer: macular RNFL (mRNFL), ganglion cell layer plus inner plexiform layer (GCL/IPL), and mRNFL plus GCL/IPL (ganglion cell complex [GCC]). Correlation of OCT parameters with visual field parameters was evaluated by Spearman's rank correlation coefficients (rs). RESULTS: The GCC-related parameters had a significantly larger AUC (0.82-0.97) than GCL/IPL (0.81-0.91), mRNFL-related parameters (0.72-0.94), or average pRNFL (0.88) in more than half of all comparisons. The central 44 grids had a significantly lower AUC than other analytical areas in GCC and mRNFL thickness. Conversely, the peripheral 56 grids had a significantly lower AUC than the 100 grids in GCL/IPL inferior thickness. Inferior thickness of GCC (rs, 0.45-0.49) and mRNFL (rs, 0.43-0.51) showed comparably high correlations with central visual field parameters to average pRNFL thickness (rs, 0.41, 0.47) even in the central 44 grids. CONCLUSIONS: The diagnostic ability of macular OCT parameters for early glaucoma differed by inner retinal sublayers and also by the analytical areas studied.

Structural and functional assessment by hemispheric asymmetry testing of the macular region in preperimetric glaucoma.

PURPOSE: To investigate structural measurements of the macular area in preperimetric glaucoma (PG) patients using spectral domain optical coherence tomography with two functional measurements [10-2 Humphrey visual field (HFA) and 10-2 Microperimeter-1 (MP-1)] and by macular symmetry testing. METHODS: Fifteen eyes of 15 PG subjects with a retinal nerve fiber layer defect in the inferior hemisphere and 15 eyes of 15 normal control subjects were enrolled. Macular symmetry testing was performed between the superior and inferior zones by comparing zone thickness in each hemisphere. Perimetric sensitivity asymmetry was calculated with two functional measurements. Structure-function relationships between macular symmetry testing and the mean retinal sensitivity of the corresponding hemifield or perimetric sensitivity asymmetry were calculated using Spearman's rank correlation and linear regression. RESULTS: Macular zone thickness in the abnormal hemispheres was significantly less than that in normal hemispheres in PG eyes and the corresponding hemispheres in control eyes (P < 0.001). Macular symmetry testing was significantly lower in PG eyes compared to control eyes (P < 0.001). HFA (10-2) and MP-1 (10-2) correlated significantly (rs = 0.81, P < 0.0001). Macular symmetry testing values were significantly correlated with perimetric sensitivity and perimetric sensitivity asymmetry with two functional measurements (rs = 0.61, P = 0.02; HFA and rs = 0.68, P = 0.006; MP-1). CONCLUSIONS: Our results suggest that macular asymmetry analysis can reveal the structure-functional relationship in PG eyes.

Successful treatment of corneal wasp sting-induced panuveitis with vitrectomy.

BACKGROUND: This study aims to present the management and clinical findings of a case of corneal wasp sting and to report the outcome of corneal change and panuveitis after vitrectomy. FINDINGS: Clinical findings, anterior segment photographs, corneal endothelial changes, and medical treatment of corneal wasp sting-induced panuveitis are presented. A 95-year-man was stung by a wasp on his left cornea. A severe conjunctival hyperemia, marked corneal edema, corneal epithelial defect, and uveitis developed. As soon as the patient visited our clinic, topical corticosteroid and antibiotics were given, but corneal endothelial damage and uveitis did not improve. Anterior chamber irrigation was performed with oxiglutatione solution to rinse out the wasp venom. Corneal edema and anterior uveitis improved but the endothelial cell density gradually decreased and the vitreous opacity deteriorated. Therefore, a 23-gauge vitrectomy was performed. Subsequently, the corneal edema and panuveitis improved. CONCLUSIONS: Vitrectomy may be an effective treatment for corneal endothelial damage and endophthalmitis induced by a corneal wasp sting.

Effect of cataract and its removal on ganglion cell complex thickness and peripapillary retinal nerve fiber layer thickness measurements by fourier-domain optical coherence tomography.

