Effect of positron range on PET quantification in diseased and normal lungs.

The impact of positron range on PET image reconstruction has often been investigated as a blurring effect that can be partly corrected by adding an element to the PET system matrix in the reconstruction, usually based on a Gaussian kernel constructed from the attenuation values. However, the physics involved in PET is more complex. In regions where density does not vary, positron range indeed involves mainly blurring. However, in more heterogeneous media it can cause other effects. This work focuses on positron range in the lungs and its impact on quantification, especially in the case of pathologies such as cancer or pulmonary fibrosis, for which the lungs have localised varying density. Using Monte Carlo simulations, we evaluate the effects of positron range for multiple radionuclides (18F, 15O, 68Ga, 89Zr, 82Rb, 64Cu and 124I) as, for novel radiotracers, the choice of the labelling radionuclide is important. The results demonstrate quantification biases in highly heterogeneous media, where the measured uptake of high-density regions can be increased by the neighbouring radioactivity from regions of lower density, with the effect more noticeable for radionuclides with high-energy positron emission. When the low-density regions are considered to have less radioactive uptake (e.g. due to the presence of air), the effect is less severe.

Effect of lutein on methotrexate-induced oxidative lung damage in rats: a biochemical and histopathological assessment.

BACKGROUND/AIMS: This study aimed to investigate the effect of lutein on methotrexate (MTX)-induced pulmonary toxicity in rats biochemically and histopathologically. METHODS: The rats in the MTX + lutein (MTXL, n = 6) group were given 1 mg/kg of lutein orally. A 0.9% NaCl solution was administered orally to the MTX (n = 6) group and the healthy group (HG, n = 6). One hour later, a single 20 mg/kg dose of MTX was injected intraperitoneally in the MTXL and MTX. Lutein or 0.9% NaCl solution was administered once a day for 5 days. At the end of this period, malondialdehyde (MDA), myeloperoxidase (MPO), total glutathione (tGSH), interleukin 1 beta (IL-1ß), and tumor necrosis factor alpha (TNF-α) were measured in the lung tissues from the animals euthanized with 50 mg/kg thiopental sodium anesthesia. Subsequently, histopathological examinations were performed. RESULTS: The levels of MDA, MPO, IL-1ß, and TNF-α in the lung tissue of the MTX were significantly higher than those of the MTXL and HG groups (p < 0.0001), and the amount of tGSH was lower. The histopathological findings in the MTX group, in which the oxidants and cytokines were higher, were more severe. CONCLUSION: Lutein prevented the MTX-induced oxidative lung damage biochemically and histopathologically. This result indicates that lutein may be useful in the treatment of MTX-induced lung damage.

Human pluripotent stem cell-derived alveolar epithelial cells are alternatives for in vitro pulmotoxicity assessment.

Human pluripotent stem cell (hPSC)-derived alveolar epithelial cells (AECs) provide new opportunities for understanding lung development and the treatment of pulmonary diseases. However, toxicity assessments using hPSC-AECs have not been undertaken. In this study, we generated functional AECs from hPSCs and evaluated their inflammatory and apoptotic responses to cadmium (Cd) exposure (1, 5, and 10 µM) for 24 h compared with the human bronchial epithelial cell line (BEAS-2B) and primary AECs as controls. Our data showed that Cd (10 µM) treatment induced substantial inflammatory responses and apoptosis in BEAS-2B cells, but not in both hPSC-AECs and primary AECs. Interestingly, conditioned medium from AEC cultures significantly alleviated apoptotic and inflammatory responses to Cd exposure in BEAS-2B cells. Using cytokine arrays, several potential factors secreted from hPSC-AECs and primary AECs were detected and may be involved in reducing Cd-induced cytotoxicity. We also observed higher expression of surfactant proteins B and C in both hPSC-AECs and primary AECs, which may contribute to protection against Cd-induced cytotoxicity. These results suggested that hPSC-AECs phenotypically and functionally resemble primary AECs and could be more biologically relevant alternatives for evaluating the pathological contribution of confirmed or potential pulmotoxic materials included in smoking and microdust.

Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia.

