Functional imaging using computer methods to compare the effect of salbutamol and ipratropium bromide in patient-specific airway models of COPD.

BACKGROUND: Salbutamol and ipratropium bromide improve lung function in patients with chronic obstructive pulmonary disease (COPD). However, their bronchodilating effect has not yet been compared in the central and distal airways. Functional imaging using computational fluid dynamics offers the possibility of making such a comparison. The objective of this study was to assess the effects of salbutamol and ipratropium bromide on the geometry and computational fluid dynamics-based resistance of the central and distal airways. METHODS: Five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner with a 1-week interval between treatments. Patients underwent lung function testing and a multislice computed tomography scan of the thorax that was used for functional imaging. Two hours after dosing, the patients again underwent lung function tests and repeat computed tomography. RESULTS: Lung function parameters, including forced expiratory volume in 1 second, vital capacity, overall airway resistance, and specific airway resistance, changed significantly after administration of each product. On functional imaging, the bronchodilating effect was greater in the distal airways, with a corresponding drop in airway resistance, compared with the central airways. Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient. Salbutamol was more effective in the other patients. CONCLUSION: This pilot study gives an innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD, using the new techniques of functional imaging and computational fluid dynamics.

Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation.

The effect of a bronchodilator in asthmatics is only partially described by changes in spirometric values since no information on regional differences can be obtained. Imaging techniques like high-resolution computed tomography (HRCT) provide further information but lack detailed information on specific airway responses. The aim of the present study was to improve the actual imaging techniques by subsequent analysis of the imaging data using computational fluid dynamics (CFD). We studied 14 mild to moderately severe asthmatics. Ten patients underwent HRCT before and 4h after inhalation of a novel long acting beta(2) agonist (LABA) that acts shortly after inhalation. Four patients were studied for chronic effects and underwent CT scans twice after adequate wash-out of bronchodilators. In the active group, a significant bronchodilator response was seen with a forced expiratory volume in 1s (FEV1) increase of 8.78 +/- -6.27% pred vs -3.38 +/- 6.87% pred in the control group. The changes in FEV1 correlated significantly with the changes in distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = -0.76, p = 0.002) as calculated with the CFD method. The changes in distal R(aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD-based changes in R(aw) were still detectable. We conclude that CFD calculations, based on airway geometries of asthmatic patients, provide additional information about changes in regional R(aw). All changes in the CFD-based calculated R(aw) significantly correlate with the observed changes in spirometric values therefore validating the CFD method for the studied application.

Functional imaging using computational fluid dynamics to predict treatment success of mandibular advancement devices in sleep-disordered breathing.

Mandibular advancement devices (MADs) have emerged as a popular alternative for the treatment of sleep-disordered breathing. These devices bring the mandibula forward in order to increase upper airway (UA) volume and prevent total UA collapse during sleep. However, the precise mechanism of action appears to be quite complex and is not yet completely understood; this might explain interindividual variation in treatment success. We examined whether an UA model, that combines imaging techniques and computational fluid dynamics (CFD), allows for a prediction of the treatment outcome with MADs. Ten patients that were treated with a custom-made mandibular advancement device (MAD), underwent split-night polysomnography. The morning after the sleep study, a low radiation dose CT scan was scheduled with and without the MAD. The CT examinations allowed for a comparison between the change in UA volume and the anatomical characteristics through the conversion to three-dimensional computer models. Furthermore, the change in UA resistance could be calculated through flow simulations with CFD. Boundary conditions for the model such as mass flow rate and pressure distributions were obtained during the split-night polysomnography. Therefore, the flow modeling was based on a patient specific geometry and patient specific boundary conditions. The results indicated that a decrease in UA resistance and an increase in UA volume correlate with both a clinical and an objective improvement. The results of this pilot study suggest that the outcome of MAD treatment can be predicted using the described UA model.

Correlation between severity of sleep apnea and upper airway morphology based on advanced anatomical and functional imaging.

