Heterogeneity of Particle Deposition by Pixel Analysis of 2D Gamma Scintigraphy Images.

BACKGROUND: Heterogeneity of inhaled particle deposition in airways disease may be a sensitive indicator of physiologic changes in the lungs. Using planar gamma scintigraphy, we developed new methods to locate and quantify regions of high (hot) and low (cold) particle deposition in the lungs. METHODS: Initial deposition and 24 hour retention images were obtained from healthy (n=31) adult subjects and patients with mild cystic fibrosis lung disease (CF) (n=14) following inhalation of radiolabeled particles (Tc99m-sulfur colloid, 5.4 µm MMAD) under controlled breathing conditions. The initial deposition image of the right lung was normalized to (i.e., same median pixel value), and then divided by, a transmission (Tc99m) image in the same individual to obtain a pixel-by-pixel ratio image. Hot spots were defined where pixel values in the deposition image were greater than 2X those of the transmission, and cold spots as pixels where the deposition image was less than 0.5X of the transmission. The number ratio (NR) of the hot and cold pixels to total lung pixels, and the sum ratio (SR) of total counts in hot pixels to total lung counts were compared between healthy and CF subjects. Other traditional measures of regional particle deposition, nC/P and skew of the pixel count histogram distribution, were also compared. RESULTS: The NR of cold spots was greater in mild CF, 0.221±0.047(CF) vs. 0.186±0.038 (healthy) (p<0.005) and was significantly correlated with FEV1 %pred in the patients (R=-0.70). nC/P (central to peripheral count ratio), skew of the count histogram, and hot NR or SR were not different between the healthy and mild CF patients. CONCLUSIONS: These methods may provide more sensitive measures of airway function and localization of deposition that might be useful for assessing treatment efficacy in these patients.

Azithromycin treatment alters gene expression in inflammatory, lipid metabolism, and cell cycle pathways in well-differentiated human airway epithelia.

Prolonged macrolide antibiotic therapy at low doses improves clinical outcome in patients affected with diffuse panbronchiolitis and cystic fibrosis. Consensus is building that the therapeutic effects are due to anti-inflammatory, rather than anti-microbial activities, but the mode of action is likely complex. To gain insights into how the macrolide azithromycin (AZT) modulates inflammatory responses in airways, well-differentiated primary cultures of human airway epithelia were exposed to AZT alone, an inflammatory stimulus consisting of soluble factors from cystic fibrosis airways, or AZT followed by the inflammatory stimulus. RNA microarrays were conducted to identify global and specific gene expression changes. Analysis of gene expression changes revealed that the AZT treatment alone altered the gene profile of the cells, primarily by significantly increasing the expression of lipid/cholesterol genes and decreasing the expression of cell cycle/mitosis genes. The increase in cholesterol biosynthetic genes was confirmed by increased filipin staining, an index of free cholesterol, after AZT treatment. AZT also affected genes with inflammatory annotations, but the effect was variable (both up- and down-regulation) and gene specific. AZT pretreatment prevented the up-regulation of some genes, such as MUC5AC and MMP9, triggered by the inflammatory stimulus, but the up-regulation of other inflammatory genes, e.g., cytokines and chemokines, such as interleukin-8, was not affected. On the other hand, HLA genes were increased by AZT. Notably, secreted IL-8 protein levels did not reflect mRNA levels, and were, in fact, higher after AZT pretreatment in cultures exposed to the inflammatory stimulus, suggesting that AZT can affect inflammatory pathways other than by altering gene expression. These findings suggest that the specific effects of AZT on inflamed and non-inflamed airway epithelia are likely relevant to its clinical activity, and their apparent complexity may help explain the diverse immunomodulatory roles of macrolides.

Blood transfusion is an independent predictor of increased mortality in nonoperatively managed blunt hepatic and splenic injuries.

BACKGROUND: Management strategies for blunt solid viscus injuries often include blood transfusion. However, transfusion has previously been identified as an independent predictor of mortality in unselected trauma admissions. We hypothesized that transfusion would adversely affect mortality and outcome in patients presenting with blunt hepatic and splenic injuries after controlling for injury severity and degree of shock. METHODS: We retrospectively reviewed records from all adults with blunt hepatic and/or splenic injuries admitted to a Level I trauma center over a 4-year period. Demographics, physiologic variables, injury severity, and amount of blood transfused were analyzed. Univariate and multivariate analysis with logistic and linear regression were used to identify predictors of mortality and outcome. RESULTS: One hundred forty-three (45%) of 316 patients presenting with blunt hepatic and/or splenic injuries received blood transfusion within the first 24 hours. Two hundred thirty patients (72.8%) were selected for nonoperative management, of whom 75 (33%) required transfusion in the first 24 hours. Transfusion was an independent predictor of mortality in all patients (odds ratio [OR], 4.75; 95% confidence interval [CI], 1.37-16.4; p = 0.014) and in those managed nonoperatively (OR, 8.45; 95% CI, 1.95-36.53; p = 0.0043) after controlling for indices of shock and injury severity. The risk of death increased with each unit of packed red blood cells transfused (OR per unit, 1.16; 95% CI, 1.10-1.24; p < 0.0001). Blood transfusion was also an independent predictor of increased hospital length of stay (coefficient, 5.45; 95% CI, 1.64-9.25; p = 0.005). CONCLUSION: Blood transfusion is a strong independent predictor of mortality and hospital length of stay in patients with blunt liver and spleen injuries after controlling for indices of shock and injury severity. Transfusion-associated mortality risk was highest in the subset of patients managed nonoperatively. Prospective examination of transfusion practices in treatment algorithms of blunt hepatic and splenic injuries is warranted.

Effect of ventilatory rate on airway cytokine levels and lung injury.

BACKGROUND: Controversy exists regarding the effect of large-volume mechanical ventilation (MV), as a sole stimulus, on the pulmonary cytokine milieu. We used a well described experimental model of ventilator-induced lung injury (VILI) to examine the impact of large volume ventilation on pulmonary cytokines in vivo and to study the effect of respiratory rate (RR) variation on these levels. MATERIALS AND METHODS: Sixty rats (410 +/- 47 g) were randomized to: 1) non ventilated control; 2) V(t) = 40 ml/kg, RR = 40 bpm; 3) V(t) = 40 ml/kg, RR = 20 bpm; 4) V(t) = 7 ml/kg, RR = 40 bpm; or 5) V(t) = 7 ml/kg, RR = 20 bpm. After 1 h of MV, bronchoalveolar lavage (BAL) and serum were collected. BAL was analyzed for urea, protein, lactate dehydrogenase (LDH), tumor necrosis factor (TNF)alpha and interleukin (IL)-6. Epithelial lining fluid volume (ELF) was calculated. RESULTS: Regardless of RR, animals ventilated at 7 ml/kg did not differ from control in any outcome. In contrast, MV at 40 ml/kg V(t) with 40 bpm produced lung injury characterized by significant elevations of BAL TNFalpha, IL-6, protein, ELF, and LDH. At 40 ml/kg V(t), RR reduction (20 bpm) significantly reduced all injury measures. CONCLUSION: This study confirms that large-volume MV, as a sole stimulus, produces lung injury and cytokine release. Whereas increasing RR at low V(t) has little impact on injury parameters, RR reduction under VILI-promoting conditions significantly limits lung injury.