PURPOSE: To examine the effect of cataract on signal strength index (SSI) and thickness measurements of the ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (pRNFL) with the RTVue-100 Fourier-domain optical coherence tomography device. METHOD: GCC and pRNFL measurements were obtained preoperatively in 53 eyes of 53 patients, including 13 glaucoma patients and measurements were repeated postoperatively. Cataract degree was graded by the Lens Opacities Classification System III. Factors associated with segmentation error and with changes in SSI or average thickness of GCC and pRNFL were determined. RESULTS: The prevalence and proportion of segmentation error were higher in GCC measurements compared with pRNFL measurements (prevalence: 28.3% vs. 5.6%, P<0.001; proportion: 5.9% vs. 1.3%, P=0.01). Multivariate analysis showed that segmentation error in GCC measurements was significantly associated with preoperative SSI and the degree of posterior subcapsular opacity. In eyes without segmentation error, postoperative SSI was significantly higher for GCC and pRNFL measurements, whereas postoperative thickness was slightly but significantly higher for all GCC and pRNFL parameters. Multivariate analysis indicated that preoperative SSI was highly correlated with SSI changes and that the presence of glaucoma and preoperative SSI were significantly correlated with average thickness changes of GCC and pRNFL, respectively. CONCLUSIONS: In eyes with cataract, segmentation error occurred more frequently in GCC measurements than in pRNFL measurements. After cataract surgery, all thickness parameters in GCC and pRNFL measurements increased slightly. Segmentation errors should be determined, especially in GCC measurements of eyes with cataract and low SSI.

Detection of visual field defects in pre-perimetric glaucoma using fundus-oriented small-target perimetry.

PURPOSE: To evaluate the usefulness of automated fundus-oriented small-target perimetry in detecting glaucomatous visual field abnormalities. MATERIALS AND METHODS: One eye from each of 60 normal, 37 pre-perimetric glaucoma (PPG) and 29 early stage of primary open-angle glaucoma (POAG) persons were included. The new perimeter had two monitors, one for a campimeter and the other for the examiner's operation. A test area within the central 15° was set in the fundus image. The target size was 2.9 min in diameter, and the distance between the two adjacent targets was 60 min. The rate of negative response (RNR) among the age-matched controls, PPG and POAG were compared. The relationship between the RNR and age of the normal or standard automated perimetry (SAP) global indices in PPG and POAG was examined. The areas under the receiver-operating characteristic curve (AROC) to discriminate PPG or POAG versus normal were determined. RESULTS: The RNR increased significantly with age in normal and differed significantly (P < 0.001) among control (1.8 ± 1.3 %), PPG (9.2 ± 10.4 %) and POAG (21.2 ± 14.3 %). Significant correlation was found between the RNR and SAP global indices. The AROC was 0.89 for PPG and 0.95 for POAG. CONCLUSION: Fundus-oriented small-target perimetry is useful in detecting visual field abnormalities in PPG.

Evaluation of macular thickness and peripapillary retinal nerve fiber layer thickness for detection of early glaucoma using spectral domain optical coherence tomography.

PURPOSE: To evaluate the diagnostic ability of macular parameters and peripapillary retinal nerve fiber layer (RNFL) parameters for early glaucoma using spectral domain optical coherence tomography (SD-OCT). MATERIALS AND METHODS: One eye from 32 early glaucoma patients (including preperimetric glaucoma) and 32 normal participants underwent macular scans and peripapillary RNFL scans with SD-OCT 3 times on the same day. The discrimination power of each parameter to detect early glaucoma was determined by areas under receiver operating characteristics curve (AROC) and sensitivity at fixed specificity. Correlation of OCT data with visual field defects was evaluated by linear regression analysis. Reproducibility was also evaluated. RESULTS: Significant differences between early glaucoma and normal participants were found for all parameters except fovea in macular scans and in the superior and inferior quadrants, at 12, 3, 6, 7, 11 o'clock, and average RNFL thickness in RNFL scans. The best parameters based on AROC and sensitivity at a specificity of >90% were temporal outer macula thickness (AROC, 0.79; sensitivity, 63%) in macular parameters and inferior quadrant (AROC, 0.82; sensitivity, 53%) in RNFL parameters. The highest correlation with mean deviation was found in inferior inner macular volume (r=0.50, P<0.001). The mean intraclass correlation coefficient was 0.96 in macular scans and 0.84 in RNFL scans. Test-retest variability ranged from 2.3 to 10.1 µm in macular thickness, 0 to 0.06 mm in macular volume, and 5.8 to 18.9 µm in RNFL thickness. CONCLUSION: For the diagnosis of early glaucoma by SD-OCT, macular parameters had high discriminating power and high reproducibility comparable with peripapillary RNFL parameters.

