Therapeutic efficacy of latoconazole in formulations of clinical use on experimental dermatophytosis in guinea pigs.

Therapeutic efficacy of clinical dosage forms of latoconazole (NND-318, CAS 101530-10-3), related compound of ketene dithioacetals with an imidazole ring, was examined on two experimental tinea models: a recently developed tinea pedis model and a conventional tinea corporis model in guinea pigs. The efficacy of the dosage forms was estimated on the basis of the rate of fungus-positive skin cultures and/or the score of skin lesions, and was compared to the other antifungal agents, bifonazole, clotrimazole and tolnaftate. While these reference agents exhibited curative effect on the tinea corporis model, the tinea pedis model was considerably resistant to the therapeutic treatment of the agents. The cream preparation and solution of lactoconazole at concentrations of more than 0.25% were highly effective in either tinea models, and at concentrations of more than 1%, lactoconazole achieved complete mycological cure. These results suggest that 1% of lactonazole is an optimal concentration for clinical use.     

A possible involvement of oxygen free radicals in the development of myocardial acidosis during coronary occlusion in dogs

Summary The present study was designed to examine whether free radical scavengers attenuate myocardial acidosis induced by partial occlusion of the coronary artery in dogs. The myocardial pH was determined by a micro glass pH electrode inserted in the endocardial layers of the left ventricular wall perfused by the left anterior descending coronary artery. The left anterior'descending coronary artery was occluded for 90 min incompletely so that the flow would be 1/2–1/3 the original flow. The myocardial pH before partial occlusion was 7.54–7.55. Partial occlusion decreased the flow in the left anterior descending coronary artery by 49.3–64.9% and the myocardial pH by 0.71–0.76, and increased the ST segment (surface electrocardiogram) by 6.3–9.3 mV. Saline (0.5 ml/kg), recombinant human superoxide dismutase (70,000 or 210,000 U/kg), or catalase (55,000 or 165,000 U/kg) was injected intravenously 30 min after partial occlusion. The injection of recombinant human superoxide dismutase or catalase alone did not restore the myocardial pH that had been decreased by coronary occlusion. The combined injection of recombinant human superoxide dismutase (70,000 U/kg) + catalase (55,000 U/kg), however, restored the myocardial pH without restoration of ST segment. In conclusion, recombinant human superoxide dismutase + catalase attenuated myocardial acidosis during ischaemia, suggesting a possible involvement of oxygen free radicals in the development of myocardial acidosis (especially in the endocardial layers) during ischaemia. Send offprint requests to Y. Abiko at the above adress     

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12-135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 - 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21-9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.     

Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer

Understanding the molecular action of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, might allow us to perform more effective therapies for hormone-independent advanced prostate cancer. A DNA microarray study was undertaken to comprehensively analyze the alteration of levels of 1,081 genes after gefitinib treatment in androgen-independent PC3 and DU145 cells and androgen-dependent LNCaP cells. The proliferation of PC3, DU145 and LNCaP cells was significantly inhibited by 50.2%, 83.8% and 55.2%, respectively, 6 days after 10 microM gefitinib administration. Of the above 1,081 genes, we identified 23, 13 and 33 genes with significantly different expression in PC3, DU145 and LNCaP cells, respectively, 24 h after 10 microM-gefitinib exposure. Among the identified genes, only Quiescin Q6, a negative cell cycle regulator, was increased after gefitinib treatment in all three cell lines regardless of gefitinib sensitivity. Except for Quiescin Q6, there were no overlapping genes between PC3 and DU145 cells. However, levels of several oncogenes or proliferation-related genes were changed after gefitinib treatment in the 2 androgen-independent cell lines. We also identified 7 unique genes [glycyl-tRNA synthetase, interferon, alpha-inducible protein, stratifin, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1, dual specificity phosphatase 9, guanine nucleotide binding protein (G protein) beta polypeptide 2, neural retina leucine zipper] whose levels were altered exclusively after gefitinib administration in gefitinib-resistant PC3 and LNCaP cells, but not in DU145 cells, suggesting that these 7 genes could be targets for overcoming gefitinib resistance. Collectively, our molecular profiling data will serve as a framework for understanding the molecular action of gefitinib for prostate cancer.     

Deposition of extracellular matrix on silicone intraocular lens implants in rabbits

Purpose: To examine the deposition of extracellullar matrix on silicone intraocular lenses (IOLs) implanted experimentally into rabbit eyes by electron microscopy and to determine the immunolocalization of extracellular matrix components, including collagen types and cellular fibronectin, on these IOLs. Methods: We performed phacoemulsification and aspiration of the crystalline lens and implanted a foldable silicone IOL in the capsular bag of one eye of each of 26 adult albino rabbits under general anesthesia. After 8 weeks the animals were killed and the eyes were enucleated. The silicone IOLs were processed for electron microscopy and for immunohistochemical detection of collagen types I, III, and IV and cellular fibronectin. Results: Electron microscopy revealed deposition of a presumed cell matrix complex on the optic portion of all silicone IOLs, as well as the adhesion of presumed macrophages and foreign-body giant cells. Cellular deposits showed immunoreactivity for cellular fibronectin. Fibrous or membranous deposits exhibited immunoreactivity for cellular fibronectin and collagen types I and III. A few type IV collagen-immunoreactive deposits were also seen. Conclusion: Deposits of extracellular matrix components were observed on silicone IOLs. These deposits may form the scaffolding for the adhesion and proliferation of cells. These matrix components appeared to be the products of cells adhering to the surfaces of IOLs, including lens epithelial cells, macrophages and foreign-body giant cells, indicating that the process of granulation was incomplete.     