Determination of the apnea hypopnea index (AHI) as a measure of the severity of obstructive sleep apnea/hypopnea syndrome (OSAHS) is a widely accepted methodology. However, the outcome of such a determination depends on the method used, is time consuming and insufficient for prediction of the effect of all treatment modalities. For these reasons more methods for evaluating the severity of OSAHS, based on different imaging modalities, have been looked into and recent studies have shown that anatomical properties determined from three-dimensional (3D) computed tomography (CT) images are good markers for the severity of the OSAHS. Therefore, we correlated anatomical measurements of a 3D reconstruction of the upper airway together with flow simulation results with the severity of OSAHS in order to find a combination of variables to indicate the severity of OSAHS in patients. The AHI of 20 non-selected, consecutive patients has been determined during a polysomnography. All patients also underwent a CT scan from which a 3D model of the upper airway geometry was reconstructed. This 3D model was used to evaluate the anatomical properties of the upper airway in OSAHS patients as well as to perform computational fluid dynamics (CFD) computations to evaluate the airflow and resistance of this upper airway. It has been shown that a combination of the smallest cross-sectional area and the resistance together with the body mass index (BMI) form a set of markers that predict very well the severity of OSAHS in patients within this study. We believe that these markers can be used to evaluate the outcome of an OSAHS treatment.

Hemispheric asymmetries for whole-based and part-based face processing in the human fusiform gyrus.

Behavioral studies indicate a right hemisphere advantage for processing a face as a whole and a left hemisphere superiority for processing based on face features. The present PET study identifies the anatomical localization of these effects in well-defined regions of the middle fusiform gyri of both hemispheres. The right middle fusiform gyrus, previously described as a face-specific region, was found to be more activated when matching whole faces than face parts whereas this pattern of activity was reversed in the left homologous region. These lateralized differences appeared to be specific to faces since control objects processed either as wholes or parts did not induce any change of activity within these regions. This double dissociation between two modes of face processing brings new evidence regarding the lateralized localization of face individualization mechanisms in the human brain.

Characterization of growth hormone-binding protein in cattle plasma: prolactin-binding activity and 24-hour profile.

The purpose of this study was to characterize circulating growth hormone-binding proteins (GHBP) and prolactin-binding proteins (PRLBP) in cattle blood plasma. In particular, the 24-hr profile of these molecules was investigated. The preincubation of bull plasma with iodinated bovine growth hormone (bGH) or bovine prolactin (bPRL), followed by gel filtration chromatography (Superdex 200; 1.6 x 60 cm column), resulted in the formation of essentially two complexes. The majority of [125I]bPRL eluted with the first one (M(r) approximately 600 kDa), whereas [125I]bGH mainly appeared in the second one (M(r) approximately 70 kDa). The fractions corresponding to these two peaks were analyzed by western ligand blotting (WLB), under reducing conditions. WLB revealed, respectively, 190-, 56-, 52-, and 28-kDa bands for the first peak and only 52- and 28-kDa bands for the second one. The nature of the 600-kDa peak is at present undetermined, but the 70-kDa one was previously identified as high-affinity GHBP. Displacement studies demonstrated that bGH and bPRL were both able to bind to this GHBP, because the bGH- and bPRL-binding activities of this protein could be saturated by an excess of either of these two hormones. This was indirectly confirmed by the close correlation (r = 0.615; P = 0.0001; n = 155) observed between plasma bGH- and bPRL-binding activities, because this correlation could suggest that both ligands are bound to the same proteins. The temporal concentrations of plasma GHBP were measured in samples collected at 20-min intervals for 24 hr from 8 young bulls. The evaluation of GHBP was realized by WLB, followed by densitometric analysis. Some fluctuations were observed, but these were not correlated with bGH release, even with a +/- 2-hr lag period. In summary, we found that bovine high-affinity GHBP binds not only bGH, but also bPRL. A second type of protein, of higher molecular weight, also binds these two hormones, but further investigations are needed to determine its nature. Finally, GHBP concentrations in cattle blood plasma apparently show fluctuations over a 24-hr period, but no correlation was found between these fluctuations and plasma growth hormone concentrations.

TaqI restriction fragment length polymorphisms for growth hormone in bovine breeds and their association with quantitative traits.

The objectives of the present study were (1) to reveal GH-TaqI RFLPs in different bovine breeds and (2) to look for association between quantitative traits and GH-TaqI RFLPs in bulls highly selected for growth and meat production. Blood was sampled from 269 Holstein heifers, 48 Italian and 45 Hungarian Simmental heifers, 30 Normande heifers and 41 bulls and 13 heifers of the double-muscled Belgian White Blue breed. Bulls were weighed from 7 until 13 months of age and the average daily gain, the feed efficiency, the height and the phenotypic index were determined at the end of the experiment. GH-TaqI RFLPs revealed 4 DNA fragments of 6 (A), 5.2 (B), 4.4 (C) and 4.2 (D) kbp. The distribution of genotypes was different between Normande and the other breeds (P < 0.001) and between Belgian White Blue and Holstein (P < 0.001) or Hungarian Simmental breed (P < 0.005). The Normande heifers were also characterized by a high frequency of the AB genotype (53%) compared with other experimental breeds (range values: 7-24%). In the statistical analysis of the relationships between quantitative traits and GH-TaqI RFLPs in double-muscled Belgian White Blue bulls, the AC genotypic class was not used because of its low distribution. The AA class showed greater records of weight at 7 (P < 0.07) and 13 (P < 0.06) months of age than the AB class. In conclusion, this study has shown a correlation between the GH-TaqI RFLPs and weight at 7 and 13 months of age in Belgian White Blue bulls.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the hypophysial-gonadal axis during the onset of puberty in young bulls.

