Relationship between indices of Humphrey perimetry and Frequency Doubling Technology Perimetry in glaucoma

PURPOSE: To study whether the correlation between indices of Humphrey perimetry and Frequency Doubling Technology (FDT) perimetry differs in the early and later stages of glaucoma. METHODS: This study included 200 eyes of 200 patients with primary open-angle glaucoma or normal-tension glaucoma. The eyes were classified into the early and later stages by the median value (-4.51 dB) (Classification 1; n = 100 and 100, respectively) or the average value of the maximum and minimum values (-11.90 dB) (Classification 2; n = 165 and 35, respectively) of mean deviation (MD) obtained from a set of measurements with the Humphrey Full-Threshold 30-2 program in all eyes. The correlation between MD (H-MD) or pattern standard deviation (PSD) (H-PSD), as obtained from another set of measurements with the Humphrey Full-Threshold 30-2 program, and MD (F-MD) or PSD (F-PSD), as calculated by the Full-Threshold N-30 program of FDT perimetry, were evaluated using linear regression analysis. RESULTS: Overall, H-MD and H-PSD significantly correlated with F-MD (r = 0.713; P < 0.001) and F-PSD (r = 0.731; P < 0.001), respectively. In each of Classifications 1 and 2, H-MD and H-PSD significantly correlated with F-MD and F-PSD, respectively, both in the early and later stages. However, in each classification, the correlation between H-MD and F-MD differed significantly between the two stages (Classification 1; P < 0.001; Classification 2, P = 0.003), while the correlation between H-PSD and F-PSD did not differ significantly between the two stages. CONCLUSION: The degree of correlation between H-MD and F-MD differed between the early and later stages of glaucoma.     

Optic disc topography as measured by confocal scanning laser ophthalmoscopy and visual field loss in Japanese patients with primary open-angle or normal-tension glaucoma

PURPOSE: To determine whether differences in the optic disc topography and those in the relation between the optic disc topography and visual field indices exist between Japanese patients with primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). METHODS: The study included consecutive Japanese patients with POAG (n = 60) or NTG (n = 60). Using the Heidelberg Retina Tomograph (HRT), we measured disc area, cup area, cup-to-disc area ratio, rim area, cup volume, rim volume, cup shape measure, and height variation contour. Each HRT parameter was measured in the total optic disc and in its four 90 degree quadrants (superior, temporal, inferior, and nasal). The mean deviation for the entire field and the sum of the total deviation values corresponding to each optic disc quadrant were calculated using the Humphrey full-threshold 30-2 program. RESULTS: No significant differences were found between the POAG and NTG groups for any HRT parameter either globally or regionally. There were no significant differences between the two groups in the correlation coefficients between any HRT parameter and the corresponding visual field indices either globally or regionally. CONCLUSION: No significant differences were apparent between Japanese patients with POAG and NTG both in the optic disc parameters as measured by HRT and in the degree of correlation between HRT parameter and the corresponding visual field indices.     

Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide

Ebselen (2-phenyl-1, 2-benzisoselenazol-3[2H]-one) is a seleno-organic compound exhibiting both glutathione peroxidase and antioxidant activity. Although it has been reported that ebselen is effective against hydrogen peroxide (H(2)O(2))-induced cell death in several cell types, its effect on endothelial cell damage has not yet been elucidated. In the present study, we examined the effect of ebselen on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs) death, and its intracellular mechanism. Our findings showed that pretreatment of HUVECs with ebselen resulted in a significant recovery from H(2)O(2)-induced cell death in a concentration-dependent manner. In addition to the inhibition of lactate dehydrogenase (LDH) leakage, ebselen inhibited H(2)O(2)-induced cytochrome c release and caspase-3 activation and the resultant apoptosis in HUVECs. Moreover, it was observed that H(2)O(2) significantly stimulated activation of mitogen-activated protein (MAP) kinases, i.e., p38 MAP kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2). Ebselen inhibited H(2)O(2)-induced p38 MAP kinase, but not JNK or ERK1/2 activation. Furthermore, SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]-1H-imidazole), a specific p38 MAP kinase inhibitor, inhibited H(2)O(2)-induced p38 MAP kinase phosphorylation, cytochrome c release, caspase-3 activation, as well as cell death in HUVECs. These findings suggest that ebselen attenuates H(2)O(2)-induced endothelial cell death through the inhibition of signaling pathways mediated by p38 MAP kinase, caspase-3, and cytochrome c release. Thus, inhibition of p38 MAP kinase by ebselen may imply its usefulness for prevention and/or treatment of endothelial cell dysfunction, which was suggested to be the first step in the development of atherosclerosis.     

Aldosterone and renal injury

Our recent efforts have been focused on the mechanisms responsible for the progression of aldosterone-induced renal injury. We have demonstrated in rats that chronic treatment with aldosterone (0.75 micro g/H, SC) and 1% NaCl (in drinking solution) results in severe proteinuria and glomerular injury, characterized by cell proliferation and mesangial matrix expansion. Increased renal cortical NAD(P)H oxidase expression, reactive oxygen species (ROS) generation, and mitogen-activated protein kinase (MAPK) activation were also observed. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone(0.125% in chow), or an antioxidant, tempol (3 mM in drinking solution), prevented elevations of ROS levels and MAPK activity, as well as ameliorating glomerular injury, indicating that aldosterone-induced glomerular injury is associated with redox-sensitive MAPK activation. In vitro studies showed that mineralocorticoid receptors are highly expressed in rats mesangial cells, particularly in the cytoplasm. Aldosterone (100 nM) application activates MAPK and causes cellular proliferation and deformation. These data suggest that aldosterone contributes to the progression of glomerular injury through its direct actions.     

Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates

The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.     

Twice-daily administration of a long-acting angiotensin-converting enzyme inhibitor has greater effects on neurohumoral factors than a once-daily regimen in patients with chronic congestive heart failure

Although many clinical trials have evaluated the use of long-acting angiotensin-converting enzyme (ACE) inhibitors in patients with chronic congestive heart failure (CHF), there are no data regarding whether a once-daily or twice-daily regimen is preferable with respect to effects on the neuroendocrine system. To address this issue, the authors evaluated the comparative effects of the administration schedule on neurohumoral factors and autonomic nervous activity in patients with CHF. Thirty-two patients with mild compensated CHF received lisinopril (5-20 mg/d) orally either once a day (n = 17) or twice a day (n = 15) for more than 3 months. After this initial therapy, patients receiving a once-daily regimen switched to a twice-daily regimen and vice-versa, and patients were followed for an additional 3 months. Neurohumoral factors and the coefficient of variance in the electrocardiographic R-R interval (CVRR) were measured. Hemodynamic parameters, renal function, plasma concentrations of brain natriuretic peptide and aldosterone, and CVRR did not differ between the two regimens. However, the plasma concentration of norepinephrine was significantly lower, and plasma renin activity tended to be lower with the twice-daily regimen. These findings suggest that twice-daily administration of long-acting ACE inhibitors may have better effects on the neuroendocrine system than a once-daily regimen in patients with mild CHF.     

Analysis of interleukin-13 receptor alpha2 expression in human pediatric brain tumors

BACKGROUND: Compared with normal brain tissue cells, human malignant glioma cells express higher levels of interleukin-13 receptor (IL-13R). However, whether this receptor is expressed in situ has not been carefully examined. With IL-13R-targeted cytotoxin (IL13-PE38QQR, comprising IL-13 and a mutated form of Pseudomonas exotoxin [PE]) being tested in three Phase I/II clinical trials for the treatment of adult human glioma, and with pediatric studies being planned, the authors set out to analyze pediatric brain tumor tissue specimens for the expression of IL-13R. METHODS: Using in situ hybridization and immunohistochemical staining, the authors examined 58 pediatric brain tumor specimens for expression of the predominant IL-13 binding and internalizing protein (IL-13Ralpha2) chain at the mRNA and protein levels. RESULTS: Overall, approximately 83% of pediatric brain tumor samples expressed IL-13Ralpha2. One hundred percent (11 of 11) high-grade astrocytoma, 79% (26 of 33) low-grade astrocytoma, 67% (4 of 6) medulloblastoma, and 67% (2 of 3) ependymoma samples were positive for IL-13Ralpha2. Among IL-13Ralpha2-positive samples, 88% (42 of 48 samples) had positive expression in > or = 50% of all tumor fields. The results obtained using both assays were consistent with each other. CONCLUSIONS: The current study established that pediatric brain tumor specimens expressed the IL-13Ralpha2 chain. Because the IL-13Ralpha2 chain is a major binding component of the IL-13R complex, these results suggest that the targeting of IL-13R may represent a useful approach for the treatment of pediatric brain tumors.     

Analysis of the oligosaccharide chain of human serum immunoglobulin g in patients with localized or metastatic cancer

A quantitative imbalance between matrix metalloproteinases produced by cancer cells and tissue inhibitors of metalloproteinases produced by fibroblasts and other types of cells has been demonstrated to be a causative factor in invasion and metastasis of cancer cells. On the other hand, it is reported that sugar chains of adhesion molecules such as integrins and CD44 also influence the metastasis of cancer cells. Here, alterations of serum IgG oligosaccharide chain structure were investigated during tumor progression using the new method of fluorophore-assisted carbohydrate electrophoresis (FACE). The structure of serum IgG oligosaccharide chains from 22 cancer patients (11 localized cancer, 11 metastatic cancer) and 10 healthy controls was evaluated by FACE. It was clearly demonstrated that serum IgG oligosaccharide chains without galactose (agalactosyl IgG oligosaccharide) significantly increased with tumor progression of lung and gastric cancers. It is concluded that a marked increase of agalactosyl IgG oligosaccharide in these cancer patients is associated with carcinogenesis and metastasis. Therefore, the analysis of serum IgG oligosaccharide chain structure by FACE may be useful for evaluating diagnosis and prognosis in patients with these carcinomas.     

Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia

Bone marrow cells of patients with myelodysplastic syndromes (MDS) frequently undergo apoptosis, though the apoptotic cell ratio decreases when overt leukemia (OL) develops. Thus, we compared the expression of the inhibitor of apoptosis protein (IAP) gene family proteins in bone marrow samples from control, MDS, OL transformed from MDS (MDS --> OL), and de novo acute myelogenous leukemia (AML) subjects by the quantitative real-time RT-PCR method and an immunohistochemical approach. Overexpression of mRNA for survivin, cIAP1, NAIP and XIAP was significant in MDS bone marrow cells compared with control samples. However, the expression of mRNA for survivin, cIAP1 and cIAP2 exhibited a remarkable decrease after the development of OL (MDS --> OL). By immunohistochemistry, survivin was found to localize to the nucleus of myeloid cells in the majority of MDS cases. Next, the chronological changes in the expression of IAPs were determined in cases of MDS with evolution of OL. Although the expression of cIAP1 and cIAP2 revealed a sudden or gradual decrease as OL developed, survivin in many cases and XIAP in the majority of cases exhibited a peak of expression before a decline, indicating that these IAPs could be associated with the early events in the development of OL.