Value of thyroid stimulating antibody in the diagnosis of thyroid associated ophthalmopathy of euthyroid patients

AIMS/BACKGROUND—Thyroid associated ophthalmopathy (TAO) of euthyroid patients is difficult to diagnose because clinical findings overlap with other conditions, and no confirmatory diagnostic tests are available. Recently, it was reported that TSH binding inhibitor immunoglobulin (TBII) and thyroid stimulating antibody (TSAb) are sensitive markers of TAO. The sensitivity of these antibodies in the detection of TAO were therefore studied to determine if they could be a useful criterion in the diagnosis of TAO of euthyroid patients.
METHODS—Serum values of TBII and TSAb of 35 patients with euthyroid TAO (group A) were compared with those of 27 patients with Graves' disease and TAO (group B). The relation between the serum value of TSAb and the eye symptoms of patients with euthyroid TAO were also examined by multiple linear regression analysis.
RESULTS—In group A, TBII was positive in 10 cases (28.6%) and TSAb was positive in 29 cases (82.9%). In group B, both TBII and TSAb were positive in all cases (100%). The titre of serum TBII in group A (15.6% (SD 18.0%)) was significantly lower (p<0.0001) than in group B (57.9% (21.5%)). The titre of serum TSAb in group A (1400.9% (2163.9%)) was significantly lower (p=0.0026) than in group B (2243.9% (1472.8%)). Among the eye findings of patients with euthyroid TAO, keratopathy was significantly (p=0.034) related to the value of TSAb.
CONCLUSION—These results suggest that the activity of TSAb is a more sensitive marker of euthyroid TAO than is TBII, and could be a useful criterion in the diagnosis of TAO of euthyroid patients.

     

New era of research on cancer‐associated glycosphingolipids

Cancer‐associated glycosphingolipids have been used as markers for diagnosis and targets for immunotherapy of malignant tumors. Recent progress in the analysis of their implications in the malignant properties of cancer cells revealed that cancer‐associated glycosphingolipids are not only tumor markers, but also functional molecules regulating various signals introduced by membrane microdomains, lipid rafts. In particular, a novel approach, enzyme‐mediated activation of radical sources combined with mass spectrometry, has enabled us to clarify the mechanisms by which cancer‐associated glycosphingolipids regulate cell signals based on the interaction with membrane molecules and formation of molecular complexes on the cell surface. Novel findings obtained from these approaches are now providing us with insights into the development of new anticancer therapies targeting membrane molecular complexes consisting of cancer‐associated glycolipids and their associated membrane molecules. Thus, a new era of cancer‐associated glycosphingolipids has now begun.     

Strong antibody reaction against glycosphingolipids injected in liposome-embedded forms in beta3GN-T5 knockout mice

It is known that mutant mice of the beta-1,3-N-acetylglucosaminyltransferase gene (beta3Gn-T5) respond well to T-cell dependent and independent antigens. Here, we examined the effectiveness of anti-ganglioside antibody generation by immunization of beta3Gn-T5 mutant mice with liposome-embedded glycosphingolipids such as GD1a and GT1b. Consequently, the mutant mice showed a more efficient generation of anti-GD1a or anti-GT1b antibodies than wild-type mice in an enzyme-linked immunosorbent assay using sera during immunization. Thus, the beta3Gn-T5 deficient mutant mice proved more responsive than wild-type mice to not only protein antigens, but also to carbohydrates in glycolipids. Furthermore, about 50% of monoclonal antibodies generated using splenocytes of the immunized mutant mice were of the IgG class. Besides general high responsiveness to proteins and glycolipids, it could be expected that the mutant mice of beta3Gn-T5 would be useful in the generation of monoclonal antibodies towards lacto-/neolacto-series glycolipids, since these mutants lack lacto-/neolacto-series glycolipids. In fact, they showed a good serum response in immuno-fluorescence assay with cultured living cells when immunized by glycolipids extracted from ovarian cancer cell lines. These results suggested that beta3Gn-T5 mutant mice are useful for the generation of anti-glycolipid antigens with lacto-/neolacto-core structures expressed in cancer cells.     

Congenital coronary artery fistula draining into the superior vena cava with giant saccular aneurysm--report of a case

A 42-year-old woman who had a coronary artery fistula, associated with a giant coronary saccular aneurysm was reported. The coronary artery fistula originated from the proximal portion of the right coronary artery drained into the superior vena cava. The chief complaint was heart murmur which was detected at the 2nd intercostal space of the right sternal border. No other symptoms were present. The aneurysm was approximately 5 X 7 cm in size. In the operation using cardiopulmonary bypass, the proximal and distal portions of the coronary artery fistula were ligated successfully without aneurysmorrhaphy. The postoperative conditions was even without any complications. Congenital coronary artery fistulas with a giant saccular aneurysm should be surgically treated as soon as possible because of potential risk of aneurysmal rupture.     

Experimental intraocular lens implantation in the rabbit eye and in the mouse peritoneal space. Part III: Giant cell formation on the implanted lens surface

Among the cell components appearing on an implanted intraocular lens (IOL), the macrophage is the most active participant in the foreign-body response. The morphological stages of the macrophage in the response include not only an activated form and a flat epithelioid cell, but also a giant cell observed in the later stage of the response. The giant cells on the IOLs implanted in the rabbit eye and in the mouse peritoneal space were investigated by means of Wolter's implant cytology staining and scanning and transmission electron microscopic observation. Differences in the two biological environments as the site of IOL implantation are discussed.