Sven Nyrén

A novel quantitative dual-isotope method for simultaneous ventilation and perfusion lung SPET.

Abstract A quantitative dual-isotope single-photon emission tomography (SPET) technique for the assessment of lung ventilation (V) and perfusion (Q) using, respectively, technetium-99m labelled Technegas (140xa0keV) and indium-113m labelled macro-aggregated albumin (392xa0keV), is presented, validated and clinically tested in a healthy volunteer. In order to assess V, Q and V/Q distributions in quantitative terms, algorithms which correct for down scattering, photon scattering and attenuation, as well as an organ outline algorithm, were implemented. Scatter and down-scatter correction were made in the spatial domain by pixel-wise image subtraction of projection-dependent global scattering factors obtained from the energy domain. The attenuation correction was based on an iterative projection/back-projection method. All studies were made on a three-headed SPET system (Trionix) with medium-energy parallel-hole collimators. The set of input data for quantification was based on SPET acquisition of emission data in four separate energy windows, the associated cumulative energy spectra and transmission data. The attenuation correction routine as well as the edge detection algorithm utilized data from 99mTc transmission tomography. Attenuation data for 113mIn were obtained by linear scaling of the 99mTc attenuation maps. The correction algorithms were experimentally validated with a stack phantom system and applied on a healthy volunteer. The mean difference between the corrected SPET data of the dense stack lung phantom and those obtained from the corresponding scatter- and attenuation-free version was only 1.9% for 99mTc and 0.9% for 113mIn. The estimated fractional V/Q distribution in the 3-D lung phantom volume had its peak at V/Q=1, with a width (FWHM) of 0.31 due to noise, particularly in the 113mIn images, and to partial volume effects. For a healthy volunteer, the corresponding values were 0.9 and 0.35, respectively. This method allows accurate assessment of radionuclide distribution on a regional basis. For basic lung physiology and clinical practice, the method allows assessment of the global frequency functions of the V, Q and V/Q distributions.

Lung Ventilation and Perfusion in Prone and Supine Postures with Reference to Anesthetized and Mechanically Ventilated Healthy Volunteers

Background:The literature on ventilation (V) and lung perfusion (Q) distributions during general anesthesia and controlled mechanical ventilation in supine and prone position is contradictory. The authors aimed to investigate whether V, Q, and ventilation to perfusion ratio (V/Q ratio) matching in anesthetized and mechanically ventilated volunteers are gravity dependent irrespective of posture. Methods:Seven healthy volunteers were studied at two different occasions during general anesthesia and controlled mechanical ventilation. One occasion studied ventral to dorsal V and Q distributions in the supine posture and the other in the prone posture. Imaging was performed in supine posture at both occasions. A dual radiotracer technique and single photon emission computed tomography were used. V and Q were simultaneously tagged with 99mTc-Technegas (Tetley Manufacturing Ltd., Sydney, Australia) and 113mIn-labeled macroaggregates of human albumin (TechneScan LyoMAA, Mallinckrodt Medica, Petten, The Netherlands), respectively. Results:No differences in V between postures were observed. Q differed between postures, being more uniform over different lung regions in prone posture and dependent in supine posture. The contribution of the vertical direction to the total V/Q ratio heterogeneity was larger in supine (31.4%) than in prone (16.4%) (P = 0.0639, two-tailed, paired t test) posture. Conclusions:During mechanical ventilation, prone posture favors a more evenly distributed Q between lung regions. V distribution is independent of posture. This results in a tendency toward lower V/Q gradients in the ventral to dorsal direction in prone compared with supine posture.

