The role of immunostimulation in the treatment of invasive fungal infection

Invasive fungal infections (IFI) constitute a severe and increasing problem in an expanding patient population with immunodeficiency due to various reasons. Despite current management strategies, IFI remain a common and frequently devastating problem. New antifungals have been introduced in the medical armamentarium, but the results in patients’ survival are not yet optimal. The compromised host defense mechanisms of these patients contribute to the high failure rates. Immunoregulation includes strategies for restoration or augmentation of impaired immune responses that increase phagocytes’ number or enhance their function. Although there are extensive preclinical data, clinical investigations are very limited. Administration of certain beneficial cytokines, antibodies and other immune molecules, granulocyte transfusions, and stimulation of adaptive immunity through vaccination are potential, promising future preventive and therapeutic modalities and could be adjuncts to antifungal therapy for IFI. This review highlights and comments on preclinical and clinical studies published since 2005.     

Application of an independent dose calculation software for estimating the impact of inter-fractional setup shifts in Helical Tomotherapy treatments

The purpose of this study is to validate the capability of in-house independent point dose calculation software to be used as a second check for Helical Tomotherapy treatment plans. The software performed its calculations in homogenous conditions (using the Cheese phantom, which is a cylindrical phantom with radius 15 cm and length 18 cm) using a factor-based algorithm. Fifty patients, who were treated for pelvic (10), prostate (14), lung (10), head & neck (12) and brain (4) cancers, were used. Based on the individual patient kVCT images and the pretreatment MVCT images for each treatment fraction, the corresponding daily patient setup shifts in the IEC-X, IEC-Y, and IEC-Z directions were registered. For each patient, the registered fractional setup shifts were grouped into systematic and random shifts. The average systematic dosimetric variations showed small dose deviation for the different cancer types (1.0%–3.0%) compared to the planned dose. Of the fifty patients, only three had percent differences larger than 5%. The average random dosimetric variations showed relatively small dose deviations (0.2%–1.1%) compared to the planned dose. None of the patients had percent differences larger than 5%. By examining the individual fractions of each patient, it is observed that only in 31 out of 1358 fractions the percent differences exceeded the border of 5%. These results indicate that the overall dosimetric impact from systematic and random variations is small and that the software is a capable platform for independent point dose validation for the Helical Tomotherapy modality.     

Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells

Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology.     

The effect of fire history in shaping diversity patterns of flower-visiting insects in post-fire Mediterranean pine forests

Fire affects diversity and structure of flower-visitor communities. We explored the effect of fire history on the diversity patterns and structure of the flower-visitor guilds (bees, beetles, flies, sawflies, and wasps), across a post-fire regeneration sequence of pine forests in Rhodes Island, Greece. Fire history was defined by fire frequency and post-fire age of sites. We did not find significant differences in species richness and abundance per guild between fire-history regimes except for the abundance of flies, sawflies and the entire flower-visitor community. Fire strongly affected the community structure of bees, beetles, and sawflies. Some of the most abundant and common species responded significantly to fire in terms of abundance; yet, we observed no significant variation in the abundance of the common species of bees, the most prominent pollinator group, implying that provision of pollination services may not be considerably affected by fire. Long-unburnt sites displayed higher heterogeneity in species composition compared to recently-burnt sites (either burnt once or twice). This pattern deviated significantly from null expectations when analyzing the abundance-based metric of β-diversity and was obscure in the case of the presence/absence-based metric, indicating that fire affected mainly the spatial distribution of individuals, i.e. the main change is not due to species turnover but to changes in relative abundance. Furthermore, the species composition in recently-burnt sites (burnt once in 2008) were more similar than in twice-burnt sites (including areas burnt once between 1984 and 1992, and in 2008), indicating that fire frequency affected post-fire heterogeneity of species composition.     

The structure of the 2[4Fe–4S] ferredoxin from Pseudomonas aeruginosa at 1.32-Å resolution: comparison with other high-resolution structures of ferredoxins and contributing structural features to reduction potential values

The structure of the 2[4Fe–4S] ferredoxin (PaFd) from Pseudomonas aeruginosa, which belongs to the Allochromatium vinosum (Alvin) subfamily, has been determined by X-ray crystallography at 1.32-Å resolution, which is the highest up to now for a member of this subfamily of Fds. The main structural features of PaFd are similar to those of AlvinFd. However, the significantly higher resolution of the PaFd structure makes possible a reliable comparison with available high-resolution structures of [4Fe–4S]-containing Fds, in an effort to rationalize the unusual electrochemical properties of Alvin-like Fds. Three major factors contributing to the reduction potential values of [4Fe–4S]^2+/+ clusters of Fds, namely, the surface accessibility of the clusters, the N–H···S hydrogen-bonding network, and the volume of the cavities hosting the clusters, are extensively discussed. The volume of the cavities is introduced in the present work for the first time, and can in part explain the very negative potential of cluster I of Alvin-like Fds.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

