An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images.

Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (fMRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie food while brain activity was measured via fMRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype (AA) had increased activity compared with the non-risk (TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.

Self-Reported Psychosomatic Complaints and Conduct Problems in Swedish Adolescents.

Physical conditions in children and adolescents are often under reported during mainstream school years and may underlie mental health disorders. Additionally, comparisons between younger and older schoolchildren may shed light on developmental differences regarding the way in which physical conditions translate into conduct problems. The aim of the current study was to examine the incidence of psychosomatic complaints (PSC) in young and older adolescent boys and girls who also report conduct problems. A total of 3132 Swedish adolescents (age range 15-18 years, 47% boys) completed the Uppsala Life and Health Cross-Sectional Survey (LHS) at school. The LHS question scores were categorised by two researchers who independently identified questions that aligned with DSM-5 conduct disorder (CD) criteria and PSC. MANOVA assessed the effects of PSC, age, and gender on scores that aligned with the DSM criteria for CD. The main effects of gender, age, and PSC on the conduct problem scores were observed. Adolescents with higher PSC scores had higher conduct problem scores. Boys had higher serious violation of rules scores than girls, particularly older boys with higher PSC scores. Psychosomatic complaints could be a useful objective identifier for children and adolescents at risk of developing conduct disorders. This may be especially relevant when a reliance on a child's self-reporting of their behavior may not help to prevent a long-term disturbance to their quality of life.

Analyzing 13NN lung washout curves in the presence of intraregional nonuniformities.

The use of 13NN and positron imaging provides a powerful noninvasive means of assessing regional pulmonary function. Current techniques for analyzing lung washout curves, however, are subject to error due to intraregional nonuniformities, particularly in the presence of areas with very long time constants or gas trapping. This paper presents a simple "hybrid" method for analyzing 13NN-washout studies that addresses the problems of regions of air trapping and long time constants within a region of interest. This method assumes an exponential washout form for the slow regions, estimates their fractional volume, and subtracts their contribution from the overall washout curve. The modified Stewart-Hamilton method is then applied to the remaining washout curve to calculate its ventilation. The over-all specific ventilation of the region is calculated as the volume-weighted average of the specific ventilations of the two compartments. The performance of the hybrid method is compared with other currently used correction techniques by using a simulated two-compartment lung washout in which there is a variable amount of gas trapping. The analysis techniques are also applied to washout data with intraregional nonuniformities obtained during experimentally created unilateral bronchial obstruction. This new approach has the advantages of automatically correcting for washout truncation, estimating the relative size of the trapped or slow region while eliminating its bias on the regional ventilation, and yet retaining the unrestricted and robust nature of the Stewart-Hamilton method in the analysis of the well-ventilated regions.

Changes in regional lung mechanics and ventilation distribution after unilateral pulmonary artery occlusion.

Regional pneumoconstriction induced by alveolar hypocapnia is an important homeostatic mechanism for optimization of ventilation-perfusion matching. We used positron imaging of 13NN-equilibrated lungs to measure the distribution of regional tidal volume (VT), lung volume (VL), and lung impedance (Z) before and after left (L) pulmonary artery occlusion (PAO) in eight anesthetized, open-chest dogs. Measurements were made during eucapnic sinusoidal ventilation at 0.2 Hz with 4-cmH2O positive end expiratory pressure. Right (R) and L lung impedances (ZR and ZL) were determined from carinal pressure and positron imaging of dynamic regional VL. LPAO caused an increase in magnitude of ZL relative to magnitude of ZR, resulting in a shift in VT away from the PAO side, with a L/R magnitude of Z ratio changing from 1.20 +/- 0.07 (mean +/- SE) to 2.79 +/- 0.85 after LPAO (P < 0.05). Although mean L lung VL decreased slightly, the VL normalized parameters specific admittance and specific compliance both significantly decreased with PAO. Lung recoil pressure at 50% total lung capacity also increased after PAO. We conclude that PAO results in an increase in regional lung Z that shifts ventilation away from the affected area at normal breathing frequencies and that this effect is not due to a change in VL but reflects mechanical constriction at the tissue level.