Gender differences in the bronchoalveolar lavage cell proteome of patients with chronic obstructive pulmonary disease

BACKGROUNDnChronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and is increasing, primarily among women. Underdiagnosis is common, and because of the heterogeneous disease characteristics, molecular markers of specific disease phenotypes and more efficacious treatment regimens are urgently needed.nnnOBJECTIVEnIn this study the soluble proteome of bronchoalveolar lavage cells, primarily consisting of macrophages, was investigated with the aim of identifying phenotypic differences in early disease development.nnnMETHODSnTwo-dimensional difference gel electrophoresis was used for relative quantification of protein levels, and multivariate modeling was applied to identify proteins of interest that were subsequently identified by means of liquid chromatography-mass spectrometry.nnnRESULTSnSignificant gender differences were unveiled, with numerous alterations in the bronchoalveolar lavage cell proteome occurring in female but not male patients with COPD. Specifically, a subset of 19 proteins provided classification of female healthy smokers from female patients with COPD with 78% predictive power. Subsequent pathway analyses linked the observed alterations to downregulation of the lysosomal pathway and upregulation of the oxidative phosphorylation pathway, possibly linking dysregulation of macroautophagy to a female-dominated COPD disease phenotype.nnnCONCLUSIONnThis investigation makes an important contribution to the elucidation of putative molecular mechanisms underlying gender-based differences in the pathophysiology of COPD, linking alterations of specific molecular pathways to previously observed gender differences in clinical COPD phenotypes. Furthermore, these results stress the importance of the gender-specific search for biomarkers, diagnosis, and treatment in COPD.

High continuous positive airway pressure level induces ventilation/perfusion mismatch in the prone position.

ObjectiveGas exchange in patients with adult respiratory distress syndrome is influenced by posture. The combined effect of continuous positive airway pressure and posture has not been investigated. We studied the effect of normal spontaneous breathing, and that of continuous positive airway pressure, on ventilation/perfusion distributions in healthy volunteers while they were in supine and prone positions. SettingNuclear medicine department in a university hospital. DesignExperimental study. SubjectsSixteen healthy volunteers. InterventionsIn the supine or prone position, the subjects inhaled a technetium-labeled aerosol (technetium-99m diethylenetriamine pentaacetic acid) through a tight-fitting mask. Single photon emission computed tomography images of the lungs were obtained. The subjects then received an intravenous injection of technetium-99m-labeled macroaggregates of albumin, and an identical single photon emission computed tomography imaging was performed. In the group that received continuous positive airway pressure, an end-expiratory pressure of 10 cm H2O was applied during both inhalation and injection. Measurements and Main Results During spontaneous breathing, ventilation/perfusion distribution assessed by regression analysis was uniform (i.e., not significantly different from zero) both in supine and prone positions, with a slope of −1.5 ± 3.5%/cm supine and 1.5 ± 3.5%/cm prone. During continuous positive airway pressure breathing in the supine position, ventilation/perfusion had a slope of −3.4 ± 2.4 compared with 8.3 ± 1.1%/cm in the prone position according to analysis of spatial resolution. ConclusionThere was a less favorable ventilation/perfusion ratio in the prone position when the subjects were exposed to continuous positive airway pressure of 10 cm H2O.

One-leg standing time and hip-fracture prediction

SummaryA hip fracture results in a lower quality of life and a cost of £30,000. In this study, one-leg standing time (OLST) had a negative linear relationship to the risk of a hip fracture. OLST could be a useful tool to assess the need for fracture-preventive interventions.IntroductionA hip fracture immobilizes, restricts autonomy, shortens life expectancy, and results in a cost of £30,000 in the UK health care system. However, effective preventive treatments can be offered to high-risk individuals. Impaired postural balance is an important risk factor for hip fractures, and the aim of this study was to evaluate whether OLST can predict hip fractures in elderly women. FRAX is the most established fracture risk assessment tool worldwide and a secondary aim was to relate the predictive ability of OLST to that of FRAX in this population.MethodsThree hundred fifty-one women aged between 69 and 79xa0years were timed standing on one leg up to 30xa0s with eyes open and assessed with FRAX. Fracture data was obtained from registers.ResultsThe main outcome, a hip fracture, occurred in 40 of the 351 participants (11.4xa0%). The age-adjusted risk of a hip fracture was 5xa0% lower with 1xa0s longer OLST (Hazard ratio 0.95, 95xa0% CI 0.927–0.978). The relation between OLST and hip fracture risk was linear. Harrell’s c was 0.60 for FRAX and 0.68 for OLST adjusted for age.ConclusionWith 1xa0s longer OLST, the risk of a hip fracture decreased significantly by 5xa0%. This risk reduction was not explained by differences in the classic fracture risk factors included in FRAX. OLST had a predictive ability similar to FRAX. OLST is an easily performed balance test which may prove to be valuable in the assessment of hip fracture risk.

