Single-compartment Model Research Articles

Regional patterns of cardiac sympathetic denervation in patients with type 2 diabetes mellitus and it's relationship to autonomic dysfunction

Objective: In this study we evaluated regional myocardial blood flow (MBF) and left ventricular (LV) sympathetic innervation using positron emission tomography (PET) and its relationship to standard autonomic function tests (AFT). Methods: We studied 12 diabetic patients (7M, 5F) (mean age 62±8), and 5 healthy controls (2M, 3F) (mean age 59±10). All patients underwent AFT and cardiac PET imaging with oxygen-15 labeled water to measure myocardial blood flow (MBF) and carbon –11 hydroxyephedrine (HED) to assess presynaptic cardiac sympathetic nerves. HED images were read semiquantitatively (summed score 4 segment/4 point model) and quantitatively (3-compartment model) to quantify cardiac HED density and flux (B-max). Single compartment model was used for MBF quantification. Results: All 5 controls had normal MBF, homogeneous uptake of HED, no regional difference in B-max and normal AFT. All 12 diabetic patients had normal MBF, 5 had homogeneous uptake of HED and 7 had heterogeneous uptake. The average HED defects summed score in diabetic patients was 9 in apical, 15 in basal lateral, 11 in distal lateral and 0 in septal region. In heterogeneous group there was a significant difference in B-max between the septal and lateral wall regions (24±12 vs.18 ± 10). On AFT all 12 diabetic patients had normal resting heart rate, RR and normal postural heart rate variability but 6/12 had postural hypotension. All 6 of these patients had heterogeneous HED uptake. Conclusions: Diabetic patients exhibited LV sympathetic dysfunction predominantly in the lateral wall region and only postural hypotension was significantly correlated with it.

On Single Compartment Pharmacokinetic Model Systems that Obey Free Radical Copolymerization Kinetics and Multiplicity

This study examines the issues in development of pharmacokinetic single compartment model for systems that obey free radical copolymerization kinetics. Copolymer composition as a function of reactivity ratios of comonomers for well mixed case was derived. For some cases, such as DEF-AN, diethyl fumarate and acrylonitrile system multiplicity in composition were found. The analysis is extended to n monomers. State space model expressions are used and the QSSA assumption is stated in state space equation form. Conditions when damped oscillations can be expected are noted. In addition to multiplicity in product composition, an account of reactivity ratios and other instances of multi- plicity were found during the pharmacodynamics of the free radical polymerization reactions. A careful study of initiated case, thermal case, 1 CSTR and 2 CSTRS was undertaken and results were presented. Numerical integration techniques were employed on the desktop computer. Steady state and transient state conversion for initiated case and thermal case for 1 CSTR and 2 CSTRs were calculated and plotted in Figures 7-9 and 12. No multiplicity was found in the thermal case for 1 CSTR in the dynamics of transient monomer conversion. Multiplicity was found in the initiated case for 1 CSTR in the dynamics of transient conversion of monomer. The multiplicity was found in the second CSTR for the case of 2 CSTRs in series. No multiplicity was found in the case of initiator decay.

Nonlinear multiplicative dendritic integration in neuron and network models

Neurons receive inputs from thousands of synapses distributed across dendritic trees of complex morphology. It is known that dendritic integration of excitatory and inhibitory synapses can be highly non-linear in reality and can heavily depend on the exact location and spatial arrangement of inhibitory and excitatory synapses on the dendrite. Despite this known fact, most neuron models used in artificial neural networks today still only describe the voltage potential of a single somatic compartment and assume a simple linear summation of all individual synaptic inputs. We here suggest a new biophysical motivated derivation of a single compartment model that integrates the non-linear effects of shunting inhibition, where an inhibitory input on the route of an excitatory input to the soma cancels or “shunts” the excitatory potential. In particular, our integration of non-linear dendritic processing into the neuron model follows a simple multiplicative rule, suggested recently by experiments, and allows for strict mathematical treatment of network effects. Using our new formulation, we further devised a spiking network model where inhibitory neurons act as global shunting gates, and show that the network exhibits persistent activity in a low firing regime.

