Publications

IL-10 is a pleiotropic cytokine produced by monocytes and T cells that has potent inhibitory effects on monocyte/macrophage function. Because monocytes and macrophages are capable of releasing the C-C chemokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), which is a potent chemoattractant for activated T cells, we studied the effects of IL-10 on the expression of MIP-1 alpha in these cells. Low levels of MIP-1 alpha were detectable in resting monocytes and macrophages. Both LPS (1 micrograms/ml) and IL-1 beta (10 ng/ml) induced the expression of MIP-1 alpha mRNA and the release of MIP-1 alpha protein from these cells. The addition of exogenous human rIL-10 inhibited induced MIP-1 alpha mRNA expression as well as the release of MIP-1 alpha protein measured after 24 h. This inhibition was significantly higher in monocytes compared with alveolar macrophages. In monocytes, IL-10-induced inhibition of MIP-1 alpha was only partially accounted for by alterations in mRNA stability and was dependent on de novo protein synthesis. In the presence of an anti-human IL-10-neutralizing Ab, the release of MIP-1 alpha induced by LPS and IL-1 beta was further enhanced in monocytes but unchanged in alveolar macrophages. MIP-1 alpha mRNA was also increased in monocytes. There was no detectable release of IL-10 from alveolar macrophages after LPS or IL-1 beta in contrast to modest amounts released from monocytes. Thus, IL-10 is an inhibitor of the induced transcription of MIP-1 alpha mRNA and of the release of MIP-1 alpha protein, with a greater effect on monocytes as compared with alveolar macrophages. IL-10 may indirectly regulate effects on cells such as activated T lymphocytes partly through the inhibition of MIP-1 alpha expression from monocytes and macrophages.

Nitric oxide (NO) is detectable in the exhaled air of human subjects, and its concentration is increased in patients with asthma. We have investigated the origin of the increase in exhaled NO in asthmatic patients by using different expiratory maneuvers and by direct sampling from the upper and lower respiratory tracts. Exhaled NO was measured by a chemiluminescence analyzer. Concentrations of NO measured during expiration against the resistance of the analyzer with exhaled flow of 1 L/min, were 78 +/- 3 ppb in normal subjects (n = 46) and significantly elevated in patients with asthma (301 +/- 26 ppb, n = 30, p < 0.001). Values of exhaled NO were lower when measured during unobstructed expiration with a flow of 5 L/min with sampling from a side-arm (7 +/- 1 ppb), but again were elevated in patients with asthma (46 +/- 6 ppb, p < 0.001). Breath-holding for 20 s resulted in an initial peak of NO, but end-expiration values similar to the unobstructed expiration. The concentration of NO in the nose was considerably greater than in expired air (996 +/- 39 ppb) and was elevated in patients with asthma (1,390 +/- 71 ppb, p < 0.002). Direct sampling from trachea and right middle lobe bronchus via a fiberoptic bronchoscope gave similar values in five normal and 15 asthmatic subjects to the values recorded during unobstructed expiration, and there was a good correlation between values in expired air and direct sampling (trachea r = 0.91, right middle lobe r = 0.87, p < 0.001). We conclude that exhaled NO measured in an unobstructed breath reflects concentrations in the lower respiratory tract, but that breath-holding or expiration against resistance is contaminated by residual NO derived from the upper respiratory tract. We also provide evidence that the elevated levels of exhaled NO in asthmatic patients are derived predominantly from the lower respiratory tract.

Objectives This study sought to investigate the relationship between thin-cap fibroatheromas (TCFAs) on major adverse cardiac events (MACEs) arising from medically treated nonculprit lesions (NCLs) in patients with acute coronary syndromes (ACS) with and without diabetes mellitus (DM). Background MACEs occur frequently in patients with DM and ACS. The impact of plaque composition on subsequent MACEs in DM patients with ACS is unknown. Methods In the PROSPECT (Providing Regional Observations Study Predictors of Events in the Coronary Tree) study, using 3-vessel radiofrequency intravascular ultrasound, we analyzed the incidence of NCL-MACE in 2 propensity-matched groups according to the presence of DM and TCFA. Results Among 697 patients, 119 (17.7%) had DM. The 3-year total MACE rate (29.4% vs. 18.8%; p = 0.01) was significantly higher in patients with versus without DM, driven by a higher rate of NCL-MACE in DM (18.7% vs. 10.4%; p = 0.02). Propensity score matching generated 2 balanced groups with and without DM of 82 patients each. Among DM patients, the presence of ≥1 TCFA was associated with higher NCL-MACE at 3 years (27.8% vs. 8.9% in patients without a TCFA, hazard ratio: 3.56; 95% confidence interval: 0.98 to 12.96; p = 0.04). DM patients without a TCFA had a similar 3-year rate of NCL-MACE as patients without DM (8.9% vs. 8.9%; hazard ratio: 1.09; 95% confidence interval: 0.27 to 4.41; p = 0.90). Conclusions ACS patients with DM and ≥1 TCFA have a high rate of NCL-MACE at 3 years. In contrast, the prognosis of ACS patients with DM but no TCFAs is favorable and similar to patients without DM.

