VT Values Research Articles

11C]Erlotinib PET cannot detect acquired erlotinib resistance in NSCLC tumor xenografts in mice

Introduction[11C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [11C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib. MethodsThe following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [11C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (VT) of [11C]erlotinib in tumors. ResultsIn vitro experiments revealed significantly higher uptake of [11C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [11C]erlotinib uptake (−19% to −66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [11C]erlotinib VT values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral VT was significantly reduced following co-injection of unlabeled erlotinib (−20% to −35%). ConclusionsWe found no significant differences in the in vitro and in vivo binding of [11C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [11C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib.

Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion.

Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV (n = 6/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH2O, fraction of inspired oxygen (FiO2) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated VT values (n = 1200; mean VT = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH20/ml and 2.0 ± 0.8 cmH20/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9–33.1] and VV 5.4% [3.1–8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and intercellular adhesion molecule-1 compared to NV, with no significant differences between VV and NV. Compared to VCV, VV increased the expression of surfactant protein-D, suggesting protection from type II epithelial cell damage. In conclusion, in this experimental lung ischemia-reperfusion model, VV improved respiratory system elastance and reduced lung damage compared to VCV.

Tidal Volume Delivery during the Anesthetic Management of Neonates Is Variable

To describe expiratory tidal volume (VT) during routine anesthetic management of neonates at a single tertiary neonatal surgical center, as well as the proportion of VT values within the range of 4.0-8.0 mL/kg. A total of 26 neonates needing surgery under general anesthesia were studied, of whom 18 were intubated postoperatively. VT was measured continuously during normal clinical care using a dedicated neonatal respiratory function monitor (RFM), with clinicians blinded to values. VT, pressure, and cardiorespiratory variables were recorded regularly while intubated intraoperatively, during postoperative transport, and for 15 minutes after returning to the neonatal intensive care unit (NICU). In addition, paired VT values from the anesthetic machine were documented intraoperatively. A total of 2597 VT measures were recorded from 26 neonates. Intraoperative and postoperative transport expiratory VT values were highly variable compared with the NICU VT (P < .0001, Kruskal-Wallis test), with 51% of inflations outside the 4.0-8.0 mL/kg range (35% and 38% of VT >8.0 mL/kg, respectively), compared with 29% in the NICU (P < .001, χ2 test). The use of a flow-inflating bag resulted in a median (range) VT of 8.5 mL/kg (range, 5.3-11.4 mL/kg) vs 5.6 ml/kg (range, 4.3-7.9 mL/kg) using a Neopuff T-piece system (P < .0001, Mann-Whitney U test). The mean anesthetic machine expiratory VT was 3.2 mL/kg (95% CI, -4.5 to 10.8 mL/kg) above RFM. VT is highly variable during the anesthetic care of neonates, and potentially injurious VT is frequently delivered; thus, we suggest close VT monitoring using a dedicated neonatal RFM.

Protective Ventilation Improves Gas Exchange, Reduces Incidence of Atelectases, and Affects Metabolic Response in Major Pancreatoduodenal Surgery

Protective perioperative ventilation has been shown to improve outcomes and reduce the incidence of postoperative pulmonary complications. The goal of this study was to assess the effects of ventilation with low tidal volume (VT) either alone or in a combination with moderate permissive hypercapnia in major pancreatoduodenal interventions. Sixty adult patients scheduled for elective pancreatoduodenal surgery with duration >2 h were enrolled into a prospective single-center study. All patients were randomized to three groups receiving high VT [10 mL/kg of predicted body weight (PBW), the HVT group, n = 20], low VT (6 mL/kg PBW, the LVT group, n = 20), and low VT combined with a moderate hypercapnia and hypercapnic acidosis (6 mL/kg PBW, PaCO2 45-60 mm Hg, the LVT + HC group, n = 20). Cardiopulmonary parameters and the incidence of complications were registered during surgery and postoperatively. The values of VT were 610 (563-712), 370 (321-400), and 340 (312-430) mL/kg for the HVT, the LVT, and the LVT + HC groups, respectively (p < 0.001). Compared to the HVT group, PaO2/FiO2 ratio was increased in the LVT group by 15%: 333 (301-381) vs. 382 (349-423) mm Hg at 24 h postoperatively (p < 0.05). The HVT group had significantly higher incidence of atelectases (n = 6), despite lower incidence of smoking compared with the LVT (n = 1) group (p = 0.017) and demonstrated longer length of hospital stay. The patients of the LVT + HC group had lower arterial lactate and bicarbonate excess values by the end of surgery. In major pancreatoduodenal interventions, preventively protective VT improves postoperative oxygenation, reduces the incidence of atelectases, and shortens length of hospital stay. The combination of low VT and permissive hypercapnia results in hypercapnic acidosis decreasing the lactate concentration but adding no additional benefits and warrants further investigations.

