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Isavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis established in mice with chronic granulomatous disease (CGD) (gp91phox−)., Isavuconazole, the active moiety of the prodrug isavuconazonium sulfate, has potent activity against a wide spectrum of fungal pathogens and is approved for the treatment of invasive aspergillosis, yet little is known about the tissue penetration of isavuconazole at the target sites of infection. Here, we explored the spatial and quantitative distribution of isavuconazole in tissue lesions in experimental pulmonary aspergillosis established in mice with chronic granulomatous disease (CGD) (gp91phox−). Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze infected lungs and brain tissues collected 1, 3, 6, and 24 h after a single oral administration of the prodrug at a dose of 256 mg/kg of body weight (corresponding to 122.9 mg/kg of isavuconazole). Drug enrichment within granulomatous lesions was observed in lung tissue at 1 h postdose, although drug levels quickly equilibrated afterwards between lesion and nonlesion areas. A prominent antifungal effect in the infected lung tissue was revealed by histopathological analysis. Isavuconazole also penetrated into the brain with high efficiency. These data further support the value of isavuconazole to treat patients with invasive aspergillosis.

Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance ( FKS1 / FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.

During space missions, such as the prospective Mars mission, crew labor time is a strictly limited resource. The diet for such a mission (based on crops grown in a bioregenerative life support system) will require astronauts to prepare their meals essentially from raw ingredients. Time spent on food processing and preparation is time lost for other purposes. Recipe design and diet planning for a space mission should therefore incorporate the time required to prepare the recipes as a critical factor. In this study, videotape analysis of an experienced chef was used to develop a database of recipe preparation time. The measurements were highly consistent among different measurement teams. Data analysis revealed a wide variation between the active times of different recipes, underscoring the need for optimization of diet planning. Potential uses of the database developed in this study are discussed and illustrated in this work.

Two hundred and thirty patients with histologically proven chronic hepatitis C were randomized to receive one of the following treatment protocols: (a) 3 million units of interferon alfa-2b thrice weekly for 6 months, (b) 5 million units thrice weekly for 6 months, or (c) 3 million units thrice weekly for 2 years. The short-term response to treatment was defined by normal alanine aminotransferase for at least 3 months and until the end of treatment, and was confirmed by loss of hepatitis C viraemia in 42 (91%) of 46 cases as determined by reverse transcription-polymerase chain reaction. Short-term response to interferon alfa-2b was independent of the incremental dose, being 64% for 5 million units and 58% for 3 million units. Long-term response to interferon alfa-2b was defined by continued normality of alanine aminotransferase levels for at least 6 months after treatment withdrawal. The long-term response rates among responders treated for 6 months and those treated for 2 years were 29% and 54%, respectively ( p p p p p

Endothelial cell injury is one of the earliest detectable changes in the initiation of arterial intimai hyperplasia and atherosclerosis (Ross and Glomset, 1976; Moore, 1981; Ross, 1986). These early pathological changes are associated with the development of lesions which result in clinical conditions such as myocardial infarction, stroke and peripheral vascular disease. Cigarette smoking has been linked to arterial disease for over 30 years (Surgeon General USA, 1964; 1979) and is a well-recognized risk factor. However the direct relationship between smoking and the pathogenesis of arterial disease has not been precisely defined.

Endothelial injury and increased mitotic activity are early features in the pathogenesis of intimal thickening in arteries. This study examines the effect of systemic nicotine on mitotic activity in endothelial cells. Nine adult mice were given nicotine in their drinking water for 5 weeks. The dose (5 mg/kg body wt/day) was equivalent to a human smoking 50–100 cigarettes/day. A group of 8 similar mice, not exposed to nicotine, was the control. At the end of the exposure period all mice were injected with [ 3 H]thymidine (1 μCi/g body wt) and were killed 24 h later. After perfusion fixation, en-face preparations of aortic endothelium were processed for autoradiography. In nicotine-affected endothelium 0.46 ± 0.11% (SEM) of cells were labelled, which was significantly higher ( P Because other studies have shown that increased mitotic activity and cell loss are established features of endothelial injury, the present findings provide evidence in support of the hypothesis that nicotine contributes to the pathogenesis of arterial disease in smokers.