Cellular Accumulation, Localization, and Activity of a Synthetic Cyclopeptamine in Fungi

A novel synthetic cyclopeptamine, A172013, rapidly accumulated by passive diffusion into Candida albicans CCH442. Drug influx could not be totally facilitated by the membrane-bound target, β-(1,3)-glucan synthase, since accumulation was unsaturable at drug concentrations up to 10 μg/ml (about 1.6 × 10⁻⁷ molecules/cell), or 25× MIC. About 55 and 23% of the cell-incorporated drug was associated with the cell wall and protoplasts, respectively. Isolated microsomes contained 95% of the protoplast-associated drug, which was fully active against glucan synthesis in vitro. Drug (0.1 μg/ml) accumulation was rapid and complete after 5 min in several fungi tested, including a lipopeptide/cyclopeptamine-resistant strain of C. albicans (LP3-1). The compound penetrated to comparable levels in both yeast and hyphal forms of C. albicans, and accumulation in Aspergillus niger was 20% that in C. albicans. These data indicated that drug-cell interactions were driven by the amphiphilic nature of the compound and that the cell wall served as a major drug reservoir.     

药物稳定性自由变温加速试验及其计算方法研究

介绍了一种以袖珍电子计算机为核心,用于药物稳定性自由变温加速试验的测温记录装置;介绍了一种用优选法和辛普森数值积分法处理自由变温加速试验数据的新算法。在这一新算法中,未作任何近似处理,也不需用多项式(或任何其它函数式)拟合温度—时间曲线,计算简明而结果准确,用袖珍电子计算机即可完成全部温度测量、记录和数据处理工作。     

DNA topoisomerases from pathogenic fungi: targets for the discovery of antifungal drugs.

DNA topoisomerases, a class of enzymes that change the topological structure of DNA, have been shown to be the target of many therapeutic agents, including antibacterial agents (quinolones) and anticancer agents. These drugs inhibit the enzyme in a unique way so that the enzyme is converted into a cellular poison. Candida albicans and Aspergillus niger are two major opportunistic fungal pathogens. Our results show that these fungi have high levels of both type I and type II topoisomerases (with a minimum of 5 x 10(5) ATP-independent relaxation units and 2 x 10(5) P-4 unknotting units per liter of wild-type C. albicans). The ATP-dependent type II topoisomerase (termed C. albicans topoisomerase II) was purified by approximately 2,000-fold from C. albicans cells by using a simple isolation scheme that consists of three column procedures: hydroxylapatite, phosphocellulose, and heparin-agarose chromatographies. The responses of the Candida and the calf thymus topoisomerase II to some known topoisomerase II inhibitors were measured. Etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide, compounds known to inhibit catalysis and to enhance DNA breakage by mammalian topoisomerase II, and A-80198, an etoposide derivative, enhanced cleavage by both enzymes at similar concentrations of these compounds, with the response of the calf thymus topoisomerase II from slightly to fourfold higher in magnitude than the response of the Candida enzyme in the same concentration range. In contrast, A-75272 (a cytotoxic tricyclic quinolone) shows a slightly stronger DNA cleavage enhancement effect with the Candida enzyme than with the mammalian counterpart. The abundance of the enzyme in cells and the different drug responses of the host enzyme and the fungal enzyme suggest that the fungal topoisomerase may serve as a target for the discovery of effective and safe antifungal agents.     

Intraluminal stents in atherosclerotic iliac artery stenosis: preliminary report of a multicenter study

Fifteen patients with symptomatic iliac artery stenosis were treated with intraluminal placement of balloon-expandable stents. Before treatment, 14 patients had intermittent claudication, and one had a limb at risk for amputation. One patient had diabetes mellitus, nine had hypertension, and all were long-term smokers. Two patients had surgical placement of the stent; in one patient this was part of a combined revascularization procedure. All other stents were placed percutaneously. The transstenotic gradient after injection of vasodilating drugs distal to the lesion decreased from a mean of 32.3 mm Hg +/- 16.7 to 3.1 mm Hg +/- 4.2 after stent placement. Ankle-arm Doppler systolic pressure index increased from a mean of 0.68 +/- 0.22 to 0.96 +/- 0.24 after the procedure. The treatment eliminated intermittent claudication in 14 patients and increased exercise tolerance to 500 m in the patient with a limb at risk for amputation before the procedure. The improved condition persisted in all patients during the follow-up of 6-12 months. Stent placement may be a valuable adjunct in the management of iliac artery disease.     

Acute and long-term effects of massive balloon dilation on the aortic wall and vasa vasorum

To investigate the acute and long-term effects on the vasa vasorum after massive overdilation, canine aortic segments were dilated with Gruentzig balloon catheters to more than 100% over normal size. In the acute study, the significant lumen increase was the result of intimal and medial rupture with stretching and thinning of the adventitia. In these areas, the vasa vasorum were stretched and severed, causing adventitial hemorrhage. In the chronic study, areas of previous subtotal wall rupture with adventitial thinning were repaired by scar tissue. This repair included formation of a neomedia, hyperplasia of the adventitia, and proliferation of the vasa vasorum. No progression of luminal dilatation was seen. This study showed that in subtotal aortic wall rupture, even a severely damaged adventitia is capable of preserving the lumen from further dilatation and rupture until healing. Blood flow to the damaged vessel wall was reestablished by revascularization via capillary budding in the aortic wall.     

Transesophageal drainage of mediastinal abscesses

Esophageal perforation with subsequent formation of a mediastinal abscess is a well-recognized clinical entity. Causes include perforation due to rigid and fiberoptic endoscopy, bouginage, breakdown of surgical anastomoses, and protracted vomiting. This disorder is associated with a high morbidity and, without intervention, a high mortality. In the past, surgery has been the treatment of choice. Although percutaneous drainage techniques have been used in some cases, they are frequently less attractive due to the location of the esophagus and its proximity to thoracic organs and vascular structures. In this study, eight abscesses caused by esophageal perforations were drained through a transesophageal route with minimal patient morbidity. These cases are presented with a discussion of the techniques and patient follow-up.     

Renal and related retroperitoneal abscesses: percutaneous drainage

Renal and related retroperitoneal abscesses cause significant morbidity and mortality and almost always require drainage. The authors report 18 cases of percutaneous drainage of renal and related retroperitoneal abscesses, all of which were successfully managed. In 11 of these cases (61%), percutaneous drainage constituted the only treatment required. In the remaining seven (39%), the patients' clinical status improved after percutaneous drainage, and they were able to undergo subsequent elective nephrectomy with fewer complications. These results are comparable to those achieved with percutaneous abdominal abscess drainage and justify the use of percutaneous drainage for renal and related retroperitoneal abscesses as the therapeutic procedure of choice.