TAIL SHEDDING IN ISLAND LIZARDS [LACERTIDAE, REPTILIA]: DECLINE OF ANTIPREDATOR DEFENSES IN RELAXED PREDATION ENVIRONMENTS

The ability of an animal to shed its tail is a widespread antipredator strategy among lizards. The degree of expression of this defense is expected to be shaped by prevailing environmental conditions including local predation pressure. We test these hypotheses by comparing several aspects of caudal autotomy in 15 Mediterranean lizard taxa existing across a swath of mainland and island localities that differ in the number and identity of predator species present. Autotomic ease varied substantially among the study populations, in a pattern that is best explained by the presence of vipers. Neither insularity nor the presence of other types of predators explain the observed autotomy rates. Final concentration of accumulated tail muscle lactate and duration of movement of a shed tail, two traits that were previously thought to relate to predation pressure, are in general not shaped by either predator diversity or insularity. Under conditions of relaxed predation selection, an uncoupling of different aspects of caudal autotomy exists, with some elements (ease of autotomy) declining faster than others (duration of movement, lactate concentration). We compared rates of shed tails in the field against rates of laboratory autotomies conducted under standardized conditions and found very high correlation values ( r > 0.96). This suggests that field autotomy rates, rather than being a metric of predatory attacks, merely reflect the innate predisposition of a taxon to shed its tail.     

Reproduction is adapted to survival characteristics across geographically isolated medfly populations

We propose the hypothesis that individual longitudinal trajectories of fertility are closely coupled to varying survival schedules across geographically isolated populations of the same species, in such a way that peak reproduction takes place before substantial increases in mortality are observed. This reproductive adaptation hypothesis is investigated for medflies through a statistical analysis of biodemographic data that were obtained for female medflies from six geographically far apart regions. The following results support the hypothesis: (i) both survival and reproductive schedules differ substantially between these populations, where early peaks and subsequently fast declining reproduction are observed for short-lived and protracted reproductive schedules for long-lived flies; (ii) when statistically adjusting reproduction for the observed differences in survival, the differences in reproductive schedules largely vanish, and thus the observed differences in fertility across the populations can be explained by differences in population-specific longevity; and (iii) specific survival patterns of the medflies belonging to a specific population predict the individual reproductive schedule for the flies in this population. The analysis is based on innovative statistical tools from functional data analysis. Our findings are consistent with an adaptive mechanism whereby trajectories of fertility evolve in response to specific constraints inherent in the population survival schedules.     

Monocytic microparticles promote atherogenesis by modulating inflammatory cells in mice

Microparticles (MP) are generated during a vast number of biological processes such as inflammation, cell activation and apoptosis. Increasing evidence points towards an important role of MP as intercellular messengers of biological information. During atherogenesis, monocytes infiltrate the vascular wall and foster inflammation, accompanied by the release of monocytic MP (mono-MP). To date, only little is known about the biological function of mono-MP in the vascular wall. Here, we investigated the role of mono-MP during atherogenesis. Mono-MP were generated by starvation of THP-1 monocytes and isolated by ultracentrifugation. To investigate whether mono-MP influence atherogenesis, ApoE^−/− mice were fed a high-fat, cholesterol-rich diet for 8 weeks and simultaneously treated with mono-MP or vehicle twice a week. Mice treated with mono-MP showed significantly increased monocyte and T-cell infiltration into the vessel wall, as assessed by Moma-2 and CD3 staining, and enhanced plaque formation, as assessed by oil-red-O staining. However, atherosclerotic plaque composition was not influenced by mono-MP application. In vitro, incubation of mono-MP with murine macrophages and endothelial cells resulted in the uptake of calcein-labelled mono-MP. Mono-MP uptake initiated the generation of intracellular reactive oxygen species. Murine macrophages pre-treated with mono-MP showed significantly enhanced expression of CCR2, migration to MCP-1 and increased release of pro-inflammatory interleukin-6. Co-incubation of mono-MP with endothelial cells resulted in significantly increased expression of ICAM-1, as assessed by RT-PCR and ELISA. Mono-MP act as paracrine messengers that intensify inflammation during atherogenesis by stimulating vascular-bound and inflammatory cells in their vicinity.     

Study of multiparameter respiratory pattern complexity in surgical critically ill patients during weaning trials

Background  

Separation from mechanical ventilation is a difficult task, whereas conventional predictive indices have not been proven accurate enough, so far. A few studies have explored changes of breathing pattern variability for weaning outcome prediction, with conflicting results. In this study, we tried to assess respiratory complexity during weaning trials, using different non-linear methods derived from theory of complex systems, in a cohort of surgical critically ill patients.