Laterality of the performance of glaucoma mass screening using frequency-doubling technology

PURPOSE: This study investigated laterality during the performance of glaucoma mass screening with a frequency-doubling technology perimetry test. MATERIALS AND METHODS: A frequency-doubling technology screening mode (C-20-1, version 2.6) test was performed on both eyes of 14,784 persons. Subjects with visual field abnormalities detected by the frequency-doubling technology test or with fixation error underwent retesting without a specified interval for rest. Consequently, 206 subjects who fulfilled the screening criteria of the frequency-doubling technology-based glaucoma screening protocol [FDT-GSP(+)] were further investigated using the Humphrey visual field analyzer (30-2). As a result, 74 right eyes and 57 left eyes were shown to have definite glaucoma. RESULTS: Frequency-doubling technology data for the left eye demonstrated a significantly (P<0.001) higher rate of artifacts, such as no reproducibility of results between the first and second tests (left/right: 2.4%/1.7%) as well as fixation errors (left/right: 2.8%/1.0%). The false-positive rate of the FDT-GSP for glaucoma was more than 1.5-fold higher in the left eye than in the right eye (16.3%/9.8%). In the case that either eye exhibited FDT-GSP(+), the positive predictive value of the FDT-GSP for definite glaucoma in the left eye was almost half of that in the right eye (28.4% vs. 53.8%). Specificity of the FDT-GSP for detection of definite glaucoma also exhibited a lower trend (P = 0.097) in the left eye (44.6%) than in the right eye (55.3%), but the sensitivity of the test was similar in both eyes (91.2% vs. 90.5%, respectively). CONCLUSIONS: When frequency-doubling technology-based mass screening is performed on the general population, performance is lower for the left eye than for the right eye. This performance disparity is likely to be primarily associated with a difference in specificity.     

Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78+/-0.10 to 0.38+/-0.03 microg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30+/-0.06 to 0.57+/-0.05 microg h/ml and from 17.63+/-1.66 to 4.18+/-0.94 microg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake.     

Inflammatory breast cancer: Vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model

We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, vasculogenic mimicry, which showed an absence of endothelial cells, was observed. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-course dynamic micro-magnetic resonance angiography analysis (with a newly developed intravascular macromolecular contrast agent for magnetic resonance imaging) demonstrated that the WIBC-9 tumor had blood flow and a vascular mimicry-angiogenesis junction.     

Angle dependence of intravascular ultrasound imaging and its feasibility in tissue characterization of human atherosclerotic tissue

BACKGROUND: Intravascular ultrasound (IVUS) images vary in intensity because of the angle of the transducer relative to the plaque. The purpose of this study was to determine the angle dependence of ultrasound backscatter when the IVUS transducer is aligned coaxially in atherosclerotic arteries and to examine its feasibility in tissue characterization of human atherosclerotic tissue. METHODS AND RESULTS: Thirty-nine noncalcified regions of interest (ROI, 0.4 to 0. 6 mm in diameter) within cross sections of formalin-fixed human iliac arterial plaque were imaged with a 3.9F, 25-MHz IVUS catheter in saline at room temperature. The catheter was moved coaxially from 8 to 16 positions and spanned 50 to 122 degrees relative to the ROI and the lumen center. Echo intensity for each ROI was defined as the videointensity relative to a standard reflector. The angle dependence of echo intensity was defined as the slope of the regression line between the angle of incidence and echo intensity. Each ROI was histologically classified into 4 groups: fibro-acellular (fibrous cap, n=7), fibro-cellular (n=9), fibro-fatty (n=13), or fatty tissue (n=10). The echo intensity of the majority (72%) of plaque components in IVUS images are significantly affected by the angle of incidence of the transducer. The angle dependence of fibro-acellular samples was significantly greater than that of the other 3 groups (4.69 +/- 3.29 x 10(-3) x echo intensity/degree vs 1.06 +/- 1.10 in fibro-cellular area, 2.09 +/- 1.75 in fibro-fatty area, and 2.16 +/- 1.92 in fatty area, P <. 05). CONCLUSIONS: The angle dependence of ultrasound reflections from the fibrous cap of atherosclerotic plaque is another method of tissue characterization in addition to spatial distribution and echo intensity. This technique may be useful in determining the thickness of the fibrous cap, which may be an important predictor of plaque rupture.     

Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, induces apoptosis in multiple myeloma cells in an IkappaBalpha-independent manner

Nuclear factor-kappaB (NF-kappaB) is constitutively activated in multiple myeloma cells. Several proteasome inhibitors have been shown to be effective against multiple myeloma and may act by inhibiting degradation of IkappaBalpha. Here, we examined the biological effects of a new type of NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is reported to directly inhibit the cytoplasm-to-nucleus translocation of NF-kappaB. A multiple myeloma cell line, 12PE, which is defective for IkappaBalpha protein, was utilized to determine if IkappaBalpha is concerned with the action of DHMEQ. Meanwhile, U266 was used as a multiple myeloma cell line with normal IkappaBalpha. A proteasome inhibitor, gliotoxin, which is an inhibitor of degradation of phosphorylated IkappaBalpha, failed to inhibit translocation of NF-kappaB in 12PE. In contrast, DHMEQ equally inhibited translocation of NF-kappaB to the nucleus and induced apoptosis to both multiple myeloma cell lines, suggesting that apoptosis resulting from DHMEQ is IkappaBalpha independent. DHMEQ also induced apoptosis in freshly isolated multiple myeloma cells. After DHMEQ treatment, cleavage of caspase-3 and down-regulation of cyclin D1 were observed in both cell lines. In addition, administration of DHMEQ resulted in a significant reduction in tumor volume in a plasmacytoma mice model compared with control mice. Our results show that DHMEQ could potentially be a new type of molecular target agent for multiple myeloma.     

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.     

Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.