The effect of PAF on eosinophil activation was investigated. TxB2 release required a lower concentration of PAF (ED50 = 17.2 nM) whereas for superoxide anion (O2) production doses in excess of 1 μM (ED50 = 31.7 μM) were needed. The PAF-induced O2 release occurred in the absence of increased [Ca2+]i whereas the production of TxB2 paralleled the magnitude of the [Ca2+]i increase. Pretreatment of the eosinophils with pertussis toxin (PTX) reduced both the PAF-induced release of TxB2 and the PAF-induced rise in [Ca2+]i. However, PTX failed to inhibit PAF-induced O2 generation. Experiments with the microsomal (100,000 g) fraction from these cells demonstrated that PTX pretreatment had ADP-ribosylated a 41-kD protein in the membrane, confirming that GTP binding proteins are present in eosinophil membranes. Scatchard plot analysis of radioligand binding to eosinophil membranes indicated the presence or two binding sites with an apparent Kd of 0.33 and 11.5 nM, respectively. The results suggest that two distinct forms of the PAF receptor can be identified in eosinophil membranes.

Results A significant decrease in mean end-diastolic volume index (86 ± 14 ml/m2 to 78 ± 15 ml/m2; p = 0.02) and mean end-systolic volume index (35 ± 13 ml/m2 to 30 ± 13 ml/ m2; p = 0.03) was observed three years after recanalisation. Mean ejection fraction tended to improve (60 ± 9% to 63 ± 11%; p = 0.11). SWT significantly increased at 5 month follow-up (p < 0.001) and an additional improvement was found at 3 years (p = 0.04) follow-up in segments with TEI of < 25%. In segments with TEI between 25% and 75%, SWT remained unchanged at 5-month follow-up (p = 0.89), but improved after 5 months (p = 0.04). SWT remained unchanged in segments with transmural scars (Figure 1). TEI was a better predictor for segmental functional recovery than EDWT (odds ratio 5.6, CI: 1.5–21.1; p = 0.01 versus 2.5, CI: 0.7–8.3; p = 0.14).

No abstract is provided for this article.

Glucocorticoids are hypothesized to induce beta2-adrenergic receptors (beta2-R) and their functions. The ability of dexamethasone (DEX) in vitro and beclomethasone dipropionate (BDP) in vivo to induce beta2-R messenger RNA (mRNA) and function was investigated in human nasal mucosa. In this tissue, albuterol does not stimulate exocytosis either in vivo or in vitro (Mullol and coworkers, 1992). Therefore, induction of beta2-R-mediated glandular exocytosis by glucocorticoids was proposed as an unambiguous outcome measure. Human nasal mucosa was cultured for 3 d with and without 1 microM DEX, then challenged with media or 100 microM albuterol. Culture supernatants were collected for measurement of exocytosed glandular products. Explant mRNA was extracted for reverse transcriptase-polymerase chain reaction (RT-PCR), and in situ hybridization of beta2-R mRNA performed. In vivo, normal subjects received saline or BDP for 3 d before albuterol nasal provocation. Concentrations of exocytosed products were measured in nasal secretions. RNA was extracted from nasal epithelial scrapings for RT-PCR. In vitro, DEX treatment induced albuterol-mediated glandular exocytosis (p < 0.04), and increased the steady-state beta2-R/beta-actin mRNA ratio (p < 0.05), and expression of beta2-R mRNA in glands. In vivo, BDP increased the beta2-R/beta-actin mRNA ratio in epithelial scrapings (p < 0.04), but did not induce albuterol-mediated glandular secretion. We conclude that glucocorticoids increase steady-state beta2-R mRNA levels in vivo and in vitro, and can induce beta2-R function as assessed by submucosal gland exocytosis in vitro. While topical BDP induced epithelial beta2-R mRNA, it did not modulate exocytosis from the deeper submucosal glands.

A synthesis of recent progress is presented on a topic that lies at the heart of both structural engineering and nonlinear science. The emphasis is on thin elastic structures that lose stability subcritically --- without a nearby stable post-buckled state --- a canonical example being a uniformly axially-loaded cylindrical shell. Such structures are hard to design and certify because imperfections or shocks trigger buckling at loads well below the threshold of linear stability. A resurgence of interest in structural instability phenomena suggests practical stability assessments require stochastic approaches and imperfection maps. This article surveys a different philosophy; the buckling process and ultimate post-buckled state are well described by the perfect problem. The significance of the Maxwell load is emphasised, where energy of the unbuckled and fully-developed buckle patterns are equal, as is the energetic preference of localised states, stable and unstable versions of which connect in a snaking load-deflection path. The state of the art is presented on analytical, numerical and experimental methods. Pseudo-arclength continuation (path-following) of a finite-element approximation computes families of complex localised states. Numerical implementation of a mountain-pass energy method then predicts the energy barrier through which the buckling process occurs. Recent developments also indicate how such procedures can be replicated experimentally; unstable states being accessed by careful control of constraints, and stability margins assessed by shock sensitivity experiments. Finally, the fact that subcritical instabilities can be robust, not being undone by reversal of the loading path, opens up potential for technological exploitation. Several examples at different length scales are discussed; a cable-stayed prestressed column, two examples of adaptive structures inspired by morphing aeroelastic surfaces, and a model for a functional auxetic material.