The effect of the molecular adsorbent recirculating system on moxifloxacin and meropenem plasma levels

Adequate plasma antibiotic concentrations are necessary for effective elimination of invading microorganism; however, extracorporeal organ support systems are well known to alter plasma concentrations of antibiotics, requiring dose adjustments to achieve effective minimal inhibitory concentrations in the patient's blood. A mock molecular adsorbent recirculating system (MARS) circuit was set using 5000 ml of bovine heparinized whole blood to simulate an 8-h MARS treatment session. After the loading dose of 400 mg of moxifloxacin or 2 g of meropenem had been added, blood was drawn from the different parts of the MARS circuit at various time points and analyzed by high-performance liquid chromatography. The experiments were performed in triplicate. Additionally, meropenem concentrations were determined in the plasma of one patient treated with MARS suffering from acute liver failure due to an idiosyncratic reaction to immunosuppressive medication. In our single-compartment model, a significant decrease in the quasi-systemic concentration of moxifloxacin and meropenem could be detected as early as 15 min after the commencing of the MARS circuit. Moreover, within 60 min the moxifloxacin and meropenem concentrations were less than 50% of the initial value. The activated charcoal removed the majority of moxifloxacin and meropenem in the albumin circuit. In our patient, the meropenem concentrations in the return line after MARS were constantly lower than in the access line, indicating a likely removal of meropenem through MARS. Our data provide evidence that moxifloxacin and meropenem are effectively removed from the patient's blood by MARS, leading to low plasma levels. Dose adjustments of both antibiotic compounds may be required.

IB1001, an Investigational Recombinant Factor IX, Pharmacokinetics in Pediatric Patients with Hemophilia B.

AbstractAbstract 2225 IntroductionIB1001 is a recombinant factor IX product being investigated for the treatment and prevention of bleeding in individuals with hemophilia B. Pharmacokinetics (PK) in adults (>12 years) demonstrated that IB1001 had results similar to the currently available recombinant FIX with respect to parameters such as terminal phase half-life and incremental recovery.We report the interim findings from a PK assessment in children <12 years, with severe hemophilia B (FIX <2%), >50 prior exposure days to FIX, and no history of or currently detectable inhibitor to FIX. MethodsNon-randomized, open-label PK study with patients receiving 75±5 IU/kg of IB1001 following a washout period of ≥4 days from a previous FIX infusion. Factor IX levels were determined pre-infusion and at 15–30 minutes, 4–6, 24–26, and 68–72 hours post-infusion. Additional samples could be drawn at 1–3 and 10–14 hours.Calculated PK parameters were: half-life (β-phase t1/2, determined using a robust regression approach [Lee ML et al. XVIth ISTH Congress, Florence, Italy, 1997]) but generally assuming a single compartmental model because of the small number of points, maximum plasma concentration (Cmax), in vivo recovery (IVR) and AUC(0-∞) (determined by the trapezoidal rule). In addition, the AUC(0-t) and mean residence time (MRT) were calculated. ResultsSubjectt 1/2 α (hr)t 1/2 β (hr)MRT (hr)Cmax (IU/dl)In vivo Recovery (IU/dl)AUC0-∞ (IU/dl/hr)AUC0-t (IU/dl/hr)Age (years)Subjects 6 - 12 Years of Age32001n/a17.722630.8414611359912001n/a17.521.2570.76113810627.532003720.724580.77106797711.135002n/a33.655220.2960541010mean±SD (median)22.4±7.6 (19.2)30.6±16.3 (23)50±19 (57.5)0.66±0.25 (0.765)1068±353 (1102.5)952±397 (1019.5)9.4±1.5 (9.5)Subjects < 6 Years of Age4001n/a7.612.1600.8942941235001n/a16.319.5640.8512171147432002n/a21.929.4400.539868704.5mean±SD (median)15.3±7.2 (16.3)20.3±8.7 (19.5)55±13 (60)0.73±0.17 (0.8)1048±148 (986)986±144 (941)3.5±1.3 (4)When compared to the findings previously reported with IB1001 in adult (≥12 years of age) subjects (Martinowitz U et al. Haemophilia, 18, 2012), the results in pediatric patients demonstrate a more rapid metabolism of factor IX as is indicated by the shorter terminal half-life (mean±SD of 19.3±7.8 h versus 29.6±18.2 h in adults) and the smaller AUC0-∞ (mean±SD of 1059±264 versus 1668±598 in adults). In addition, the in vivo recovery was lower (mean±SD of 0.69±0.21) versus that seen in adults (mean±SD of 0.98±0.22). These results are similar to those reported by Berntorp et al (Haemophilia, 7, 2001) with nonacog alfa. ConclusionsThe pharmacokinetics of IB1001 has previously been shown to be non-inferior to nonacog alfa, another recombinant factor IX, in hemophilia B individuals >12 years of age. The current study is intended to provide information on children <12 and, particularly, <6 years of age. IB1001 is metabolized faster and has a lower recovery than the comparable findings in patients >12 years of age. Although the study is ongoing, these may represent important implications for the potential use of IB1001 in pediatric patients. Disclosures:Gomperts:Inspiration Biopharmaceuticals Inc: Consultancy. Apte:Inspiration Biopharmacauticals Inc: Research Funding. Chaudhuri:Inspiration Biopharmaceuticals Inc: Research Funding. John:Inspiration Biopharmaceuticals Inc: Research Funding. Ramanan:Inspiration Biopharmaceuticals Inc: Research Funding. Liesner:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Honoraria, Research Funding. Mills:Inspiration Biopharmaceuticals Inc: Employment. Lee:Inspiration Biopharmaceuticals Inc: Employment.

