米曲菌胰酶片治疗功能性消化不良的上市后药物经济学评价

目的:对米曲菌胰酶片治疗功能性消化不良的成本-效果进行分析。方法:收集多中心非随机同期病例数据,采用成本-效果分析对其进行药物经济学评价。结果:米曲菌胰酶片组相对于对照组(非米曲菌胰酶片治疗),每增加1个效果单位,成本可节约768.52元。使用米曲菌胰酶片治疗可通过提高治疗效果而降低病人的总费用。结论:米曲菌胰酶片治疗功能性消化不良有效、经济。     

Extracellular proteinase formation in carbon starving Aspergillus nidulans cultures--physiological function and regulation

Extracellular proteinase formation in carbon depleted cultures of the model filamentous fungus Aspergillus nidulans was studied to elucidate its regulation and possible physiological function. As demonstrated by gene deletion, culture optimization, microbial physiological and enzymological experiments, the PrtA and PepJ proteinases of A. nidulans did not appear to play a decisive role in the autolytic decomposition of fungal cells under the conditions we tested. However, carbon starvation induced formation of the proteinases observable in autolytic cultures. Similar to other degradative enzymes, production of proteinase was regulated by FluG-BrlA asexual developmental signaling and modulated by PacC-dependent pH-responsive signaling. Under the same carbon starved culture conditions, alterations of CreA, MeaB or heterotrimeric G protein mediated signaling pathways caused less significant changes in the formation of extracellular proteinases. Taken together, these results indicate that while the accumulation of PrtA and PepJ is tightly coupled to the initiation of autolysis, they are not essential for autolytic cell wall degradation in A. nidulans. Thus, as Aspergillus genomes contain a large group of genes encoding proteinases with versatile physiological functions, selective control of proteinase production in fungal cells is needed for the improved industrial use of fungi.     

Analysis of Aspergillus nidulans germination, initial growth and carbon source response by flow cytometry

In this work, flow cytometry was utilized to analyze the initial vegetative growth of the model fungus Aspergillus nidulans as measured by the number of events increasing size and internal complexity. It was established the ideal parameters for the analysis of conidial populations, whose growth was followed after germination in glucose or sucrose. While glucose in culture increased growth several magnitudes in comparison to control cultures in saline, growth was less intense in cultures amended with sucrose. Results indicated that flow cytometry could be a useful tool to study fungal germination and initial growth since it allowed rapid identification of different populations by means of their increasing in size and granularity with good reproducibility and without the need for direct observation and count of individual cells.     

An isoquinoline alkaloid, berberine, can inhibit fungal alpha amylase: enzyme kinetic and molecular modeling studies

Aspergillus flavus is a commonly found fungal pathogen, which produces aflatoxins, highly toxic and hepatocarcinogenic natural compounds. Inhibition of fungal alpha amylase activity has been found to limit the ability of the fungus to produce aflatoxins. Berberine, an isoquinoline alkaloid commonly found in many medicinal plants, was identified to inhibit the growth of A. flavus. The amount of berberine required to inhibit the fungal mycelial growth was determined. The compound was also found to inhibit the alpha amylase from the A. flavus. The binding affinity of the compound toward alpha amylase and the enzyme inhibitory activity have been determined by enzyme kinetic studies and Isothermal Titration Calorimetric analysis. Molecular modeling and docking studies were carried out to understand the enzyme–ligand interactions.     

Cerebral aspergillosis caused by Aspergillus ustus following orthotopic heart transplantation: case report and review of the literature

Abstract:  This report describes the first case of cerebral aspergillosis in a heart transplantation patient caused by Aspergillus ustus and reviews 15 previously reported cases of invasive aspergillosis in immunocompromised hosts caused by this mold. The utility of molecular analysis for the identification of unusual fungal pathogens is also described. The refractory nature of A. ustus to treatment is similar to other Aspergillus species and treatment options are reviewed.     

Use of a microbial toxicity test (Microtox) to determine the toxigenicity of Aspergillus fumigatus strains isolated from different sources

The toxic activity of Aspergillus fumigatus is attributable to substances secreted by its cells. Specific toxic compounds synthesized by the fungi such as gliotoxin, can be detected by sensitive chemical procedures like TLC or HPLC. Measuring the total toxigenicity of a strain extract, however, requires a bioassay. In the present study, we evaluated the possibility of using the Microtox^® bioassay to determine the toxigenicity of A. fumigatus, using 32 strains from different sources. The Microtox^® method is based on the ability of Vibrio fischeri to produce luminescence, and their sensitivity to toxins. A. fumigatus strains, grouped according to their original sources, showed differences in toxigenicity. Strains isolated from invasive aspergillosis patients proved to be more toxigenic than environmental strains, or strains from colonized patients. Since the strains that were more toxigenic were isolated from sick patients, it is not surprising they showed more virulence than the other strains, and as expected, virulence could be correlated with high toxigenicity. The Microtox bioassay could be a useful tool in the study of toxigenicity of the mycelial fungi and their possible pathogenic roles, and for rapid assessment of secreted toxic compounds.     