PURPOSE: To study pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH), investigators have been employing a fetal rat model based on nitrofen administration to dams. Herein, we aimed to: (1) investigate the validity of the model, and (2) synthesize the main biological pathways implicated in the development of PH associated with CDH. METHODS: Using a defined strategy, we conducted a systematic review of the literature searching for studies reporting the incidence of CDH or factors involved in PH development. We also searched for PH factor interactions, relevance to lung development and to human PH. RESULTS: Of 335 full-text articles, 116 reported the incidence of CDH after nitrofen exposure or dysregulated factors in the lungs of nitrofen-exposed rat fetuses. CDH incidence: 54% (27-85%) fetuses developed a diaphragmatic defect, whereas the whole litter had PH in varying degrees. Downregulated signaling pathways included FGF/FGFR, BMP/BMPR, Sonic Hedgehog and retinoid acid signaling pathway, resulting in a delay in early epithelial differentiation, immature distal epithelium and dysfunctional mesenchyme. CONCLUSIONS: The nitrofen model effectively reproduces PH as it disrupts pathways that are critical for lung branching morphogenesis and alveolar differentiation. The low CDH rate confirms that PH is an associated phenomenon rather than the result of mechanical compression alone.

Immunological and toxicological risk assessment of e-cigarettes.

Knowledge of the long-term toxicological and immunological effects of e-cigarette (e-cig) aerosols remains elusive due to the relatively short existence of vaping. Therefore, we performed a systematic search of articles published in public databases and analysed the research evidence in order to provide critical information regarding e-cig safety. Electronic nicotine delivery systems (or e-cigs) are an alternative to traditional cigarettes for the delivery of nicotine and are typically filled with glycerol or propylene glycol-based solutions known as e-liquids. Though present in lower quantities, e-cig aerosols are known to contain many of the harmful chemicals found in tobacco smoke. However, due to the paucity of experimental data and contradictory evidence, it is difficult to draw conclusive outcomes regarding toxicological, immunological and clinical impacts of e-cig aerosols. Excessive vaping has been reported to induce inflammatory responses including mitogen-activated protein kinase, Janus tyrosine kinase/signal transducer and activator of transcription and nuclear factor-κB signalling, similar to that induced by tobacco smoke. Based on recent evidence, prolonged exposure to some constituents of e-cig aerosols might result in respiratory complications such as asthma, chronic obstructive pulmonary disease and inflammation. Future studies are warranted that focus on establishing correlations between e-cig types, generations and e-liquid flavours and immunological and toxicological profiles to broaden our understanding about the effects of vaping.

Basic science of electronic cigarettes: assessment in cell culture and in vivo models.

Electronic cigarettes (e-cigarettes, ECIGs) were introduced into the market a decade ago as an alternative to tobacco smoking. Whether ECIGs are safe and whether they qualify as smoking cessation tool is currently unknown. Their use has markedly expanded in that period, despite the fact that potential toxic effects of the vapour created by the e-cigarette and the nicotine-containing cartridge fluid have been incompletely studied. Marketing targets diverse groups including older smokers but also young people. Whereas the adverse health effects of nicotine inhaled by users of ECIGs has been well documented, less is known about the other components. An increasing number of in vitro and in vivo studies demonstrate a range of adverse effects of both the vapour created by ECIGs as well as the nicotine-containing fluid. Importantly, these studies demonstrate that toxicity from ECIGs, although this may be less than that caused by tobacco products, not only arises from its nicotine content. Furthermore, there are no data on the long-term consequences of ECIG use. The wide range of ECIG products available to consumers and the lack of standardisation of toxicological approaches towards ECIG evaluation complicates the assessment of adverse health effects of their use. Here we review the current data on preclinical studies on ECIGs describing their effects in cell culture and animal models.

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease.

Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC80). The tigecycline efficacy was 5.38 ± 2.35 log10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC80 and 46% for 1-log kill. For both the EC80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.

The Role of Flow-Independent Exhaled Nitric Oxide Parameters in the Assessment of Airway Diseases.

