Limited Activity Of Miltefosine In Murine Models Of Cryptococcal Meningoencephalitis And Disseminated Cryptococcosis

Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.Pharmac

A preliminary design study of a microparticle accelerator final report, 30 jan. - 13 apr. 1964

Design study for 2MV microparticle accelerato

Statoconia Formation in Molluscan Statocysts

The gravity sensors of all molluscs phylogenetically below the cephalopods are spherical organs called statocysts. The wall of the sphere contains mechanosensory cells whose sensory cilia project into the lumen of the cyst. The lumen is filled with fluid and dense stones , the statoconia or statoliths, which sink under the influence of gravity to load, and stimulate, those receptor cells which are at the bottom. The statuconia of Aplysia californica are shown to be calcified about a lamellar arrangement of membranes. Similar lamellar membrane arrangements are seen within the receptor cells, and their possible role in the formation of the statoconia is discussed. SEM of unfixed statoconia reveals plate-like crystallization on their surface. Elemental analysis shows a relatively high Sr content, which is of interest, since others have recently reported that Sr is required in the culture medium of several laboratory-reared molluscs in order for the statoconia to develop

Neuroscience of Virtual Reality: From Virtual Exposure to Embodied Medicine

Is virtual reality (VR) already a reality in behavioral health? To answer this question, a meta-review was conducted to assess the meta-analyses and systematic and narrative reviews published in this field in the last twenty-two months. Twenty-five different articles demonstrated the clinical potential of this technology in both the diagnosis and the treatment of mental health disorders: VR compares favorably to existing treatments in anxiety disorders, eating and weight disorders, and pain management, with long-term effects that generalize to the real world. But why is VR so effective? Here, the following answer is suggested: VR shares with the brain the same basic mechanism: embodied simulations. According to neuroscience, to regulate and control the body in the world effectively, the brain creates an embodied simulation of the body in the world used to represent and predict actions, concepts, and emotions. VR works in a similar way: the VR experience tries to predict the sensory consequences of an individual's movements, providing to him/her the same scene he/she will see in the real world. To achieve this, the VR system, like the brain, maintains a model (simulation) of the body and the space around it. If the presence in the body is the outcome of different embodied simulations, concepts are embodied simulations, and VR is an embodied technology, this suggests a new clinical approach discussed in this article: the possibility of altering the experience of the body and facilitating cognitive modeling/change by designing targeted virtual environments able to simulate both the external and the internal world/body

Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells

Abasic (AP)-endonuclease (APE) is responsible for repair of AP sites, and single-strand DNA breaks with 3′ blocking groups that are generated either spontaneously or during repair of damaged or abnormal bases via the DNA base excision repair (BER) pathway in both nucleus and mitochondria. Mammalian cells express only one nuclear APE, 36 kDa APE1, which is essential for survival. Mammalian mitochondrial (mt) BER enzymes other than mtAPE have been characterized. In order to identify and characterize mtAPE, we purified the APE activity from beef liver mitochondria to near homogeneity, and showed that the mtAPE which has 3-fold higher specific activity relative to APE1 is derived from the latter with deletion of 33 N-terminal residues which contain the nuclear localization signal. The mtAPE-sized product could be generated by incubating (35)S-labeled APE1 with crude mitochondrial extract, but not with cytosolic or nuclear extract, suggesting that cleavage of APE1 by a specific mitochondria-associated N-terminal peptidase is a prerequisite for mitochondrial import. The low abundance of mtAPE, particularly in cultured cells might be the reason for its earlier lack of detection by western analysis