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Purpose[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.MethodsA total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.ResultsRegional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (VT) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar VT values could not be derived by the 2TCM. For cerebellum, a proposed reference region, VT values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while VT values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BPND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.ConclusionsThe method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake (BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume (VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

Parametric Methods for Dynamic 11C-Phenytoin PET Studies.

In this study, the performance of various methods for generating quantitative parametric images of dynamic 11C-phenytoin PET studies was evaluated. Methods: Double-baseline 60-min dynamic 11C-phenytoin PET studies, including online arterial sampling, were acquired for 6 healthy subjects. Parametric images were generated using Logan plot analysis, a basis function method, and spectral analysis. Parametric distribution volume (VT) and influx rate (K1) were compared with those obtained from nonlinear regression analysis of time-activity curves. In addition, global and regional test-retest (TRT) variability was determined for parametric K1 and VT values. Results: Biases in VT observed with all parametric methods were less than 5%. For K1, spectral analysis showed a negative bias of 16%. The mean TRT variabilities of VT and K1 were less than 10% for all methods. Shortening the scan duration to 45 min provided similar VT and K1 with comparable TRT performance compared with 60-min data. Conclusion: Among the various parametric methods tested, the basis function method provided parametric VT and K1 values with the least bias compared with nonlinear regression data and showed TRT variabilities lower than 5%, also for smaller volume-of-interest sizes (i.e., higher noise levels) and shorter scan duration.

Evaluation of pancreatic VMAT2 binding with active and inactive enantiomers of 18F-FP-DTBZ in baboons

Introduction18F-Fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about 18F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of 18F-FP-(+)-DTBZ and its inactive enantiomer 18F-FP-(−)-DTBZ in baboons, estimated the non-displaceable binding (VND) of the tracers, and used ex vivo studies to measure radiometabolite fractions. MethodsPET scans were conducted for up to 4h with (+) and (−) enantiomers. Displacement experiments using unlabeled (+) and (−) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (VT) were computed, and three approaches for calculation of VND were compared: (1) 18F-FP-(+)-DTBZ reference VT, (2) 18F-FP-(−)-DTBZ pancreatic VT, and (3) a scaled 18F-FP-(+)-DTBZ reference VT values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90min post-injection. ResultsSpleen uptake was lowest for both tracers. Highest uptake was in the pancreas with 18F-FP-(+)-DTBZ and renal cortex with 18F-FP-(−)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the 18F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate VND provided lowest inter-subject variability of BPND. ConclusionsVT differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with 18F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of 18F-FP-(+)-DTBZ in the pancreas.

Evaluation of [18F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood–brain barrier in rats: Kinetics, metabolism, and selectivity

P-glycoprotein is a protective efflux transporter at the blood–brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes (VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood–brain barrier.

Comparison between Variable and Conventional Volume-Controlled Ventilation on Cardiorespiratory Parameters in Experimental Emphysema.

Emphysema is characterized by loss of lung tissue elasticity and destruction of structures supporting alveoli and capillaries. The impact of mechanical ventilation strategies on ventilator-induced lung injury (VILI) in emphysema is poorly defined. New ventilator strategies should be developed to minimize VILI in emphysema. The present study was divided into two protocols: (1) characterization of an elastase-induced emphysema model in rats and identification of the time point of greatest cardiorespiratory impairment, defined as a high specific lung elastance associated with large right ventricular end-diastolic area; and (2) comparison between variable (VV) and conventional volume-controlled ventilation (VCV) on lung mechanics and morphometry, biological markers, and cardiac function at that time point. In the first protocol, Wistar rats (n = 62) received saline (SAL) or porcine pancreatic elastase (ELA) intratracheally once weekly for 4 weeks, respectively. Evaluations were performed 1, 3, 5, or 8 weeks after the last intratracheal instillation of saline or elastase. After identifying the time point of greatest cardiorespiratory impairment, an additional 32 Wistar rats were randomized into the SAL and ELA groups and then ventilated with VV or VCV (n = 8/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 3 cmH2O, fraction of inspired oxygen (FiO2) = 0.4] for 2 h. VV was applied on a breath-to-breath basis as a sequence of randomly generated VT values (mean VT = 6 mL/kg), with a 30% coefficient of variation. Non-ventilated (NV) SAL and ELA animals were used for molecular biology analysis. The time point of greatest cardiorespiratory impairment, was observed 5 weeks after the last elastase instillation. At this time point, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC)-1, amphiregulin, angiopoietin (Ang)-2, and vascular endothelial growth factor (VEGF) mRNA levels were higher in ELA compared to SAL. In ELA animals, VV reduced respiratory system elastance, alveolar collapse, and hyperinflation compared to VCV, without significant differences in gas exchange, but increased right ventricular diastolic area. Interleukin-6 mRNA expression was higher in VCV and VV than NV, while surfactant protein-D was increased in VV compared to NV. In conclusion, VV improved lung function and morphology and reduced VILI, but impaired right cardiac function in this model of elastase induced-emphysema.

Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme.

The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates. (18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data. (18)F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of (18)F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum > neocortical regions > cerebellum. Regional time-activity curves were well fitted by the 2-tissue-compartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (VT) and binding potential (BPND) with 120 min of scan data. Regional VT values (MA1) ranged from 1.28 mL/cm(3) in the cerebellum to 3.71 mL/cm(3) in the putamen, with a BPND of 0.25 in the temporal cortex and 1.92 in the putamen. Regional BPND values estimated by the simplified reference tissue model (SRTM) were similar to those from MA1. Test-retest variability in high-binding regions (striatum) was 4% ± 6% for MA1 VT, 13% ± 6% for MA1 BPND, and 13% ± 7% SRTM BPND, respectively. Pretreatment of animals with the PDE2A inhibitor PF-05180999 resulted in a dose-dependent reduction of (18)F-PF-05270430 specific binding, with a half maximal effective concentration of 69.4 ng/mL in plasma PF-05180999 concentration. (18)F-PF-05270430 displayed fast and reversible kinetics in nonhuman primates, as well as specific binding blockable by a PDE2A inhibitor. This is the first PET tracer with desirable imaging properties and demonstrated ability to image and quantify PDE2A in vivo.

Comparison of different measuring methods for body temperature in lactating cows under different climatic conditions

The aim of the research described here was to compare different methods of body temperature (BT) measurements in dairy cows. It was hypothesised that reticular temperature (RET) values reflect the physiological status of the animals in an equivalent way to rectal (RT) and vaginal (VT) measurements. RT, VT and RET temperatures of twelve lactating Holstein-Friesian cows were measured over five consecutive days in June and October 2013. While RT and VT were manually measured three times a day, RET was automatically recorded at 10 min intervals using a bolus in the reticulum. For comparison with RT and VT, different RET values were used: single values at the respective recording times (RET-SIN), and mean (RET-MEAN) and median (RET-MED) values of 2 h prior to RT and VT measurements. Overall, body temperatures averaged 38·1 ± 0·6, 38·2 ± 0·4, 38·7 ± 0·9, 38·5 ± 0·7 and 38·7 ± 0·5 °C for RT, VT, RET-SIN, RET-MEAN and RET-MED, respectively. RT and VT were lower than all RET measurements, while RET-SIN and RET-MED were higher than RET-MEAN (P < 0·001). RET-MEAN and RET-MED values were higher in the morning, whereas RT and VT were greatest in the evening (P < 0·001). Overall, records of RT and VT were strongly correlated (r = 0·75; P < 0·001). In contrast to RET-SIN and RET-MEAN, RET-MED was higher correlated to RT and VT. In June, coefficients were higher between all methods than in October. Relation of barn T to RT and VT was stronger when compared to RET measurements. RET-SIN was higher correlated to barn T than RET-MEAN or RET-MED. Correlation between VT and barn T was strongest (r = 0·48; P < 0·001). In summary, RET-MED showed highest correlation with VT and RT. However, single RET measurements (influenced by water or feed intake) can lead to extreme variations and differences to single VT and RT values.

11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A

IntroductionDevelopment of a selective and specific high affinity PET tracer, [11C]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine VT. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results3–5GBq of [11C]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65GBq/μmol. In vitro binding showed high selective binding towards SV2A. [11C]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the VT could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [11C]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. ConclusionsWe have developed the novel PET tracer, [11C]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400MBq of [11C]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline VT values. This will have to be further validated in human studies.

Effect of tidal volume and positive end-expiratory pressure on expiratory time constants in experimental lung injury.