Nitric oxide (NO), the first gas known to act as a biological messenger, is one of the most widely studied free radical/gas in medicine, both for its biological function and therapeutic applications. The measurement of endogenous NO in exhaled air is widely used in the evaluation of lung disorders. Partitioning of exhaled nitric oxide (eNO) is of increasing interest because of the additional information about lung pathology and distal lung inflammation that can be obtained. Specifically, measuring exhaled NO at multiple flow rates allows assessment of the flow-independent NO parameters: alveolar NO concentration (CalvNO), bronchial NO flux (JNO), bronchial wall NO concentration (CWNO), and bronchial diffusing capacity of NO (DNO). Several studies have reported that there were different patterns of those parameters in different airway diseases and/or in different severities of the same disease, mostly in asthma. Specifically, while JNO seems to provide the same information as FeNO50, alveolar NO concentration appears to be an independent parameter that is putatively associated with increased distal lung inflammation and more severe disease. However, despite much research interest in partitioning exhaled NO, clinical usefulness has yet to be established.

Population Pharmacokinetics in China: The Dynamics of Intravenous Voriconazole in Critically Ill Patients with Pulmonary Disease.

Pharmacokinetic research in China on the use of voriconazole in critically ill adult patients with different pulmonary diseases remains to be explored. This study evaluated the population pharmacokinetics of the use of voriconazole (VRC) in critically ill patients to determine covariate effects on VRC pharmacokinetics by NONMEM, which could further optimize VRC dosing in this population. A one-compartment model with first-order absorption and elimination best fit the data, giving 4.28 L/h clearance and 93.4 L volume of distribution of VRC. The model variability, described as an approximate percentage coefficient of interindividual variability in clearance and volume of distribution, was 72.94% and 26.50%, respectively. A significant association between Cmin and drug response or grade 2 hepatotoxicity was observed (p=0.002, <0.001, respectively, 1.5-4.0 µg/mL) via logistic multivariate regression. Monte Carlo simulations at 100, 150, 200, and 250 mg dosage predicted effectiveness at 45.99%, 99.76%, 98.76%, and 67.75% within the 1.5-4.0 µg/mL range, suggesting that a 150 or 200 mg intravenous dose twice daily is best suited to achieve the target steady state trough concentration range in critically ill patients with pulmonary disease.

MyD88-dependent signaling prolongs survival and reduces bacterial burden during pulmonary infection with virulent Francisella tularensis.

Francisella tularensis is the causative agent of the debilitating febrile illness tularemia. The severe morbidity associated with F. tularensis infections is attributed to its ability to evade the host immune response. Innate immune activation is undetectable until more than 48 hours after infection. The ensuing inflammatory response is considered pathological, eliciting a septic-like state characterized by hypercytokinemia and cell death. To investigate potential pathological consequences of the innate immune response, mice deficient in a key innate immune signaling molecule, MyD88, were studied. MyD88 knockout (KO) mice were infected with the prototypical virulent F. tularensis strain, Schu S4. MyD88 KO mice succumbed to infection more rapidly than wild-type mice. The enhanced pathogenicity of Schu S4 in MyD88 KO mice was associated with greater bacterial burdens in lungs and distal organs, and the absence of IFN-γ in the lungs, spleens, and sera. Cellular infiltrates were not observed on histological evaluation of the lungs, livers, or spleens of MyD88 KO mice, the first KO mouse described with this phenotype to our knowledge. Despite the absence of cellular infiltration, there was more cell death in the lungs of MyD88 KO mice. Thus, the host proinflammatory response is beneficial, and MyD88 signaling is required to limit bacterial burden and prolong survival during pulmonary infection by virulent F. tularensis.

[Proteomics as a fundamental tool for subclinical screening, tests verification and assessment of applied therapy].

Proteomics is a science which studies proteins of the body, interactions of proteins and their biological functions. Today, it is an essential partner in establishing preclinical diagnosis protocols. In conjunction with other sciences such as genomics and bioinformatics it will be possible to diagnose diseases on the earliest stages before its clinical onset or to gain the dynamics of pathological processes in the body and response to drug therapy. This article discusses general aspects of proteomics as well as special ones on the basis of models of cardiac diseases and cancer.

Assessment of the effects of ultrasound-mediated glucose on permeability of normal, benign, and cancerous human lung tissues with the Fourier-domain optical coherence tomography.