Functional contributions of the plasma membrane calcium ATPase and the sodium–calcium exchanger at mouse parallel fibre to Purkinje neuron synapses

We investigated how two calcium clearance mechanisms, the sodium-calcium exchanger-NCX, and the plasma membrane calcium ATPase-PMCA2, function at the facilitating cerebellar parallel fibre to Purkinje neuron (PF-PN) synapse. Forward mode NCX helped recover PF presynaptic calcium elevations when the PFs received a double stimulation and the calcium load was sufficiently high. A smaller presynaptic calcium load evoked by a single PF stimulation failed to recruit NCX in wild-type mice but did so when PMCA2 was absent in PFs from PMCA2 knockout mice. Simulated calcium dynamics using a simple single-compartment model reported qualitatively similar effects. Functionally, reduced NCX activity in the absence of PMCA also prolonged the recovery of facilitation at the PF-PN synapse, beyond that seen by reduced NCX activity alone. We conclude that PMCA and NCX work in parallel to accurately shape residual presynaptic calcium recovery dynamics and fine-tune facilitation at this important cerebellar synapse.

Inactivating ion channels augment robustness of subthreshold intrinsic response dynamics to parametric variability in hippocampal model neurons

Voltage-gated ion channels play a critical role in regulating neuronal intrinsic response dynamics (IRD). Here, we computationally analysed the roles of the two inactivating subthreshold conductances (A and T), individually and in various combinations with the non-inactivating h conductance, in regulating several physiological IRD measurements in the theta frequency range. We found that the independent presence of a T conductance, unlike that of an h conductance, was unable to sustain an inductive phase lead in the theta frequency range, despite its ability to mediate theta frequency resonance. The A conductance, on the other hand, when expressed independently, acted in a manner similar to a leak conductance with reference to most IRD measurements. Next, analysing the impact of pair-wise coexpression of these channels, we found that the coexpression of the h and T conductances augmented the range of parameters over which they sustained resonance and inductive phase lead. Additionally, coexpression of the A conductance with the h or the T conductance elicited changes in IRD measurements that were similar to those obtained with the expression of a leak conductance with a resonating conductance. Finally, to understand the global sensitivity of IRD measurements to all parameters associated with models expressing all three channels, we generated 100,000 neuronal models, each built with a unique set of parametric values. We categorized valid models among these by matching their IRD measurements with experimental counterparts, and found that functionally similar models could be achieved even when underlying parameters displayed tremendous variability and exhibited weak pair-wise correlations. Our results suggest that the three prominent subthreshold conductances contribute differently to intrinsic excitability and to phase coding. We postulate that the differential expression and activity-dependent plasticity of these conductances contribute to robustness of subthreshold IRD, whereby response homeostasis is achieved by recruiting several non-unique combinations of these channel parameters.