We utilized a multicompartment model to describe the effects of changes in tidal volume (VT) and positive end‐expiratory pressure (PEEP) on lung emptying during passive deflation before and after experimental lung injury. Expiratory time constants (τ E) were determined by partitioning the expiratory flow–volume (V˙ EV) curve into multiple discrete segments and individually calculating τ E for each segment. Under all conditions of PEEP and VT, τ E increased throughout expiration both before and after injury. Segmented τ E values increased throughout expiration with a slope that was different than zero (P < 0. 01). On average, τ E increased by 45.08 msec per segment. When an interaction between injury status and τ E segment was included in the model, it was significant (P < 0.05), indicating that later segments had higher τ E values post injury than early τ E segments. Higher PEEP and VT values were associated with higher τ E values. No evidence was found for an interaction between injury status and VT, or PEEP. The current experiment confirms previous observations that τ E values are smaller in subjects with injured lungs when compared to controls. We are the first to demonstrate changes in the pattern of τ E before and after injury when examined with a multiple compartment model. Finally, increases in PEEP or VT increased τ E throughout expiration, but did not appear to have effects that differed between the uninjured and injured state.

In Vivo Evaluation of Blood Based and Reference Tissue Based PET Quantifications of [11C]DASB in the Canine Brain.

This first-in-dog study evaluates the use of the PET-radioligand [11C]DASB to image the density and availability of the serotonin transporter (SERT) in the canine brain. Imaging the serotonergic system could improve diagnosis and therapy of multiple canine behavioural disorders. Furthermore, as many similarities are reported between several human neuropsychiatric conditions and naturally occurring canine behavioural disorders, making this tracer available for use in dogs also provide researchers an interesting non-primate animal model to investigate human disorders. Five adult beagles underwent a 90 minutes dynamic PET scan and arterial whole blood was sampled throughout the scan. For each ROI, the distribution volume (VT), obtained via the one- and two- tissue compartment model (1-TC, 2-TC) and the Logan Plot, was calculated and the goodness-of-fit was evaluated by the Akaike Information Criterion (AIC). For the preferred compartmental model BPND values were estimated and compared with those derived by four reference tissue models: 4-parameter RTM, SRTM2, MRTM2 and the Logan reference tissue model. The 2-TC model indicated in 61% of the ROIs a better fit compared to the 1-TC model. The Logan plot produced almost identical VT values and can be used as an alternative. Compared with the 2-TC model, all investigated reference tissue models showed high correlations but small underestimations of the BPND-parameter. The highest correlation was achieved with the Logan reference tissue model (Y = 0.9266 x + 0.0257; R2 = 0.9722). Therefore, this model can be put forward as a non-invasive standard model for future PET-experiments with [11C]DASB in dogs.

Adjusting tidal volume to stress index in an open lung condition optimizes ventilation and prevents overdistension in an experimental model of lung injury and reduced chest wall compliance.

IntroductionThe stress index (SI), a parameter derived from the shape of the pressure-time curve, can identify injurious mechanical ventilation. We tested the hypothesis that adjusting tidal volume (VT) to a non-injurious SI in an open lung condition avoids hypoventilation while preventing overdistension in an experimental model of combined lung injury and low chest-wall compliance (Ccw).MethodsLung injury was induced by repeated lung lavages using warm saline solution, and Ccw was reduced by controlled intra-abdominal air-insufflation in 22 anesthetized, paralyzed and mechanically ventilated pigs. After injury animals were recruited and submitted to a positive end-expiratory pressure (PEEP) titration trial to find the PEEP level resulting in maximum compliance. During a subsequent four hours of mechanical ventilation, VT was adjusted to keep a plateau pressure (Pplat) of 30 cmH2O (Pplat-group, n = 11) or to a SI between 0.95 and 1.05 (SI-group, n = 11). Respiratory rate was adjusted to maintain a ‘normal’ PaCO2 (35 to 65 mmHg). SI, lung mechanics, arterial-blood gases haemodynamics pro-inflammatory cytokines and histopathology were analyzed. In addition Computed Tomography (CT) data were acquired at end expiration and end inspiration in six animals.ResultsPaCO2 was significantly higher in the Pplat-group (82 versus 53 mmHg, P = 0.01), with a resulting lower pH (7.19 versus 7.34, P = 0.01). We observed significant differences in VT (7.3 versus 5.4 mlKg−1, P = 0.002) and Pplat values (30 versus 35 cmH2O, P = 0.001) between the Pplat-group and SI-group respectively. SI (1.03 versus 0.99, P = 0.42) and end-inspiratory transpulmonary pressure (PTP) (17 versus 18 cmH2O, P = 0.42) were similar in the Pplat- and SI-groups respectively, without differences in overinflated lung areas at end- inspiration in both groups. Cytokines and histopathology showed no differences.ConclusionsSetting tidal volume to a non-injurious stress index in an open lung condition improves alveolar ventilation and prevents overdistension without increasing lung injury. This is in comparison with limited Pplat protective ventilation in a model of lung injury with low chest-wall compliance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0726-3) contains supplementary material, which is available to authorized users.

