Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice.

BACKGROUND: Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. OBJECTIVE: The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. METHODS: Aspergillus fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 h post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. RESULT: Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4(+) T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ(+) or IL-17A(+) ) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. CONCLUSIONS & CLINICAL RELEVANCE: Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments.

Arginine-rich cell-penetrating peptides facilitate delivery of antisense oligomers into murine leukocytes and alter pre-mRNA splicing.

Phosphorodiamidate morpholino oligomers (PMO) are synthetic antisense molecules that interfere with translation, pre-mRNA splicing and RNA synthesis. Like other gene-silencing technologies, PMO are poorly taken up by primary leukocytes without the use of physical or chemical delivery techniques. We sought an alternative delivery mechanism of PMO into immune cells that eliminates the need for such manipulations. Here we demonstrate the first use of arginine-rich cell-penetrating peptides (CPPs) to deliver PMO (P-PMO) directly into primary murine leukocytes for inhibition of gene expression and promotion of altered pre-mRNA splicing. We compared the P-PMO delivery efficacy of four arginine-rich CPPs including HIV Tat and penetratin, and one histidine rich CPP, and found that the (RXR)(4) peptide was the most efficacious for PMO delivery and targeted antisense effect. The delivery and antisense effects of P-PMO are time- and dose-dependent and influenced by the activation and maturation states of T cells and dendritic cells, respectively. Targeted expression of several genes using P-PMO is shown including surface signaling proteins (CD45 and OX-40), a cytokine (interleukin-2), and a nuclear transcription factor (Foxp3). Considering the abundance of naturally occurring alternatively spliced gene products involved in immune regulation, P-PMO offer an effective method for modulating gene activity for immunological research and applications beyond traditional antisense approaches.

Cardiac arrest due to uterine inversion during caesarean section.

We describe the case of a 20-year-old G3P0 woman who was delivered by caesarean section under general anaesthesia, complicated by uterine inversion secondary to undiagnosed placenta accreta and cardiac arrest requiring cardiopulmonary resuscitation. Uterine inversion is a known complication of placenta accreta and is a rare occurrence at caesarean section. Similar cases have been reported, though cardiac arrest is an uncommon feature. The possible causes and management are discussed.

Effects of age and Alzheimer's disease on recognition of gated spoken words.

This study investigated the effects of normal aging and Alzheimer's disease on listeners' ability to recognize gated spoken words. Groups of healthy young adults, healthy older adults, and adults with Alzheimer's disease were presented isolated gated spoken words. Theoretical predictions of the Cohort model of spoken word recognition (Marslen-Wilson, 1984) were tested, employing both between-group and within-group comparisons. The findings for the young adults supported the Cohort model's predictions. The findings for the older adult groups revealed different effects for age and disease. These results are interpreted in relation to the theoretical predictions, the findings of previous gating studies, and differentiating age from disease-related changes in spoken word recognition.