Ventilation distribution and regional lung impedance during partial unilateral bronchial obstruction.

Significant degrees of main-stem bronchial obstruction may not have a detectable effect on ventilation distribution at normal breathing frequencies. We determined the effect of graded left main-stem bronchial obstruction (area reduction of 50 and 70%) on the distribution of tidal volume (VT) and mean lung volume (VL) using radioactive 13NN and two-dimensional planar positron imaging in six supine anesthetized tracheotomized dogs. Measurements were made during eucapnic high-frequency oscillatory ventilation at frequencies (f) of 0.2, 1, 5, and 10 Hz. Right and left lung respiratory system complex impedance (Z) values were assessed by simultaneous measurements of dynamic regional lung volume by positron imaging and carinal pressure. The results show a progressive shift of VT away from the obstruction at f > 1 Hz, with VT left-to-right (L/R) ratios of 0.9, 0.9, 0.58, and 0.46 at f of 0.2, 1, 5, and 10 Hz, respectively, for 70% obstruction. VT shifts with f for 50% obstruction were similar but of lesser magnitude. VL L/R ratio was 0.88 and did not change with f or obstruction. The real part of Z was frequency dependent and increased at low f independent of obstruction. The real part of Z L/R ratio increased with obstruction at 5 and 10 Hz. At low f there was a difference between left and right imaginary parts of Z due to the difference in VL. There was no significant change in the imaginary part of Z as a result of obstruction. We conclude that up to a 70% unilateral bronchial obstruction is not detectable by distribution of ventilation at f < or = 1 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of pulmonary ventilation using Xe-enhanced computed tomography in prone and supine dogs.

Xe-enhanced computed tomography (CT; Xe-CT) is a method for the noninvasive measurement of regional pulmonary ventilation in intact subjects, determined from the washin and washout rates of the radiodense, nonradioactive gas Xe, as measured in serial CT scans. We used the Xe-CT ventilation method, along with other quantitative CT measurements, to investigate the distribution of regional lung ventilation and air content in healthy, anesthetized, mechanically ventilated dogs in the prone and supine postures. Vertical gradients in regional ventilation and air content were measured in five mongrel dogs in both prone and supine postures at four axial lung locations. In the supine position, ventilation increased with dependent location, with a mean slope of 7.3%/cm lung height, whereas no ventilation gradients were found at any location in the prone position. These results agree quantitatively with other published studies. In addition, six different animals were studied (3 supine, 3 prone) to examine the longitudinal distribution of ventilation and air content. The prone lungs were more uniformly inflated compared with the supine, which were less well expanded at the base than apex. Ventilation index, a measure of regional ventilation relative to whole lung ventilation, increased steeply from apex to base in the supine animals, whereas it was again more uniform in the prone condition. We conclude that the Xe-CT method provides a reasonable, quantitative measurement of regional ventilation and promises to be a valuable tool for the noninvasive determination of regional lung function.

Parameter estimation and confidence intervals for Xe-CT ventilation studies: a Monte Carlo approach.

Xenon-enhanced computed tomography (Xe-CT) is a technique for the noninvasive measurement of regional pulmonary ventilation from the washin and/or washout time constants of radiodense stable xenon gas, determined from serial computed tomography scans. Although the measurement itself is straightforward, there is a need for methods for the estimation of variability and confidence intervals so that the statistical significance of the information obtained may be evaluated, particularly since obtaining repeated measurements is often not practical. We present a Monte Carlo (MC) approach to determine the 95% confidence interval (CI) for any given measurement. This MC method was characterized in terms of its unbiasedness and coverage of the CI. In addition, 10 identical Xe-CT ventilation runs were performed in an anesthetized dog, and the time constant was determined for several regions of varying size in each run. The 95% CI, estimated from these repeated measurements as the mean +/- 2 x SE, compared favorably with the CI obtained by the MC approach. Finally, a simulation was performed to compare the performance of three imaging protocols in estimating model parameters.

