Novel hepatitis C virus protease inhibitors: thiazolidine derivatives

This study evaluated the inhibitory effects of thiazolidine derivatives on hepatitis C virus (HCV) protease and other human serine proteases. The inhibition efficacy was tested with a reversed-phase high-performance liquid chromatography (HPLC) assay system using a NS3-NS4A fusion protein as the HCV protease and a synthetic peptide substrate that mimics the NS5A-5B junction. Nine thiazolidine derivatives showed more than 50% inhibition at 50 microg/ml. The most potent derivative was RD4-6250, with 50% inhibition at a concentration of 2.3 microg/ml; this concentration was lower than those of other protease inhibitors reported previously. The most selective derivative was RD4-6205, with 50% inhibition at a concentration of 6.4 microg/ml, a lower concentration than those on other serine proteases (chymotrypsin, trypsin, plasmin, and elastase). These results suggest that the RD4-6205 skeleton is an important structure for inhibitory activity on the HCV protease NS3-NS4A.     

Effects of combined topical metronidazole and mechanical treatment on the subgingival flora in deep periodontal pockets in cuspids and bicuspids

The Effect on the subgingival microflora of a single topical administration of a 95% collagen and 5% metronidazole device in combination with debridement was investigated in 30 adult periodontitis patients in comparison with mechanical treatment alone. For each patient, plaque samples from test and control sites in cuspids and bicuspids were collected for culture and enumeration of total anaerobically cultivable bacteria (TA), black-pigmented anaerobes (BPA), and Actinobacillus actinomycetemcomitans (Aa). Spirochetes and fusiforms were quantified by direct microscopic examination after Giemsa staining. A decrease was observed for all parameters, and a significant difference in comparison with the control group was found for fusiforms. After treatment, a lower number of Aa positive sites were observed in the test group (13/25). These results show that a single application of topical metronidazole seems to be effective as adjunctive antimicrobial treatment in adult periodontitis.     

Lack of carcinogenicity of medium-viscosity liquid paraffin given in the diet to F344 rats

The carcinogenicity of medium-viscosity liquid paraffin was examined in Fischer 344 rats. Groups of 50 males and 50 females were given the material at dietary doses of 0 (control), 2.5 or 5% for 104 wk. Slight increases in food consumption and body weight were observed in both sexes of the 5% group. However, no significant differences between the control and treated groups were noted with regard to clinical signs, mortality and haematology findings. A variety of tumours developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in F344 rats, and no statistically significant increase in the incidence of any tumour type was found for either sex in the treated groups. Granulomatous inflammation in the mesenteric lymph nodes, considered to be a reaction to paraffin absorption, was observed with similar incidence and severity in both sexes of the 2.5 and 5% groups. Thus, it is concluded that under the present experimental conditions, the high dose, about 2000-200,000 times higher than the current temporary acceptable daily intake, does not have any carcinogenic potential in F344 rats. Furthermore, granulomatous inflammation observed in mesenteric lymph nodes were not associated with any development of neoplastic lesions.     

The importance of electrochemistry-related etching in thegate-groove fabrication for InAlAs/InGaAs HFETs

For the first time, the surface metal on nonalloyed ohmic electrodes is found to significantly change the profiles of gate grooves, when resist openings are employed to monitor drain current during wet-chemical gate recess for sub-micron InAlAs/lnGaAs heterojunction field-effect transistors (HFETs). The surface metal of Ni enhances the etching rate in comparison with that in the absence of electrodes by a factor of 4 and 10, laterally and vertically, which is favorable to fabricate deep gate grooves with small side etching. The Pt surface metal, however, leads to preferential etching of InGaAs over InAlAs, which can be useful to realize large side etching. The existence of an electrochemistry-related etching component, which arises when the ohmic electrodes are present during recess etching, is considered to be responsible for these behaviors     

Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.     

YM-32890 A and B, new types of macrolide antibiotics produced by Cytophaga sp

Two new types of macrolide antibiotics, YM-32890 A and B, have been isolated from the fermentation broth of cytophaga sp. YL-02905S. In this paper, the taxonomy of the producing strain, fermentation, isolation, structure elucidation, and biological activity of the antibiotics are reported. YM-32890 A inhibits the growth of staphylococci including a macrolide-resistant strain, but shows no antimicrobial activity against other Gram-positive, Gram-negative bacteria and yeast.     

Three-dimensional display of the bronchi using helical CT

The purpose of this study was to evaluate the clinical usefulness of three-dimensional (3D) images of the bronchi obtained using helical CT. Thirteen patients with lung cancer, one with tracheal diverticulum, and one with bronchial amyloidosis were examined. The CT scanner employed was the Toshiba Xforce. The helical CT scan cycle consisted of 20 continuous rotations, each requiring 1.5 sec, for a total scanning time of 30 sec. Scans were obtained using a 5-mm X-ray beam width, a 5-mm/1.5 sec couchtop sliding speed, and a 2-mm reconstruction interval. 3D images were reconstructed using a CEMAX VIPstation. The optimal lower and upper threshold CT values for 3D images of the bronchi were -650 and -100 HU, respectively, and 3D images clearly depicted endobronchial lesions. Cartilage crescents were also demonstrated, but longitudinal and circular mucosal folds could not be visualized. In conclusion, 3D images of the bronchi acquired using helical CT were useful in evaluating endobronchial lesions.     

A streamlined approximation and duality scheme for structural optimization

An efficient and commonly used approach to structural optimization is to solve a sequence of approximate design problems that are constructed iteratively. As is well-known, a major part of the computational burden of this scheme lies in the sensitivity analysis needed to state the approximate problems. We propose a possibility for reducing this burden by streamlining the calculations in a combined approximation and duality scheme for structural optimization. The difference between this scheme and the traditional one is that, instead of calculating all the constraint gradients to state an approximate design problem explicitly, linear combinations of these gradients are generated as they are needed during the solution of the approximate problem by the dual method. We show, by analysing some typical scenarios of problem characteristics, that this rearrangement of the calculations may be a computationally viable alternative to the traditional scheme. An advantage of streamlining the calculations is that there is no need to incorporate an active set strategy in the scheme, as is usually done, since all the design constraints may be taken into consideration without any loss of computational efficiency. This may, clearly, enhance the practical rate of convergence of the overall approximation scheme. Moreover, the proposed rearrangement of the calculations may make it computationally viable to apply iterative equation solvers to the structural analysis problem. Numerical results with direct as well as iterative equation solvers show that the streamlined scheme is a feasible and promising approach to structural optimization.     

On singular topologies in exact layout optimization

The causes of singular structural topologies, which prevent most iterative computational algorithms from reaching the global optimal solution, are explained in the light of the theory of exact optimal layouts. This theory is also used for deriving eight fundamental characteristics of singular topologies. The above findings are illustrated with case studies of exact optimal layouts for a single load and for two load conditions with stress constraints.     

Cardiac risk in surgery. A review and guidelines for risk evaluation and reduction of cardiac risk in general surgery

We report herein the phenotypic and functional analysis of human bone marrow and thymus derived early T cells. Commitment to T cell lineage is acquired during CD7 antigen expression by CD34+ precursors in human bone marrow and before thymus colonization. Early thymocytes show similar phenotypic characteristics as bone marrow T cells. They rapidly acquire CD4 before the dual expression of CD4 and CD8. Their expansion and differentiation is regulated by two major factors: thymic stroma and cytokines produced by these stroma cells or by thymocytes themselves. Among cytokines, IL1 and sCD23 produced by thymic epithelial cells support in vitro early T cell development.