Publications

BACKGROUND

Cytokines mediate a variety of effector cell functions, including cellular proliferation, differentiation, and modulation of the immune response. Many cytokines activate receptor-associated Janus kinases (JAKs) that promote tyrosine phosphorylation of signal transducers and activators of transcription (STAT) factors. Although JAK activation has been correlated with phosphorylation, the role of this tyrosine phosphorylation in the regulation of JAK1 and JAK3 remains unclear. Furthermore, the relative roles of JAK1 and JAK3 in the activation of STAT5 by interleukin-2 (IL-2) remain poorly understood.

RESULTS

We targeted two conserved tyrosine residues within the activation loop of the JAK1 and JAK3 kinase domains for substitution with phenylalanines. In an overexpression system, the catalytic function of JAK1 strictly required the presence of the first of these tyrosines, Y1033. In contrast, JAK3 retained catalytic activity when either or both of these activation-loop tyrosines were mutated. Analysis of JAK1/3 chimeras demonstrated that JAK activity was also controlled by intramolecular interactions involving the amino-terminal domain of the JAK as well as by the inherent signaling properties of the kinase domain. Finally, we have reconstituted IL-2-dependent STAT5 induction in a cell line that lacks detectable expression of JAK1 and JAK3. Catalytically active versions of both JAK1 and JAK3 must be present for effective induction of STAT5.

CONCLUSIONS

JAK1 and JAK3 are differentially regulated by specific tyrosines within their respective activation loops. Additionally, the amino-terminal domain of JAK3 appears to contain regulatory sequences that modify the function of the kinase domain. Finally, both JAK1 and JAK3 must retain catalytic function for IL-2-induced STAT5 activation.

Exposure to air polluted with particles less than 2.5 micron in size is associated epidemiologically with adverse cardiopulmonary health consequences in humans. The goal of this study was to characterize human pulmonary responses to controlled experimental high-dose exposure to fine and ultrafine magnesium oxide particles. We quantified bronchoalveolar lavage (BAL) cell and cytokine concentrations, pulmonary function, and peripheral blood neutrophil concentrations in six healthy volunteers 18 to 20 hr after inhalation of fine and ultrafine magnesium oxide particles produced from a furnace system model. We compared postexposure studies with control studies from the same six subjects. Mean +/- standard deviation (SD) cumulative magnesium dose was 4,138 +/- 2,163 min x mg/m3. By weight, 28% of fume particles were ultrafine (<0.1 micron in diameter) and over 98% of fume particles were fine (<2.5 micron in diameter). There were no significant differences in BAL inflammatory cell concentrations, BAL interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor, pulmonary function, or peripheral blood neutrophil concentrations postexposure compared with control. Our findings suggest that high-dose fine and ultrafine magnesium oxide particle exposure does not produce a measurable pulmonary inflammatory response. These findings are in marked contrast with the well-described pulmonary inflammatory response following zinc oxide particle inhalation. We conclude that fine and ultrafine particle inhalation does not result in toxicity in a generic manner independent of particle composition. Our findings support the concept that particle chemical composition, in addition to particle size, is an important determinant of respiratory effects.

OBJECTIVES

We sought to determine prospectively the prevalence, evolution and embolic risk of valve excrescences in normal subjects and patients with and without suspected cardioembolism.

BACKGROUND

Valve excrescences detected by transesophageal echocardiography (TEE) have been considered a cardioembolic substrate in selected patients.

METHODS

Ninety healthy volunteers (Group I) and 88 patients without suspected cardioembolism and a normal TEE (Group II) were studied and followed up clinically for 58 +/- 21 and 48 +/- 20 months, respectively. To assess the evolution of valve excrescences, 45 of these subjects underwent repeat TEE at 31 +/- 13 months. The findings in Groups I and II were compared with those of Group III--49 patients referred for TEE for suspected cardioembolism.

RESULTS

Valve excrescences were detected in 34 subjects (38%) in Group I and in 41 patients (47%) in Group II. In Group III, 20 patients (41%) had excrescences, but 85% of them had other potential cardiac or vascular sources of embolism. In all groups, mitral valve excrescences were predominant (68% to 76%), followed by aortic (38% to 50%) and right-sided valves (<10%). Excrescences were equally frequent in men and women and between all age groups studied. During follow-up in Groups I and II, excrescences persisted unchanged, and 1 (1.4%) of 74 patients with and 2 (2%) of 99 subjects without excrescences had cerebral ischemic events (80% power to detect a clinically meaningful difference of 4%).

CONCLUSIONS

Valve excrescences are common on the left-sided heart valves of normal subjects and patients regardless of gender and age; they persist unchanged over time and do not appear to be a primary source of cardioembolism.