Effect of Zataria multiflora Boiss. essential oil on colony morphology and ultrastructure of Aspergillus flavus

The mode of inhibitory action of Zataria multiflora Boiss. essential oil (EO) on the fungus, Aspergillus flavus, was studied by colony morphology examination, light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The EO at concentrations used in this study suppressed the size of the colony as well as sporulation. SEM of mycelia treated with given concentrations of EO showed morphological alterations ranging from loss of turgidity and uniformity of mycelia at low concentrations of EO to evident destruction of the hyphae at higher concentration of EO. Semi-thin sections of mycelia exposed to different concentrations of EO were analysed by light microscopy and revealed that the major change at level as low as 50 ppm of EO was limited to vacuolisation of cytoplasm resulting in cell swelling, while at higher concentrations, detachment of the cell membrane from the cell wall, deformation of mycelia and shedding the cytoplasm from the cell were the main alterations. These damages were well documented by TEM, which showed that the main sites of action of EO were the plasma membrane and cell wall. In conclusion, morphological and structural changes observed in this study may be one of the mechanisms involved in growth inhibition of the fungi and reducing aflatoxin production.     

Endogenous filamentous fungal endophthalmitis--single-centre survey in patients with acute leukaemia or postallogeneic stem cell transplantation and review of the literature

Endogenous endophthalmitis caused by filamentous fungi has been infrequently described and its prognosis in immunocompromised patients is largely unknown. Patients were identified through a single-centre database containing patients with endophthalmitis. Cases published since 2002 were reviewed. Clinical and treatment features as well as outcomes were analysed. Six patients were identified from the database. Underlying conditions were haematological malignancies (HM) and/or allogeneic haematopoietic stem cell transplantation (HSCT). Three patients underwent vitrectomy. None of the patients survived and the median time from first evidence of endophthalmitis until death was 33 days. The median time from first evidence of an invasive fungal infection to endophthalmitis was only 5 days. Fifty-six patients were identified from the literature. The majority of these patients underwent vitrectomy (27) or enucleation (10) and received intraocular antifungal therapy (28). Only 13 (23%) of 56 patients experienced an improved vision. The survival rate was 52% in all 56 patients but was significantly less in patients with HM or post-HSCT when compared with all others (26% vs. 70%, respectively; P = 0.003). Endogenous endophthalmitis caused by filamentous fungi is frequently associated with a permanent decrease or loss of vision. This type of fungal infection carries a particular poor prognosis in patients with profound immunosuppression, requiring improved treatment strategies.     

In vitro susceptibility of 188 clinical and environmental isolates of Aspergillus flavus for the new triazole isavuconazole and seven other antifungal drugs

Recently isavuconazole, an experimental triazole agent, was found to be active against Aspergillus species. As Aspergillus flavus is the second-most common Aspergillus species isolated from human infection and the fungus has not been widely tested against the drug, we studied a large collection of clinical (n = 178) and environmental (n = 10) strains of A. flavus against isavuconazole and compared the results with seven other Aspergillus-active antifungal agents (some of them triazoles, others echinocandins or polyene antifungals: voriconazole, posaconazole, itraconazole, caspofungin, anidulafungin, micafungin and amphotericin B) using Clinical and Laboratory Standards Institute methods. Strains with high minimal inhibitory concentrations (MICs) were tested by E-test as well. The strains were collected from two different geographical locations (India and the Netherlands). Three isolates (1.6%) had high MIC (2 mg l(-1) by microbroth dilution and 8 mg l(-1) by E-test) for amphotericin B. Isavuconazole showed good activity against A. flavus strains with MIC(50) and MIC(90) values of 1 mg l(-1). As compared with voriconazole (the drug recommended for primary therapy of aspergillosis), isavuconazole had better activity (99.5% of strains had MIC of ≤ 1 mg l(-1) for isavuconazole, compared to 74% of strains with same MIC for voriconazole). All strains were, following recently proposed clinical breakpoints, susceptible for the triazoles tested except three strains, which had MICs of 4 mg l(-1) for voriconazole. Testing these strains with high MIC by E-test, gave results of 0.5-2 mg l(-1). Posaconazole had the lowest MIC(50) and MIC(90) of 0.125 mg l(-1) and 0.25 mg l(-1), respectively. Among echinocandins, 97% of strains had a minimum effective concentration (MEC) of ≤ 0.5 mg l(-1) for caspofungin, and all strains had a MEC of ≤ 0.016 mg l(-1) and ≤ 0.125 mg l(-1) for anidulafungin and micafungin, respectively.     

Current issues in the clinical management of invasive aspergillosis--the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009

The objectives of this study were to identify unsolved issues in the management of invasive aspergillosis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG) invited other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of invasive aspergillosis. Based on these contributions, a digital web-based questionnaire of 12 questions on Aspergillus spp. was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on effective preventive measures, choice of antifungal agents for pre-emptive, empiric and targeted treatment, as well as the evaluation of early chest CT control scans as a measure of treatment response assessment. Opinions on the indication for a pulmonary biopsy of a halo sign in high-risk neutropenic patients and on the role of Aspergillus spp. PCR as well as galactomannan from serum in the assessment of treatment duration diverged in spite of discussion such that a consensus could not be reached. Using a recently published two-step approach - web-based survey plus classical panel discussion - expert consensus was achieved on 10 of 12 questions concerning the diagnosis and treatment of invasive aspergillosis.