Inhalation anesthesia increases V/Q regional heterogeneity during spontaneous breathing in healthy subjects.

Background:The underlying mechanism for the increased alveolar-arterial oxygen tension difference resulting from almost all forms of general anesthesia is unknown. We hypothesized that inhalation anesthesia influences the intrapulmonary distribution of ventilation (V) and perfusion (Q), leading to less advantageous V/Q matching. Methods:Ten healthy volunteers were studied in supine position on two separate occasions, once awake and once during mild anesthesia (sevoflurane inhalation) with maintained spontaneous breathing. On both occasions, the distribution of V and Q were simultaneously imaged using single photon emission computed tomography. V was tagged with [99mTc]-labeled carbon particle aerosol and Q with [113mIn]-labeled macroaggregates of human albumin. Atelectasis formation during anesthesia was prevented using low concentrations of oxygen in inhaled air. Results:Mean V and Q distributions in the ventral-to-dorsal direction, measured in 20 equally spaced volumes of interest and in three regions of interest of equal volume, did not differ between conditions. Anesthesia, when compared with the awake state, significantly decreased the total heterogeneity of the Q distribution (P = 0.002, effect size 1.16) but did not alter V (P = 0.37, effect size 0.41). The corresponding V/Q total heterogeneity was higher under anesthesia (P = 0.002, effect size 2.64). Compared to the awake state, the V/Q frequency distribution under anesthesia became wider (P = 0.009, 1.76 effect size) with a tendency toward low V/Q ratios. Conclusion:Inhalation anesthesia alone affects Q but not V, suggesting that anesthesia has a direct effect on the active regulatory mechanism coordinating Q with V, leading to less favorable V/Q matching.

Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes

T lymphocytes are believed to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How T cells are recruited to the lungs and contribute to the inflammatory process is largely unknown. COPD is a heterogeneous disease, and discriminating disease phenotypes based on distinct molecular and cellular pathways may provide new approaches for individualized diagnosis and therapies. Bronchoalveolar lavage (BAL) and blood samples were obtained from 40 never-smokers, 40 smokers with normal lung function, and 38 COPD patients. T-cell chemokine receptor expression was analyzed with flow cytometry, and soluble BAL cytokines and chemokines were measured using a cytokine multiplex assay. Correlations with gender and clinical characteristics including lung imaging were investigated using multivariate modeling. Th1/Tc1- and Th2/Tc2-associated soluble analytes and T-cell chemokine receptors were analyzed as cumulative Th1/Tc1 and Th2/Tc2 immune responses. A higher expression of chemokine receptor CCR5 on CD8+ T cells in BAL and higher percentage of CXCR3+CD8+ T cells in blood was found in female smokers with COPD compared to those without COPD. CCR5 expression on CD4+ and CD8+ T cells was lower in BAL from male smokers with COPD compared to those without COPD. Among female smokers with COPD, Th1/Tc1 immune response was linked to BAL macrophage numbers and goblet cell density, and Th2/Tc2 response was associated with the measures of emphysema on high-resolution computed tomography. The highly gender-dependent T-cell profile in COPD indicates different links between cellular events and clinical manifestations in females compared to males. Our findings may reveal mechanisms of importance for the difference in clinical course in female COPD patients compared to males.

High Serum Insulin-Like Growth Factor-Binding Protein 1 (IGFBP-1) is Associated with High Fracture Risk Independent of Insulin-Like Growth Factor 1 (IGF-I).