Effect of hypoxia on respiratory system impedance in dogs.

The effects of hypoxia on lung and airway mechanics remain controversial, possibly because of the confounding effects of competing reflexes caused by systemic hypoxemia. We compared the effects of systemic hypoxemia with those of unilateral alveolar hypoxia (with systemic normoxemia) on unilateral respiratory system impedance (Z) in intact, anesthetized dogs. Independent lung ventilation was obtained with a Kottmeier endobronchial tube. Individual left and right respiratory system Z was measured during sinusoidal forcing with 45 ml of volume at frequencies of 0.2-2.1 Hz during control [100% inspired O2 fraction (FIO2)], systemic hypoxemia (10% FIO2), and unilateral alveolar hypoxia (0% FIO2 to left lung, 100% FIO2 to right lung). During systemic hypoxemia, there was a mean Z magnitude increase of 18%. This change was entirely attributable to a decrease in the imaginary component of Z; there was no change in the real component of Z. Administration of atropine (0.2 mg/kg) did not block the increase in Z with systemic hypoxemia. In contrast, there was no change in Z in the lung subjected to unilateral alveolar hypoxia. We conclude that alveolar hypoxia has no direct effect on lung mechanical properties in intact dogs. In contrast, systemic hypoxemia does increase lung impedance, apparently through a noncholinergic mechanism.

A comprehensive equation for the pulmonary pressure-volume curve.

Quantification of pulmonary pressure-volume (P-V) curves is often limited to calculation of specific compliance at a given pressure or the recoil pressure (P) at a given volume (V). These parameters can be substantially different depending on the arbitrary pressure or volume used in the comparison and may lead to erroneous conclusions. We evaluated a sigmoidal equation of the form, V = a + b[1 - e-(P-c)/d]-1, for its ability to characterize lung and respiratory system P-V curves obtained under a variety of conditions including normal and hypocapnic pneumoconstricted dog lungs (n = 9), oleic acid-induced acute respiratory distress syndrome (n = 2), and mechanically ventilated patients with acute respiratory distress syndrome (n = 10). In this equation, a corresponds to the V of a lower asymptote, b to the V difference between upper and lower asymptotes, c to the P at the true inflection point of the curve, and d to a width parameter proportional to the P range within which most of the V change occurs. The equation fitted equally well inflation and deflation limbs of P-V curves with a mean goodness-of-fit coefficient (R2) of 0.997 +/- 0.02 (SD). When the data from all analyzed P-V curves were normalized by the best-fit parameters and plotted as (V-a)/b vs. (P-c)/d, they collapsed into a single and tight relationship (R2 = 0.997). These results demonstrate that this sigmoidal equation can fit with excellent precision inflation and deflation P-V curves of normal lungs and of lungs with alveolar derecruitment and/or a region of gas trapping while yielding robust and physiologically useful parameters.

Regional coupling between chest wall and lung expansion during HFV: a positron imaging study.

Apparently conflicting differences between the regional chest wall motion and gas transport have been observed during high-frequency ventilation (HFV). To elucidate the mechanism responsible for such differences, a positron imaging technique capable of assessing dynamic chest wall volumetric expansion, regional lung volume, and regional gas transport was developed. Anesthetized supine dogs were studied at ventilatory frequencies (f) ranging from 1 to 15 Hz and eucapnic tidal volumes. The regional distribution of mean lung volume was found to be independent of f, but the apex-to-base ratio of regional chest wall expansion favored the lung bases at low f and became more homogeneous at higher f. Regional gas transport per unit of lung volume, assessed from washout maneuvers, was homogeneous at 1 Hz, favored the bases progressively as f increased to 9 Hz, and returned to homogeneity at 15 Hz. Interregional asynchrony (pendelluft) and right-to-left differences were small at this large regional scale. Analysis of the data at a higher spatial resolution showed that the motion of the diaphragm relative to the excursions of the rib cage decreased as f increased. These differences from apex to base in regional chest wall expansion and gas transport were consistent with a simple model including lung, rib cage, and diaphragm regional impedances and a viscous coupling between lungs and chest wall caused by the relative sliding between pleural surfaces. To further test this model, we studied five additional animals under open chest conditions. These studies resulted in a homogeneous and f-independent regional gas transport. We conclude that the apex-to-base distribution of gas transport observed during HFV is not caused by intrinsic lung heterogeneity but rather is a result of chest wall expansion dynamics and its coupling to the lung.

