Publications

Wood processing workers are exposed to wood-associated microbiological contaminants, including fungi. Our aim was to study the potential association between sputum fungus and adverse respiratory effects in such workers. In a group of sawmill workers, we administered a respiratory questionnaire, performed lung function testing and quantified the proportions of leukocytes in spontaneously expectorated sputum samples. We identified fungal species by DNA sequencing. Of 54 sawmill workers, 19 yielded fungal positive sputum samples (mean age 42.5±10.4 years) and 35 were negative for fungus (mean age 36.9±5.2 years). The fungus was identified as sp. in all samples. Those with fungal-positive sputum, compared to others, reported more cough (26% 63%) and haemoptysis (6% 37%) (both p<0.05), manifested reduced forced midexpiratory flow rates (FEF) (82.3±4.5 69.2±9.9% predicted, p<0.001), and had higher sputum eosinophil counts (median 9.25 3.25%, p<0.01). Reduction of FEF was associated both with fungus detection in sputum (-12.7%, 95% CI-8.5- -16.9%) and sputum eosinophils (-2.1% per 1% increase in eosinophils, 95% CI -1.5- -2.8%) (both p<0.001). In sawmill workers, sp. detectable in sputum was associated with respiratory symptoms, sputum eosinophilia and reduced FEF.

The endothelial receptor tyrosine kinase (RTK) Tie1 was discovered over 20 years ago, yet its precise function and mode of action remain enigmatic. To shed light on Tie1's role in endothelial cell biology, we investigated a potential threonine phosphorylation site within the juxtamembrane domain of Tie1. Expression of a non-phosphorylatable mutant of this site (T794A) in zebrafish (Danio rerio) significantly disrupted vascular development, resulting in fish with stunted and poorly branched intersomitic vessels. Similarly, T794A-expressing human umbilical vein endothelial cells formed significantly shorter tubes with fewer branches in three-dimensional Matrigel cultures. However, mutation of T794 did not alter Tie1 or Tie2 tyrosine phosphorylation or downstream signaling in any detectable way, suggesting that T794 phosphorylation may regulate a Tie1 function independent of its RTK properties. Although T794 is within a consensus Akt phosphorylation site, we were unable to identify a physiological activator of Akt that could induce T794 phosphorylation, suggesting that Akt is not the physiological Tie1-T794 kinase. However, the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for angiogenesis and capillary morphogenesis, was found to associate with phospho-T794 but not the non-phosphorylatable T794A mutant. Pharmacological activation of Rac1 induced downstream activation of p21-activated kinase (PAK1) and T794 phosphorylation in vitro, and inhibition of PAK1 abrogated T794 phosphorylation. Our results provide the first demonstration of a signaling pathway mediated by Tie1 in endothelial cells, and they suggest that a novel feedback loop involving Rac1/PAK1 mediated phosphorylation of Tie1 on T794 is required for proper angiogenesis.

BACKGROUND

Monoclonal T-cell receptor (TCR) rearrangement is detected in 57-75% of early-stage mycosis fungoides (MF) at diagnosis. A retrospective study showed molecular residual disease (MRD) in 31% of patients in complete clinical remission (CR) after 1 year of treatment.

OBJECTIVES

To confirm the frequency of MRD at 1 year and to determine its prognostic value for further relapse.

METHODS

Patients with T1-, T2- or T4-stage MF were prospectively included in this multicentre study. At diagnosis, clinical lesions and healthy skin were biopsied. After 1 year of topical treatment, previously involved skin of patients in CR was biopsied for histology and analysis of TCR-γ gene rearrangement. The results were compared with the clinical status each year for 4 years.

RESULTS

We included 214 patients, 133 at T1, 78 at T2 and three at T4 stage. At diagnosis, 126 of 204 cases (61·8%) showed TCR clonality in lesional skin. After 1 year, 83 of 178 patients (46·6%) still being followed up were in CR and 13 of 63 (21%) showed MRD. At 4 years, 55 of 109 patients (50·5%) still being followed up were in CR and 44 of 109 (40·4%) were in T1 stage. MRD did not affect clinical status at 4 years (CR vs. T1/T2, P = 1·0; positive predictive value 36·4%; negative predictive value 67·6%).

CONCLUSIONS

T-cell clonality at diagnosis and MRD at 1 year are not prognostic factors of clinical status at 4 years.

OBJECTIVES

To describe the epidemiology and factors associated with pediatric central nervous system (CNS) tuberculosis (TB) in California from 1993 to 2011.

METHODS

We analyzed California TB registry data for persons aged ≤18 years, comparing CNS TB cases versus non-CNS TB cases reported from 1993 to 2011. Factors associated with CNS TB and TB deaths were identified by using multivariate logistic regression.

RESULTS

A total of 200 CNS TB cases were reported. Compared with non-CNS TB case patients, CNS TB case patients were more likely to be aged <5 years (72.0% vs 43.6%; odds ratio [OR]: 3.8 [95% confidence interval (CI): 2.4-5.9]), US-born (82.0% vs 58.2%; OR: 3.3 [CI: 2.3-4.7]), and Hispanic (75.0% vs 63.2%; OR: 1.7 [CI: 1.3-2.4]). Among US-born CNS TB case patients (during 2010-2011), 76.5% had a foreign-born parent. Tuberculin skin test results were negative in 38.2% of 170 CNS TB cases tested. In multivariate analysis, age <5 years (adjusted odds ratio [aOR]: 3.3 [CI: 2.0-5.4]), US birth (aOR: 1.8 [CI 1.2-2.7]), and Hispanic ethnicity (aOR: 1.5 [CI: 1.1-2.1]) were associated with an increased risk of developing CNS TB. For deaths, CNS TB (aOR: 3.8 [CI: 1.4-9.9]) and culture positivity (aOR: 6.2 [CI: 2.2-17.3]) were associated with increased risk of death, whereas tuberculin skin test positivity (aOR: 0.1 [CI: 0.04-0.2]) was associated with decreased risk.

CONCLUSIONS

Subsets of children are at increased risk for CNS TB in California and may benefit from additional prevention efforts.