Fungal Cell Gigantism during Mammalian Infection

The interaction between fungal pathogens with the host frequently results in morphological changes, such as hyphae formation. The encapsulated pathogenic fungus Cryptococcus neoformans is not considered a dimorphic fungus, and is predominantly found in host tissues as round yeast cells. However, there is a specific morphological change associated with cryptococcal infection that involves an increase in capsule volume. We now report another morphological change whereby gigantic cells are formed in tissue. The paper reports the phenotypic characterization of giant cells isolated from infected mice and the cellular changes associated with giant cell formation. C. neoformans infection in mice resulted in the appearance of giant cells with cell bodies up to 30 µm in diameter and capsules resistant to stripping with γ-radiation and organic solvents. The proportion of giant cells ranged from 10 to 80% of the total lung fungal burden, depending on infection time, individual mice, and correlated with the type of immune response. When placed on agar, giant cells budded to produce small daughter cells that traversed the capsule of the mother cell at the speed of 20–50 m/h. Giant cells with dimensions that approximated those in vivo were observed in vitro after prolonged culture in minimal media, and were the oldest in the culture, suggesting that giant cell formation is an aging-dependent phenomenon. Giant cells recovered from mice displayed polyploidy, suggesting a mechanism by which gigantism results from cell cycle progression without cell fission. Giant cell formation was dependent on cAMP, but not on Ras1. Real-time imaging showed that giant cells were engaged, but not engulfed by phagocytic cells. We describe a remarkable new strategy for C. neoformans to evade the immune response by enlarging cell size, and suggest that gigantism results from replication without fission, a phenomenon that may also occur with other fungal pathogens

Hypothalamic-pituitary-adrenocortical axis function in attention-deficit hyperactivity disorder.

The hypothalamic-pituitary-adrenocortical axis plays a critical role in mediating the physiological response to the imposition of stress. There are theoretical reasons to expect reduced basal cortisol secretion and cortisol hyporeactivity in hyperactive/impulsive or combined type attention-deficit hyperactivity disorder (ADHD). Early studies reported profound abnormalities in the diurnal rhythm of cortisol secretion or the cortisol response to stress in children with severe or persistent ADHD. However, subsequent work using larger samples or improved methods has not provided convincing evidence for changes in basal cortisol secretion in non-comorbid forms of ADHD. In contrast, children with ADHD and comorbid oppositional defiant disorder show lower basal cortisol concentrations and a blunted cortisol awakening response. With respect to cortisol reactivity to stress in ADHD, recent evidence has been mixed, with some studies reporting normal cortisol responses and others showing blunted cortisol responses in non-comorbid ADHD. Again, it appears important to consider whether comorbid disorders are present, because children with ADHD and comorbid disruptive behavior disorders exhibit blunted cortisol responses, whereas those with comorbid anxiety disorders show enhanced cortisol responses to stress. Longitudinal studies are required to investigate whether abnormalities in cortisol secretion play a causal role in the etiology of ADHD and related disruptive behavior disorders