Selective endothelial dysfunction in conscious dogs after cardiopulmonary bypass.

It has previously been demonstrated that cardiopulmonary bypass (CPB) causes prolonged pulmonary vascular hyperreactivity (D.P. Nyhan, J.M. Redmond, A.M. Gillinov, K. Nishiwaki, and P.A. Murray. J. Appl. Physiol. 77: 1584-1590, 1994). This study investigated the effects of CPB on endothelium-dependent (acetylcholine and bradykinin) and endothelium-independent (sodium nitroprusside) pulmonary vasodilation in conscious dogs. Continuous left pulmonary vascular pressure-flow (LP-Q) plots were generated in conscious dogs before CPB and again in the same animals 3-4 days post-CPB. The dose of U-46619 used to acutely preconstrict the pulmonary circulation to similar levels pre- and post-CPB was decreased (0.13 +/- 0.01 vs. 0.10 +/- 0.01 mg.kg-1.min-1, P < 0.01) after CPB. Acetylcholine, bradykinin, and sodium nitroprusside all caused dose-dependent pulmonary vasodilation pre-CPB. The pulmonary vasodilator response to acetylcholine was completely abolished post-CPB. For example, at left pulmonary blood flow of 80 ml.kg-1.min-1 acetylcholine (10 micrograms.kg-1.min-1) resulted in 72 +/- 15% reversal (P < 0.01) of U-46619 preconstriction pre-CPB but caused no change post-CPB. However, the responses to bradykinin and sodium nitroprusside were unchanged post-CPB. The impaired pulmonary vasodilator response to acetylcholine, but not to bradykinin, suggests a selective endothelial defect post-CPB. The normal response to sodium nitroprusside indicates that cGMP-mediated vasodilation is unchanged post-CPB.

Design and calibration of a high-frequency oscillatory ventilator.

High-frequency ventilation (HFV) is a modality of mechanical ventilation which presents difficult technical demands to the clinical or laboratory investigator. The essential features of an ideal HFV system are described, including wide frequency range, control of tidal volume and mean airway pressure, minimal dead space, and high effective internal impedance. The design and performance of a high-frequency oscillatory ventilation system is described which approaches these requirements. The ventilator utilizes a linear motor regulated by a closed loop controller and driving a novel frictionless double-diaphragm piston pump. Finally, the ventilator performance is tested using the impedance model of Venegas [1].

Xenon-enhanced computed tomography quantifies normal maxillary sinus ventilation.

OBJECTIVE: The purpose of this study was to determine the applicability, safety, and normal parameters of a xenon-enhanced CT technique to quantify maxillary sinus ventilation. PATIENTS AND METHODS: Nine healthy subjects inhaled a xenon-oxygen-air mixture through their noses while repeated CT scans were performed through the same section of their sinuses. Images were obtained every 1 to 3 minutes and analyzed to measure the density of the gas in the maxillary sinus as a function of time. RESULTS: Individual nasal cavity time constants ranged from 0.5 to 18 minutes. Studies performed after decongestion showed poorer sinus ventilation. CONCLUSIONS: The xenon-CT washin/washout technique is safe, effective, and gives representative data.

Dynamic assessment of paranasal sinus ventilation using xenon-enhanced computed tomography.