The objective of this study was to evaluate the effects of ultrasound-mediated analyte diffusion on permeability of normal, benign, and cancerous human lung tissue in vitro and to find more effective sonophoretic (SP) delivery in combination with the optical clearing agents (OCAs) method to distinguish normal and diseased lung tissues. The permeability coefficients of SP in combination with OCAs diffusion in lung tissue were measured with Fourier-domain optical coherence tomography (FD-OCT). 30% glucose and SP with a frequency of 1 MHz and an intensity of 0.80 W/cm2 over a 3 cm probe was simultaneously applied for 15 min. Experimental results show that the mean permeability coefficients of 30% glucose/SP were found to be (2.01±0.21)×10(-5) cm/s from normal lung (NL) tissue, (2.75±0.28)×10(-5) cm/s from lung benign granulomatosis (LBG) tissue, (4.53±0.49)×10(-5) cm/s from lung adenocarcinoma tumor (LAT) tissue, and (5.81±0.62)×10(-5) cm/s from lung squamous cell carcinoma (LSCC) tissue, respectively. The permeability coefficients of 30% glucose/SP increase approximately 36.8%, 125.4%, and 189.1% for the LBG, LAT, and LSCC tissue compared with that for the NL tissue, respectively. There were statistically significant differences in permeability coefficients of 30% glucose/SP between LBG and NL tissue (p<0.05), between LAT and NL tissue (p<0.05), and between LSCC and NL tissue (p<0.05). The results suggest that the OCT functional imaging technique to combine an ultrasound-OCAs combination method could become a powerful tool in early diagnosis and monitoring of changed microstructure of pathologic human lung tissue.

Fullerene c60: inhalation hazard assessment and derivation of a period-limited acceptable exposure level.

Fullerene C(60) has great potential for use in many industry and medical nanotechnology applications. Although the use of nanomaterials has been increasing in the recent years, limited information about its potential hazardous effects is available. Therefore, safety of nanomaterials is a world concern. Before health effects arise in workers and the general population, development and use under appropriate management are desirable. Therefore, we aimed to determine an acceptable exposure level for humans by reviewing the limited animal toxicity data available. Here, we present an initial hazard assessment, including a review of the available toxicity information of the effects of C(60) on the lungs. We then estimated the no-observed-adverse-effect level (NOAEL) of C(60) on rat lung toxicity by using lung retention of C(60) in inhalation exposure and intratracheal instillation tests. The NOAEL of C(60) on rat lung toxicity was estimated to be 3.1 mg/m(3). Because this is the NOAEL for subchronic toxicity, a period-limited acceptable exposure level (AEL(PL)) for humans was proposed, which assumed 15 years of exposure and modification within the next 10 years since more knowledge will be gained in the future. The AEL(PL) of C(60) particles with a geometric mean of 96 nm and a geometric standard deviation (GSD) of 2.0 was estimated to be 0.39 mg/m(3) for healthy workers and 1.4 × 10(-2) mg/m(3) for the general human population. The AEL(PL) of C(60) particles with different sizes was estimated to be for healthy workers and for the general human population.

Pharmacokinetic/pharmacodynamic modeling to predict in vivo effectiveness of various dosing regimens of piperacillin/tazobactam and piperacillin monotherapy against gram-negative pulmonary isolates from patients managed in intensive care units in 2002.

OBJECTIVE: This study compared the pharmacokinetic/pharmacodynamic (PK/PD) properties of piperacillin/tazobactam (PTZ) combination treatment with those of piperacillin (PIP) monotherapy against clinical gram-negative pulmonary isolates from US patients treated in intensive care units. METHODS: Computer modeling was used to integrate national in vitro microbiologic data from 2002 with pharmacokinetic data from published studies in healthy volunteers. PTZ (3.375 g q4h, 3.375 g q6h, 4.5 g q6h, and 4.5 g q8h) and PIP (3 g q4h, 3 g q6h, 4 g q6h, and 4 g q8h) were modeled using Monte Carlo simulations. The cumulative fraction of response (CFR) was determined for percentage of time that the free serum concentration remained above the MIC of >or=30% (bacteriostatic) and >or=50% (bactericidal). Because simulated comparisons with an artificially derived sample size were used, statistical methods were not applied. RESULTS: Overall, 2584 gram-negative pulmonary isolates were evaluated, including Enterobacteriaceae (n = 1430), Pseudomonas aeruginosa (n = 799), Acinetobacter baumannii (n = 179), and "other" (n = 176). The percents susceptible with PTZ and PIP were as follows: Enterobacteriaceae, 86% and 66%, respectively; P aeruginosa, 89% and 84%; and A baumannii, 47% and 34%. CFR rates with PTZ were numerically higher than those with PIP against Enterobacteriaceae (ranges, 86%-89% and 66%-73%, respectively) and A baumannii (47%-53% and 33%-42%), but not against P aeruginosa (79%-84% and 75%-81%). CONCLUSION: Results from PK/PD models with Monte Carlo simulation suggested that susceptibility differences among these selected gram-negative isolates collected in 2002 may be of sufficient magnitude to result in notable PK/PD differences between PTZ and PIP.