Incorporation and remodeling of extracellular phosphatidylcholine with short acyl residues in Saccharomyces cerevisiae.

The pem1/cho2 pem2/opi3 double mutant of Saccharomyces cerevisiae, which is auxotrophic for choline because of the deficiency in methylation activities of phosphatidylethanolamine, grew in the presence of 0.1 mM dioctanoyl-phosphatidylcholine (diC(8)PC). Analysis of the metabolism of methyl-(13)C-labeled diC(8)PC ((methyl-(13)C)(3)-diC(8)PC) by electrospray ionization tandem mass spectrometry (ESI-MS/MS) revealed that it was rapidly converted to (methyl-(13)C)(3)-PCs containing C16 or C18 acyl chains. (Methyl-(13)C)(3)-8:0-lyso-PC, (methyl-(13)C)(3)-8:0-16:0-PC and (methyl-(13)C)(3)-8:0-16:1-PC, which are the probable intermediate molecular species of acyl chain remodeling, appeared immediately after 5 min of pulse-labeling and decreased during the subsequent chase period. These results indicate that diC(8)PC was taken up by the pem1 pem2 double mutant and that the acyl chains of diC(8)PC were exchanged with longer yeast fatty acids. The temporary appearance of (methyl-(13)C)(3)-8:0-lyso-PC suggests that the remodeling reaction may consist of deacylation and reacylation by phospholipase activities and acyltransferase activities, respectively. The detailed analyses of the structures of (methyl-(13)C)(3)-8:0-16:0-PC and (methyl-(13)C)(3)-8:0-16:1-PC by MS/MS and MS(3) strongly suggest that most (methyl-(13)C)(3)-8:0-16:0-PCs have a C16:0 acyl chain at sn-1 position, whereas (methyl-(13)C)(3)-8:0-16:1-PCs have a C16:1 acyl chain at either sn-1 or sn-2 position in a similar frequency, implying that the initial C16:0 acyl chain substitution prefers the sn-1 position; however, the C16:1 acyl chain substitution starts at both sn-1 and sn-2 positions. The current study provides a pivotal insight into the acyl chain remodeling of phospholipids in yeast.

Carcinosarcoma of the lacrimal gland arising from a pleomorphic adenoma.

PURPOSE: To report a case of the lacrimal gland tumor diagnosed as carcinosarcoma (true mixed tumor) arising from a pleomorphic adenoma. DESIGN: Interventional case report. METHODS: An 80-year-old Japanese woman was referred with a well-circumscribed tumor in the lacrimal fossa. RESULTS: The tumor was excised, but the deepest portion remained because of heavy bleeding. Histopathologically, the tumor consisted of osteosarcomatous cells. No epithelial or myoepithelial component was identified by immunohistochemistry. Two months later, the tumor progressed further and was excised completely with lateral orbitotomy. The tumor consisted primarily of osteosarcomatous component but also had epithelial components including carcinoma and pleomorphic adenoma. Examinations did not detect local recurrence and metastasis at 10 post-operative months. CONCLUSION: The tumor was diagnosed as true carcinosarcoma of the lacrimal gland arising from a pleomorphic adenoma. When lacrimal gland tumors containing sarcomatous components are encountered, carcinosarcoma should be included in the differential diagnosis.