Disease of the paranasal sinuses is a common and costly condition. Evaluation of the efficacy of either medical or surgical methods of treatment is limited by the lack of quantitative methods to characterize sinus ventilation, which may be an important determinant of the baseline physiological state of the sinuses. Xenon-enhanced computed tomography (Xe-CT) measurement of sinus ventilation provides a noninvasive method of quantifying maxillary sinus ventilation using the nonradioactive, radiodense gas Xe as a tracer. Study subjects breathed a mixture of Xe gas and oxygen through a close-fitting nasal mask during serial CT imaging of a single radiographic plane through the maxillary sinuses--a generally well-tolerated protocol. Analysis of the sinus density-time curves allowed calculation of first-order exponential time constants from which specific ventilation rates could be determined for individual sinuses. Previously developed data analysis techniques were used to assess the statistical significance of the data and determine confidence intervals, allowing examination of the effects of noise in the data, and to demonstrate areas for further study protocol refinement. We conclude that Xe-CT measurement of sinus ventilation is a potentially valuable noninvasive technique for the diagnostic imaging of the human maxillary sinus.

Permissive hypercapnia with high-frequency oscillatory ventilation and one-lung isolation for intraoperative management of lung resection in a patient with multiple bronchopleural fistulae.

We report the use of high-frequency oscillatory ventilation in the operating room during repair of multiple bronchopleural fistulae in a 9-year-old boy. In addition, we used principles of permissive hypercapnia to further minimize barotrauma. There were no cardiovascular consequences due to either the high-frequency ventilation or the permissive hypercapnia. Our goals in employing this strategy were to minimize barotrauma, minimize gas flow through the fistulae, and optimize the surgical results.

Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model.

The regional distribution of inflammation during acute lung injury (ALI) is not well known. In an ovine ALI model we studied regional alveolar inflammation, surfactant composition, and CT-derived regional specific volume change (sVol) and specific compliance (sC). 18 ventilated adult sheep received IV lipopolysaccharide (LPS) until severe ALI was achieved. Blood and bronchoalveolar lavage (BAL) samples from apical and basal lung regions were obtained at baseline and injury time points, for analysis of cytokines (IL-6, IL-1ß), BAL protein and surfactant composition. Whole lung CT images were obtained in 4 additional sheep. BAL protein and IL-1ß were significantly higher in injured apical vs. basal regions. No significant regional surfactant composition changes were observed. Baseline sVol and sC were lower in apex vs. base; ALI enhanced this cranio-caudal difference, reaching statistical significance only for sC. This study suggests that apical lung regions show greater inflammation than basal ones during IV LPS-induced ALI which may relate to differences in regional mechanical events.

Impact of positive end-expiratory pressure during heterogeneous lung injury: insights from computed tomographic image functional modeling.

Image Functional Modeling (IFM) synthesizes three dimensional airway networks with imaging and mechanics data to relate structure to function. The goal of this study was to advance IFM to establish a method of exploring how heterogeneous alveolar flooding and collapse during lung injury would impact regional respiratory mechanics and flow distributions within the lung at distinct positive end-expiratory pressure (PEEP) levels. We estimated regional respiratory system elastance from computed tomography (CT) scans taken in 5 saline-lavaged sheep at PEEP levels from 7.5 to 20 cmH(2)O. These data were anatomically mapped into a computational sheep lung model, which was used to predict the corresponding impact of PEEP on dynamic flow distribution. Under pre-injury conditions and during lung injury, respiratory system elastance was determined to be spatially heterogeneous and the values were distributed with a hyperbolic distribution in the range of measured values. Increases in PEEP appear to modulate the heterogeneity of the flow distribution throughout the injured lung. Moderate increases in PEEP decreased the heterogeneity of elastance and predicted flow distribution, although heterogeneity began to increase for PEEP levels above 12.5-15 cmH(2)O. By combining regional respiratory system elastance estimated from CT with our computational lung model, we can potentially predict the dynamic distribution of the tidal volume during mechanical ventilation and thus identify specific areas of the lung at risk of being overdistended.

