Haynesbendtsen4161
nce imaging studies.
Intracranial atherosclerotic disease can be reliably produced and detected using 3T vessel wall magnetic resonance imaging-compatible Watanabe heritable hyperlipidemic and ApoE rabbit models. Further analysis is needed to characterize better the development and progression of the disease to correlate tissue-validated animal findings with those in human vessel wall magnetic resonance imaging studies.
Focal hyperintensity in the dorsal brainstem (HDB) has been described in large cerebellopontine angle tumours and is thought to represent vestibular nuclei degeneration, but its functional significance has not been thoroughly investigated. Our aim was to analyse its relationship to imaging characteristics of the tumour and inner-ear structures and to vestibulocochlear functional tests.
We retrospectively reviewed 54 patients with a histological diagnosis of vestibular schwannoma (VS). Magnetic resonance imaging tumour characteristics (size, cystic composition and distance from the cochlear aperture), signal intensity ratio of the cochlea and vestibule in fluid-attenuated inversion recovery (FLAIR) and fast imaging employing steady-state acquisition (FIESTA)/fast spin-echo imaging with variable flip angles (CUBE) and vestibulocochlear function tests (audiometry, auditory brainstem response (ABR) and video head impulse testing (vHIT)) were obtained. Statistical analyses were performed to evaluate their relation to focal HDB.
Focal HDB was found in 22% of VS. It was significantly associated with large (
< 0.001) and cystic (
= 0.004) tumours and also with tumours located further from the cochlear aperture (
= 0.039). The signal intensity ratio of the cochlea on FLAIR was higher in patients with HDB (
< 0.014), but this difference was not observed in FIESTA/CUBE (
= 0.981). Audiometry, ABR and vHIT results did not significantly differ in patients with HDB, but ABR results were worse in patients with higher cochlear signal intensity on FLAIR sequences (
= 0.026).
Focal HDB in patients with VS was associated with increased signal intensity ratio of the cochlea on FLAIR in patients with VS but not directly to the results of vestibulocochlear function tests.
Focal HDB in patients with VS was associated with increased signal intensity ratio of the cochlea on FLAIR in patients with VS but not directly to the results of vestibulocochlear function tests.Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed redox balance and increased production of reactive oxygen species (ROS), which is believed to contribute to epithelial injury and fibrotic lung scarring. The main pulmonary sources of ROS include mitochondria and NADPH oxidases (NOXs), of which the NOX4 isoform has been implicated in IPF. Tipifarnib Non-receptor SRC tyrosine kinases (SFK) are important for cellular homeostasis and are often dysregulated in lung diseases. SFK activation by the profibrotic transforming growth factor-β (TGF-β) is thought to contribute to pulmonary fibrosis, but the relevant SFK isoform and its relationship to NOX4 and/or mitochondrial ROS in the context of profibrotic TGF-β signaling is not known. Here, we demonstrate that TGF-β1 can rapidly activate the SRC kinase FYN in human bronchial epithelial cells, which subsequently induces mitochondrial ROS (mtROS) production, genetic damage shown by the DNA damage marker γH2AX, and increased expression of profibrotic genes. Moreover, TGF-β1-induced activation of FYN involves initial activation of NOX4 and direct cysteine oxidation of FYN, and both FYN and mtROS contribute to TGF-β-induced induction of NOX4. NOX4 expression in lung tissues of IPF patients is positively correlated with disease severity, although FYN expression is down-regulated in IPF and does not correlate with disease severity. Collectively, our findings highlight a critical role for FYN in TGF-β1-induced mtROS production, DNA damage response, and induction of profibrotic genes in bronchial epithelial cells, and suggest that altered expression and activation of NOX4 and FYN may contribute to the pathogenesis of pulmonary fibrosis.Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. nonfungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils, and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α, and IL-1β), neutrophil survival factors (granulocyte colony-stimulating factor), and neutrophil-targeting chemokines (CCL3 and CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5 and IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ and CXCL9) and survival factors (macrophage colony-stimulating factor). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T-cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a nonclassical immunoregulatory mechanism.