Cooperation of intrinsic bursting and calcium oscillations underlying activity patterns of model pre-Bötzinger complex neurons

Activity of neurons in the pre-Bötzinger complex (pre-BötC) within the mammalian brainstem drives the inspiratory phase of the respiratory rhythm. Experimental results have suggested that multiple bursting mechanisms based on a calcium-activated nonspecific cationic (CAN) current, a persistent sodium (NaP) current, and calcium dynamics may be incorporated within the pre-BötC. Previous modeling works have incorporated representations of some or all of these mechanisms. In this study, we consider a single-compartment model of a pre-BötC inspiratory neuron that encompasses particular aspects of all of these features. We present a novel mathematical analysis of the interaction of the corresponding rhythmic mechanisms arising in the model, including square-wave bursting and autonomous calcium oscillations, which requires treatment of a system of differential equations incorporating three slow variables.

An empirical mathematical model applied to quantitative evaluation of thioacetamide-induced acute liver injury in rats by use of dynamic contrast-enhanced computed tomography

Our purpose in this study was to apply an empirical mathematical model (EMM) to the quantitative evaluation of thioacetamide (TAA)-induced acute liver injury in rats by use of dynamic contrast-enhanced computed tomography (DCE-CT), and to investigate its usefulness in comparison with a dual-input, single-compartment model. The rats in the TAA-treated group were injected intravenously with 140 mg/kg body weight (n = 10) or 280 mg/kg body weight (n = 10) of TAA, whereas those in the control group (n = 10) were injected with saline instead of TAA. The DCE-CT studies were performed 2 days after injection of TAA or saline by use of a 4-detector row CT. The upper limit of the time-density curve (A), the rates of contrast uptake (α) and washout (β), the parameter related to the slope of early uptake (q), the area under the curve (AUC), the time to the maximum enhancement (T (max)), the maximum enhancement (C (Lmax)), and the elimination half-life of the contrast agent (T (1/2)) were calculated by use of the EMM. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also measured. Both α and q decreased significantly in the rats of the TAA-treated group compared to those in the control group, whereas T (max) and T (1/2) increased significantly. The values of α, q, AUC, and T (max) were significantly correlated with both AST and ALT. Our results suggest that the EMM is useful for quantitative evaluation of TAA-induced acute liver injury and can be used as an alternative to the dual-input single-compartment model, especially when the vascular input functions cannot be obtained.

GPU-accelerated voxelwise hepatic perfusion quantification

Voxelwise quantification of hepatic perfusion parameters from dynamic contrast enhanced (DCE) imaging greatly contributes to assessment of liver function in response to radiation therapy. However, the efficiency of the estimation of hepatic perfusion parameters voxel-by-voxel in the whole liver using a dual-input single-compartment model requires substantial improvement for routine clinical applications. In this paper, we utilize the parallel computation power of a graphics processing unit (GPU) to accelerate the computation, while maintaining the same accuracy as the conventional method. Using compute unified device architecture-GPU, the hepatic perfusion computations over multiple voxels are run across the GPU blocks concurrently but independently. At each voxel, nonlinear least-squares fitting the time series of the liver DCE data to the compartmental model is distributed to multiple threads in a block, and the computations of different time points are performed simultaneously and synchronically. An efficient fast Fourier transform in a block is also developed for the convolution computation in the model. The GPU computations of the voxel-by-voxel hepatic perfusion images are compared with ones by the CPU using the simulated DCE data and the experimental DCE MR images from patients. The computation speed is improved by 30 times using a NVIDIA Tesla C2050 GPU compared to a 2.67 GHz Intel Xeon CPU processor. To obtain liver perfusion maps with 626 400 voxels in a patient's liver, it takes 0.9 min with the GPU-accelerated voxelwise computation, compared to 110 min with the CPU, while both methods result in perfusion parameters differences less than 10−6. The method will be useful for generating liver perfusion images in clinical settings.