The objectives of this study were to determine the extent of changes in concentrations of testosterone, growth hormone (GH) and insulin-like growth factor I (IGF-I) concentrations in blood plasma and to characterize the respective plasma-binding proteins of these two peptides during the onset of puberty in male calves. The jugular veins of six male Holstein calves (11-weeks-old) were catheterized and blood was collected every 3 days (one sample every 30 min for 8 h). Hormone concentrations in plasma were determined by specific radioimmunoassay. After incubation with [125I]IGF-I, IGF-I-binding proteins (IGFBPs) were separated by gel filtration; radioactivity was determined in each fraction. Western ligand blotting using radiolabelled hormones as ligand was also used to characterize the IGF-I- and GH-binding proteins in plasma. Puberty was characterized by a rapid (in 1 or 2 days) increase in mean concentrations of testosterone in plasma (from 0.5 to > 2 ng ml-1) and a pulsatile release of the hormone. During puberty, IGF-I concentrations also increased rapidly in 8-10 days from +/- 50 ng ml-1 to > 150 ng ml-1, whereas concentrations of GH in plasma remained relatively stable during the experimental period. A significant correlation was observed between IGF-I and testosterone concentrations (r = 0.77; P < 0.001) throughout the experimental period. Three different IGF-I-binding protein fractions with apparent molecular masses of > 200, 150-170 and 45-65 kDa were found in plasma using gel filtration.(ABSTRACT TRUNCATED AT 250 WORDS)

Presence of growth hormone-binding proteins in cattle plasma and milk.

The presence of GH-binding proteins (GHBPs) in the plasma of adult cattle was investigated using Sephadex G-200 filtration, Western ligand blotting and Western blotting. The changes in the concentration of GHBP in the plasma of dairy half-sister heifers during the first year of life as well as the presence of GHBP in milk were also investigated. When analytical chromatography (on a 1.6 x 100 cm column) was performed, five peaks of recombinant bovine GH (rbGH)-associated radioactivity were revealed in cattle plasma; the first peak, which appeared near the void volume, was presumed to represent aggregates, the second (M(r) 290 kDa) and the third peaks (M(r) 75 kDa) corresponded to specific rbGH-GHBP complexes; the last two peaks representing free 125I-labelled rbGH and Na[125I]. Western ligand blotting revealed multiple GHBPs. Three major bands were observed at approximately 190, 58 and 31 kDa; an excess of unlabelled hormone blocked the binding of 125I-labelled rbGH. Minor non-specific binding bands were also detected in cattle plasma with molecular weights between 40 and 136 kDa. One monoclonal antibody (8H7) produced against synthetic peptide (amino acids 54-63 of the extracellular domain of the bovine GH receptor) specifically interacted with 190 and 58 kDa bands while the 31 kDa band was not recognized. Finally, Western ligand blots were performed to evaluate the changes in plasma GHBP during the first year of life in 55 dairy half-sister heifers and to identify GHBP in milk. In plasma, the intensity of the 31 kDa band varied greatly between animals while the other specific bands remained stable.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain glucose metabolism in postanoxic syndrome. Positron emission tomographic study.

Thirteen positron emission tomographic studies of cerebral glucose utilization were carried out in 12 patients with postanoxic syndrome due to cardiac arrest. Seven subjects were in a persistent vegetative state. The 5 other subjects were normally conscious, but disclosed focal neurological signs. When compared with normal values, mean cerebral glucose metabolism was drastically decreased (+/- 50%) in vegetative subjects, and to a lesser degree (+/- 25%) in conscious patients. The most consistent regional alterations were found in the parieto-occipital cortex (9 cases), the frontier between vertebral and carotid arterial territories, followed by the frontomesial junction (5 cases), the striatum (3 cases with dystonia), thalamus (2 cases), and visual cortex (2 cases with cortical blindness). These data suggest that brain anoxia can result in global brain hypometabolism, which appears related to the vigilance state, as well as in regional alterations preferentially located in arterial border zones.