Feasibility of assessment of regulatory lipids in breath condensate as potential presymptomatic harbingers of pulmonary pathobiology.

Regulatory lipids from the airway surface readily form aerosols that can be recovered non-invasively by cooling expired breath to form breath condensate (BC). Regulatory lipids have been detected previously utilizing enzyme-linked-immunosorbent serologic assay (ELISA). Here we test the feasibility of assessment of regulatory lipids in BC by mass spectrometry so presently unknown lipid regulatory components can be detected without addition of specific antibodies as in the ELISA procedure. Baseline regulatory lipids were detected in >pg/mL BC in control animals or human lung tissue culture cells. In nearly every case animals exposed to toxins or infectious bacteria showed increases in the BC regulatory components. Lipids were recovered from BC by solid phase extraction. Phosphatidylcholine (PC) based lipids were detected as the progenitor (parent) ions of isomers that fragmented in producing product positive ions at m/z 184 (of phosphocholine) in tandem MS using capillary HPLC and electrospray ionization. BC eicosanoids such as prostaglandins, thromboxane, and isoprostanes require capillary gas chromatography for separation and detection that necessitates methoximation, pentafluorobenzyl (PFB) ester formation, and trimethyl silylation of hydroxyls prior to gas chromatography/ion trap tandem mass spectrometry of negative ions after chemical ionization (NICI). Tetradeuterated internal standards were utilized for quantitation with the GC/NICI/MS. Changes in concentrations of lipids and eicosanoids were observed in piglets, and rats exposed to aerosolized 100 mug/kg lipopolysaccharide (LPS), or 50 mug/kg and 150 mug/kg aerosolized Staphylococcal enterotoxin B (SEB) in BC as well as in human THP-1 cell culture cell supernatants and bronchoalveolar lavage (BAL) samples in rats. Responses of the molecular species of phosphatidylcholines (PCs), platelet activating factors (PAFs) and specific eicosanoids correlated to the toxin and bacterial infections suggesting that patterns of differential responses could be detected with further experimentation. Initial targets included prostaglandins (PGE(2), PGF(2alpha)), thromboxane (TXB2), and prostacyclin (as 6-Keto PGF(1alpha)) that show differential responses to inflammation, the leukotriene (LTB4) and PGD2 for allergic responses, isoprostanes (8-iso-PGF(2alpha)) for free radical oxidative stress responses, and HETEs for differential lipoxygenase activities. PAFs and lysoPAFs have been shown to increase with inflammation and in the feasibility experiments reported here. Preliminary studies show pulmonary responses of piglets to intrathecal exposure of toxicants (LPS and SEB) or infections with Actinobacillus pleuropneumoniae induce increased levels of lipids and two eicosanoids with the suggestion that differential patterns might be detected with expanded testing. Preliminary experience indicates numerous other eicosanoids were available for assay in BC. This suggests an important potential application of BC to observe a wide array of factors to establish comprehensive profiles for physiological and pathophysiological states. Ultimately this technique could be used as a non-invasive possibly presymptomatic assessment of pulmonary pathobiology.

Energy expenditure and plasma catecholamines in preterm infants with mild chronic lung disease.