Increase in Sodium Conductance Decreases Firing Rate and Gain in Model Neurons

We studied the effects of increased sodium conductance on firing rate and gain in two populations of conductance-based, single-compartment model neurons. The first population consisted of 1000 model neurons with differing values of seven voltage-dependent conductances. In many of these models, increasing the sodium conductance threefold unexpectedly reduced the firing rate and divisively scaled the gain at high input current. In the second population, consisting of 1000 simplified model neurons, we found that enhanced sodium conductance changed the frequency-current (FI) curve in two computationally distinct ways, depending on the firing rate. In these models, increased sodium conductance produced a subtractive shift in the FI curve at low firing rates because the additional sodium conductance allowed the neuron to respond more strongly to equivalent input current. In contrast, at high input current, the increase in sodium conductance resulted in a divisive change in the gain because the increased conductance produced a proportionally larger activation of the delayed rectifier potassium conductance. The control and sodium-enhanced FI curves intersect at a point that delimits two regions in which the same biophysical manipulation produces two fundamentally different changes to the model neuron's computational properties. This suggests a potentially difficult problem for homeostatic regulation of intrinsic excitability.

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

Conductance interaction identification by means of Boltzmann distribution and mutual information analysis in conductance-based neuron models

Recent research has focused on the causal paths that explain how neuron ionic-conductances interact to produce a particular electrophysiological behavior. Pharmacological blockage methods, neuromodulators and genetic knockouts are among the techniques used to study this issue. In this paper we propose a probabilistic approach based on the computation of the Boltzmann distribution and the mutual information of conductance interactions to learn higher-order, not necessarily pair-wise, potential co-regulation mechanisms from a database of the crustacean stomatogastric ganglion pyloric circuit models. The original database was built from experimental data obtained from lobster stomatogastric neurons [2,3]. The eight currents in the single-compartment model are based on the lobster stomatogastric ganglion neurons currents. The basic idea of our work is to assign a probability value p(x) to each neuron model depending on whether or not it satisfies a given electrophysiological property. To assign these values we use the Boltzmann probability distribution, commonly used in statistical physics to associate a probability with a system state according to its energy [4]. From the Boltzmann distribution we compute the mutual information to measure the strength of interaction between a pair of conductances at the time of producing a particular electrical activity. The particular characteristics of silent neurons were captured in the uneven distribution of bivariate marginal probabilities computed from the Boltzmann distribution. Among all conductance pairs, the highest bivariate probabilities are reached for conductance pairs (gKCa,gKd), (gNa,gKCa) and (gCaT,gCaS). With respect to previous analysis of the group of silent neurons, the correlation (gCaT,gCaS) was the only significant linear correlation identified for silent models in [1]. There were another three conductance relationships reported in [1] that fitted statistical criteria for correlations, but did not appear to have a linear relationship. They were (gH,gleak), (gKCa,gKd) and (gKCa,gCaT). All these correlations were identified as significant correlations of the computed Boltzmann distribution Our results show that probabilistic modeling based on the Boltzmann distribution can capture potential co-regulations that are not captured by the correlation analysis. The extension to capture higher-order dependencies between conductances is also straightforward. Furthermore, our results indicate that mutual information analysis allows a more detailed visualization of the structure of the conductance landscape for conductance-based neuron models.

Isotopic incorporation rates for shark tissues from a long-term captive feeding study

Stable isotope analysis has provided insight into the dietary and habitat patterns of many birds, mammals and teleost fish. A crucial biological parameter to interpret field stable isotope data is tissue incorporation rate, which has not been well studied in large ectotherms. We report the incorporation of carbon and nitrogen into the tissues of leopard sharks (Triakis semifasciata). Because sharks have relatively slow metabolic rates and are difficult to maintain in captivity, no long-term feeding study has been conducted until the point of isotopic steady state with a diet. We kept six leopard sharks in captivity for 1250 days, measured their growth, and serially sampled plasma, red blood cells and muscle for stable carbon and nitrogen isotope analysis. A single-compartment model with first-order kinetics adequately described the incorporation patterns of carbon and nitrogen isotopes for these three tissues. Both carbon and nitrogen were incorporated faster in plasma than in muscle and red blood cells. The rate of incorporation of carbon into muscle was similar to that predicted by an allometric equation relating isotopic incorporation rate to body mass that was developed previously for teleosts. In spite of their large size and unusual physiology, the rates of isotopic incorporation in sharks seem to follow the same patterns found in other aquatic ectotherms.