Non-invasive imaging of regional lung function using x-ray computed tomography.

The use of imaging technologies has progressed beyond the depiction of anatomic abnormalities to providing non-invasive regional structure and functional information in intact subjects. These data are particularly valuable in studies of the lung, since lung disease is heterogeneous and significant loss of function may occur before it is detectable by traditional whole lung measurements such as oxygenation, compliance, or spirometry. While many imaging modalities are available, X-ray computed tomography (CT) is emerging as the preferred method for imaging the lung because of its widespread availability, resolution, high signal/noise ratio for lung tissue, and speed. Utilizing the quantitative density and dimensional information available from conventional CT images, it is possible to measure whole and regional lung volumes, distribution of lung aeration and recruitment behavior under various clinical conditions and interventions, and important regional mechanical properties. In addition, using the radiodense gas xenon (Xe) as a contrast agent, regional ventilation or gas transport may also be obtained. This communication will review recent advances in CT based techniques for the measurement of regional lung function.

Lung compliance changes on high-frequency ventilation in normal dogs.

To test the hypothesis that high-frequency ventilation (HFV) promotes lung stability we compared the temporal course of dynamic lung compliance changes after two inflations on HFV with those occurring on conventional mechanical ventilation (CMV) at two different lung volumes, specifically with and without 5 cmH2O positive end-expiratory pressure (PEEP). In our first set of experiments we ventilated six anesthetized paralyzed dogs first with CMV, then with HFV, then again with CMV using tidal volumes of 15 ml/kg at rates of 16-18 times/min for CMV and less than 90 ml and a rate of 15 Hz for HFV. In our second set of experiments we ventilated six dogs for 4 h, the 1st h with CMV at 0 cmH2O end-expiratory pressure, the 2nd h with CMV with 5 cmH2O PEEP, the 3rd h with HFV at the same mean pleural pressure, and the 4th h again with CMV with 5 cmH2O PEEP. We found the decreases in dynamic compliance with time following hyperinflations were similar on HFV and CMV (P greater than 0.5) at both lung volumes. With the lower lung volume the initial dynamic compliance following hyperinflation also tended to fall progressively from one hour to the next despite the inflations. However, with PEEP the initial dynamic compliance over successive hours tended to rise from one hour to the next. We found that changes in dynamic compliance were not necessarily reflected in the venous admixture or alveolar to arterial O2 partial pressure gradients. We thus conclude that lung stability in normal dogs is not improved during HFV, and blood gases cannot be used to predict compliance changes.

Mean airway pressure and alveolar pressure during high-frequency ventilation.

Studies and applications of high-frequency ventilation (HFV) are often performed under conditions of controlled mean airway pressure (Paw). In the present study we tested the assumption that controlling Paw adequately controls lung volume during HFV by investigating the relationship between a reliably measured Paw and the mean alveolar pressure (Palv) of the lungs during HFV of healthy dogs. We minimized the errors of Paw measurement due to the Bernoulli effect and various technical factors by appropriate choice of transducers, amplifiers, and measurement site. Palv was estimated by clamping the ventilator tube during oscillation and measuring the equilibration pressure of the lung and airways. Paw and Palv were determined as functions of frequency (8-25 Hz), tidal volume (60-90 ml), Paw (-5 to 12 cmH2O), and position of the animal (supine vs. lateral). We found that Paw could significantly underestimate Palv and that the degree of underestimation increased at higher frequencies, larger tidal volumes, and lower Paw. Shifting the animal from the supine to the lateral position greatly accentuated this effect. The elevation of Palv above Paw was seen to be a function of mean flow and largely independent of the frequency-tidal volume combination which produced the flow. A possible explanation of this pressure difference is that it results from differences in inspiratory and expiratory airway impedances, which in turn depend on airway geometry, compliance, lung volume, and expiratory flow limitation.