The present study examined the hypothesis that the energy expenditure (EE) increases during the development of chronic lung disease (CLD) together with serum catecholamines as indicator of stress. Sixteen spontaneously breathing infants with gestational age of 28-34 weeks and birth weight of 870-1920 g were studied. Eight patients were at risk for CLD, eight were healthy controls. Measurements of indirect calorimetry were done weekly at postnatal ages of 2, 3, 4 and 5 weeks. Serum concentrations of adrenaline and noradrenaline were measured by means of a high-pressure liquid chromatography (HPLC) method. The eight CLD risk infants developed mild CLD with FiO(2) of 0.27-0.31 and characteristic radiographic signs at 28 days. Compared to the healthy controls, preterm infants with mild CLD showed increases in EE from week 3 (+67%) to week 5 (+46%). Plasma noradrenaline was increased significantly in the CLD infants when compared to the controls at week 3 (0.7+/-0.3 vs. 0.5+/-0.1 ng/ml; P<0.05) and more pronounced at week 4 (1.4+/-0.2 vs. 0.6+/-0.2 ng/ml; P<0.001) and 5 (1.1+/-0.3 vs. 0.7+/-0.2 ng/ml; P<0.01). Plasma adrenaline was markedly higher in the CLD risk group (mean overall value: 0.64+/-0.1 ng/ml) than in the controls (<0.1 ng/ml in all controls) from week 2 to 5. Regression analysis for the combined values of the infants with and without CLD showed that EE was directly correlated with heart rate, noradrenaline and adrenaline concentration at each of the four study weeks and with respiratory rate at weeks 2 and 3. Increased plasma catecholamine concentrations in preterm infants with CLD suggest that these infants experienced marked stress during the early stages of the disease. Increased EE may in part be a result of this stress.

Dose-response assessment and effect of particles in guinea pigs exposed chronically to diesel exhaust: analysis of various biological markers in pulmonary alveolar lavage fluid and circulating blood.

To elucidate dose-response and other effects of diesel particles in guinea pigs chronically exposed to diesel exhaust, various biomarkers for chronic obstructive lung diseases were studied using bronchoalveolar lavage (BAL) fluid and blood specimens. Guinea pigs were exposed 16 h/day, 6 days/wk, for 6, 12, 18, or 24 mo to filtered air (control group, n = 8-10), a low level of diesel exhaust (L group: NO(2) = 0.22 +/- 0.03 ppm; SO(2) = 0.6 +/- 0.19 ppm; particles = 0.21 +/- 0.07 mg/m(3), n = 8-10), medium level of diesel exhaust (M group; NO(2) = 1.07 +/- 0.09 ppm; SO(2) = 2.83 +/- 0.73 ppm; particles = 1.14 +/- 0.26 mg/m(3), n = 8-10), and high level of diesel exhaust (H group: NO(2) = 2.88 +/- 0.29 ppm; SO(2) = 6.49 +/- 1.75 ppm; particles = 2.94 +/- 0.69 mg/m(3), n = 8-10), or at a medium concentration of diesel exhaust without particulate matters (MG group: NO(2) = 1.01 +/- 0.09 ppm;#10; SO(2) = 2.66 +/- 0.64 ppm; particles = 0.01 +/- 0.01 mg/m(3), n = 8-10). Anesthetized animals were sacrificed and BAL fluid from the lung and blood from right ventricle were collected. Various biomarkers of inflammation, components of mucus and surfactant, bronchoconstrictors were determined. Changes of leukotriene C4 in plasma, eosinophil counts, biomarkers of inflammation and cytotoxicity, and mucus and surfactant components in BAL fluid were statistically different among the C, L, M, and H groups after adjustment for the exposure period and group-by-exposure period with respect to their interactions in two-way analysis of variance (ANOVA). The levels of these biomarkers in the H group were higher than those of the M group, whereas those of the L group showed no significant changes compared with those of the C group during experimental period. Onset of significant changes of these biomarkers for the M group was at 18 mo of exposure, whereas that for the H group was at 12 mo of exposure, which resulted in changes in the levels of biomarkers in BAL fluid. Although numbers of eosinophils in BAL fluid increased significantly in the M and H groups at 12 mo, only leukotriene C4 increased at 18 and 24 mo in blood and at 24 mo in BAL fluid. Animals exposed to the medium level of diesel exhaust without particulate matter showed significantly less increase of these biomarkers as compared with animals exposed to the same level of diesel exhaust with particulate matters. These findings indicate that chronic exposure to diesel exhaust induced continuous inflammation, overproduction of mucus, and phospholipids in the lung. Animals exposed to the high dose of diesel exhaust showed a plateau of biological responses at 12 mo of exposure. Particulate matter in diesel exhaust appears to play an important role in development of lung injury by chronic emission exhaust exposure.