The PET Radioligand 18F-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain

A recent study from our laboratory found that (18)F-FIMX is an excellent PET radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of (18)F-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake and nondisplaceable uptake (VND) in each brain region. After injection of 189 ± 3 MBq of (18)F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 min. For 6 volunteers, images were acquired until 210 min. A metabolite-corrected arterial input function was measured from the radial artery. Four other subjects underwent whole-body scanning to estimate radiation exposure. (18)F-FIMX uptake into the human brain was high (SUV = 4-6 in the cerebellum), peaked at about 10 min, and washed out rapidly. An unconstrained 2-tissue-compartment model fitted the data well, and distribution volume (VT) (mL⋅cm(-3)) values ranged from 1.5 in the caudate to 11 in the cerebellum. A 120-min scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 min was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of (18)F-FIMX was quite low (0.5 mL⋅cm(-3)). This measure of VND in humans was similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other (18)F-labeled ligands, the effective dose was about 23 μSv/MBq. (18)F-FIMX can quantify mGluR1 in the human brain with a 120- to 170-min scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacologic doses of a blocking agent.

Imaging Striatal Microglial Activation in Patients with Parkinson's Disease.

This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [18F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson’s disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (VT) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [18F]-FEPPA VT values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.

Stability and Instability Criteria for Idealized Precipitating Hydrodynamics

Abstract A linear stability analysis is presented for fluid dynamics with water vapor and precipitation, where the precipitation falls relative to the fluid at speed VT. The aim is to bridge two extreme cases by considering the full range of VT values: (i) VT = 0, (ii) finite VT, and (iii) infinitely fast VT. In each case, a saturated precipitating atmosphere is considered, and the sufficient conditions for stability and instability are identified. Furthermore, each condition is linked to a thermodynamic variable: either a variable θs, which denotes the saturated potential temperature, or the equivalent potential temperature θe. When VT is finite, separate sufficient conditions are identified for stability versus instability: dθe/dz &amp;gt; 0 versus dθs/dz &amp;lt; 0, respectively. When VT = 0, the criterion dθs/dz = 0 is the single boundary that separates the stable and unstable conditions; and when VT is infinitely fast, the criterion dθe/dz = 0 is the single boundary. Asymptotics are used to analytically characterize the infinitely fast VT case, in addition to numerical results. Also, the small-VT limit is identified as a singular limit; that is, the cases of VT = 0 and small VT are fundamentally different. An energy principle is also presented for each case of VT, and the form of the energy identifies the stability parameter: either dθs/dz or dθe/dz. Results for finite VT have some resemblance to the notion of conditional instability: separate sufficient conditions exist for stability versus instability, with an intermediate range of environmental states where stability or instability is not definitive.

Tidal Volume Requirement in Mechanically Ventilated Infants with Meconium Aspiration Syndrome.

The aim of the study is to test the hypothesis that increased physiologic dead space and functional residual capacity seen in meconium aspiration syndrome (MAS) results in higher tidal volume (VT) requirement to achieve adequate ventilation. Retrospective review of infants with MAS admitted to our hospital from 2000 to 2010 managed with conventional ventilation. Demographics, ventilator settings, VT, respiratory rate (RR), and blood gas values were recorded. Minute ventilation (MV) was calculated as RR × VT. Only VT values with corresponding partial pressure of carbon dioxide (Paco 2) between 35 and 60 mm Hg were included. Mean VT/kg and MV/kg were calculated for each patient. Forty infants ventilated for lung disease other than MAS or pulmonary hypoplasia served as controls. Birth weights of the 28 MAS patients and 40 control infants were similar (3,330 ± 500 g and 3,300 ± 640 g). Two patients in each group required extracorporeal membrane oxygenation. Infants with MAS required 26% higher VT and 42% higher MV compared with controls to maintain equal Paco 2. Infants with MAS require larger VT and higher total MV to achieve similar alveolar ventilation, consistent with pathophysiology of MAS. Our findings provide the first reference data to guide selection of VT in infants with MAS.