High serum levels of IGFBP-1 are related both to low body mass index (BMI) and to low insulin-like growth factor 1 (IGF-I), which both in turn are related to low bone mineral density (BMD) and to increased fracture risk. However, we have found no previous prospective studies on IGFBP-1 and fracture risk. Despite its name, IGFBP-1 is not only just a binding protein but also has its own IGF-independent effects, e.g., stimulating osteoclast differentiation. IGFBP-1 might have an IGF-related and/or an IGF-independent association to fracture risk. This is a population-based prospective cohort study with a ten-year follow-up of 351 women aged 69–79 at inclusion. Fracture and mortality data were collected from national health care registers. IGFBP-1 had a positive linear relation to the risk of both hip fractures and “major osteoporotic fractures” including fractures of the hip, spine, shoulder, and wrist. The age-adjusted hazard ratio (HR) for a hip fracture was 1.46 (95xa0% CI 1.08–1.99) for one SD increase in IGFBP-1. The corresponding age-adjusted HR for major osteoporotic fractures was 1.33 (95xa0% CI 1.05–1.69). The relation between IGFBP-1 and fracture risk was not confounded by either IGF-I or BMI. Femoral neck BMD, however, mediated 56xa0% of the total “effect” of IGFBP-1 on hip fracture risk. In conclusion, IGFBP-1 had a positive linear relation to fracture risk, partly mediated by BMD but not related to IGF-I or BMD. This implies that IGFBP-1 might be an important factor in bone turnover and that further studies on this would be valuable.

Nasal nitric oxide and regulation of human pulmonary blood flow in the upright position

There are a number of evidences suggesting that lung perfusion distribution is under active regulation and determined by several factors in addition to gravity. In this work, we hypothesised that autoinhalation of nitric oxide (NO), produced in the human nasal airways, may be one important factor regulating human lung perfusion distribution in the upright position. In 15 healthy volunteers, we used single-photon emission computed tomography technique and two tracers (99mTc and 113mIn) labeled with human macroaggregated albumin to assess pulmonary blood flow distribution. In the sitting upright position, subjects first breathed NO free air through the mouth followed by the administration of the first tracer. Subjects then switched to either nasal breathing or oral breathing with the addition of exogenous NO-enriched air followed by the administration of the second tracer. Compared with oral breathing, nasal breathing induced a blood flow redistribution of approximately 4% of the total perfusion in the caudal to cranial and dorsal to ventral directions. For low perfused lung regions like the apical region, this represents a net increase of 24% in blood flow. Similar effects were obtained with the addition of exogenous NO during oral breathing, indicating that NO and not the breathing condition was responsible for the blood flow redistribution. In conclusion, these results provide evidence that autoinhalation of endogenous NO from the nasal airways may ameliorate the influence of gravity on pulmonary blood flow distribution in the upright position. The presence of nasal NO only in humans and higher primates suggest that it may be an important part of the adaptation to bipedalism.

Detection of pulmonary embolism using repeated MRI acquisitions without respiratory gating: a preliminary study

Background Pulmonary embolism (PE) is a severe medical condition with non-specific clinical findings. Computed tomography angiography (CTA) using iodinated contrast agents is the golden standard for diagnosis, but many patients have contraindications for CTA. Purpose To investigate the diagnostic accuracy of repeated acquisitions of magnetic resonance imaging (MRI), without respiratory gating or breath holding, in diagnosing PE using CTA as the reference standard. Material and Methods Thirty-three patients with clinically suspected PE underwent MRI within 48u2009h after diagnostic CTA. A control group of 37 healthy participants underwent MRI and was matched with an equal number of negative CTA exams. The MRI protocol was based on free-breathing steady-state free precession producing 4.5u2009mm slices in axial, sagittal, and coronal planes. Instead of respiratory or cardiac gating five repetitive slices were obtained in each anatomical position to compensate for movement and artifacts. Clinical assessment including d-dimer and Well’s score was performed prior to imaging. One radiologist reviewed the CTA exams and two radiologists reviewed the MRI scans. Results All 70 MRI exams were of diagnostic quality and the total acquisition time for each MRI scan was 9u2009minu200934u2009s. On CTA, 29 patients were diagnosed with PE and the MRI readers detected 26 and 27 of those, respectively. Specificity was 100% for both readers. Sensitivity was 90% and 93%, respectively. Inter-reader agreement using Cohen’s kappa was 0.97. Conclusion Our unenhanced MRI protocol shows a high sensitivity and specificity for PE, but further studies are required before considering it as a safe diagnostic test.