Resting energy expenditure and lung disease in cystic fibrosis.

Optimal nutritional support is considered to be an integral part in the management of cystic fibrosis (CF). Several factors contribute to increased resting energy expenditure (REE), which itself can lead to energy imbalance and thus contribute to deterioration of the nutritional status. We aimed to assess the impact of lung parenchyma damage on REE and correlated these findings with forced expiratory volume in 1 s (FEV(1)). Twenty patients performed respiratory function testing (FEV(1)), pulmonary high-resolution computed tomography (HRCT) and assessment of REE with open circuit indirect calorimetry. HRCT was scored by using a modified Bhalla method. Mean HRCT score was 8.4 and mean REE value was 108.4% predicted vs. 96.5% predicted of 16 healthy subjects (P<0.01). There was a significant correlation between HRCT score and REE (P<0.01), HRCT score and FEV(1) (P<0.001) and REE and FEV(1) (P<0.05). The correlations demonstrate a close correlation between lung damage and elevated REE in people with CF. Prevention of negative energy balance is an important part in follow-up of patients with CF. Any increase in REE should raise suspicion of progress in lung impairment.

[Assessment of beta-methyl lodophenyl pentadecanoic acid myocardial scintigraphy in patients with chronic pulmonary diseases].

The purpose of this study was to determine whether impaired fatty acid metabolism occurs in the right ventricle of patients with chronic pulmonary diseases (TB sequelae, TB seq.; 8, and chronic pulmonary emphysema. CPE; 14). 123I-BMIPP myocardial scintigraphy was performed on 22 subjects. The RV-BMIPP index (ratio of radioactivity in the right ventricle to that in the upper mediastinum), LV-BMIPP index (ratio of radioactivity in the left ventricle to that in the upper mediastinum), and RVc/LVc (ratio of radioactivity in the right ventricle to that in the left ventricle) were calculated to compare the distribution of radioactivity in the right and left ventricles. We also examined the correlations between these parameters and parameters of blood gas analysis and pulmonary hemodynamics. The RV-BMIPP index. LV-BMIPP index, and RVc/LVc were elevated in the TB seq. and CPE patient groups compared to the control group. The RV-BMIPP and LV-BMIPP indices demonstrated significant, negative correlations with PaO2; also a significant positive correlation was observed between the RV-BMIPP index and mean pulmonary arterial pressure. On the other hand, no significant correlation was found between the LV-BMIPP index and mean pulmonary arterial pressure. In the arm-stretching test under right heart catheterization, the RV-BMIPP and LV-BMIPP indices demonstrated significant, positive correlations with the cardiac index during exercise. These results suggest that hypoxemia accelerates fatty acid metabolism in the myocardium, and that local pressure overloading accelerates fatty acid metabolism in the right ventricle. Anomalies of fatty acid metabolism in the right ventricle may appear in patients with chronic pulmonary disease, and could be an adaptation to hypoxemia and overload, not an impairment.

Differentiating benign from malignant lung lesions using "quantitative" parameters of FDG PET images.

UNLABELLED: Fluorine-18 labeled deoxyglucose positron-emission tomography (FDG-PET) applications in oncology include the differential diagnosis of chest masses and single pulmonary nodules. However, FDG is not tumor-specific; rather, it also accumulates in inflammatory processes. This study was performed to identify image parameters that would improve the specificity of PET. METHODS: Twenty-six patients who had benign and malignant lung lesions were examined retrospectively. Positron-emission tomography data were acquired in dynamic scanning mode after intravenous bolus of 250-402 MBq of FDG. Standardized uptake values (SUVs) were calculated and Patlak analyses were performed in selected regions of interest in the PET images. Positron-emission tomography results were related to histological diagnosis (N = 49) or clinical follow-up (N = 3). RESULTS: The specificity and sensitivity of the original PET scan reports, which was based on visual image interpretation and loosely applied SUVs, was 100% and 73%, respectively. Using the SUVs with a cut-off value of 3.8 and Kpat value with a cut-off at 0.025 min-1 improved the specificity to 81% and 85%. CONCLUSION: FDG-PET image interpretation can be facilitated by using SUV information or the accumulation rate of the radiotracer (Patlak). With additional validation, this method could have a significant cost-effective impact on the medical/surgical management of chest masses.