A Two‐Compartment Mixed‐Effects Gamma Regression Model for Quantifying Between‐Unit Variability in Length of Stay among Children Admitted to Intensive Care

To quantify between-unit variability in mean length of stay (LoS) between intensive care units (ICUs) after adjusting for differences in case mix using a method that does not require arbitrary trimming of data. An analysis of registry data from pediatric ICUs (PICUs) in Australia and New Zealand. The relationships between patient LoS and associated patient factors were modeled as a log-linear function of the covariates using two gamma distributions. The predicted distribution is estimated as a weighted average of the two distributions where the relative weighting is conditional on the patient's elective status. Data for 12,763 admissions submitted to the Australian and New Zealand Paediatric Intensive Care Registry from the eight dedicated PICUs in Australia and New Zealand in 2007 and 2008. The two distributions of the mixture model accurately described the distribution of short- and long-stay patients in ICUs. After adjusting for patient case mix, several sites had a statistically significant effect on patient LoS. The two-compartment model characterizes ICU LoS for short- and long-stay patients more effectively than a single-compartment model. There is significant site-level variation in the LoS among children admitted to ICUs in Australia and New Zealand. Differences in the site-level variation between short- and long-stay patients indicate differences in discharge practice.

Brain tissue water comes in two pools: Evidence from diffusion and R2’ measurements with USPIOs in non human primates

Diffusion-weighted MRI of non-human primates revealed that USPIO Bulk Magnetic Susceptibility (BMS) T2' effects of Ultrasmall Superparamagnetic Particles with Iron Oxide (USPIO) in the brain cannot be explained by a single compartment model, as diffusion and T2' effects appear coupled: Apparent Diffusion Coefficient (ADC) values depend on USPIO concentration and relaxivity effects of USPIO decrease with the b value. On the other hand, USPIO and diffusion effects could be well uncoupled using a model consisting in a fast and a slow diffusion pool with different relaxivities. Diffusion-weighting acts as a filter which emphasizes the contribution of the slow pool when increasing b values (apparent decrease in ADC and R2'). Those results have implications for human studies using BMS contrast agents, as well as BOLD and diffusion fMRI.

Detection of Tidal Recruitment/Overdistension in Lung-Healthy Mechanically Ventilated Patients Under General Anesthesia

The volume-dependent single compartment model (VDSCM) has been applied for identification of overdistension in mechanically ventilated patients with acute lung injury. In this observational study we evaluated the use of the VDSCM to identify tidal recruitment/overdistension induced by tidal volume (Vt) and positive end-expiratory pressure (PEEP) in lung-healthy anesthetized subjects. Fifteen patients (ASA physical status I-II) undergoing general anesthesia for elective plastic breast reconstruction surgery were mechanically ventilated in volume-controlled ventilation (VCV), with Vt of 8 mL•kg(-1) and PEEP of 0 cm H(2)O. With these settings, ventilatory mode was randomly adjusted in VCV or pressure-controlled ventilation (PCV) and PEEP was sequentially increased from 0 to 5 and 10 cm H(2)O, 5 min per step. Thereafter, PEEP was decreased to 0 cm H(2)O, Vt increased to 10 mL•kg(-1) and, keeping minute ventilation constant, PEEP was similarly increased to 5 and 10 cm H(2)O. Airway pressure and flow were continuously recorded and fitted to the VDSCM with or without considering flow-dependencies. A "distension index" (%E(2)) derived from the VDSCM was used to assess Vt and PEEP-induced recruitment/overdistension. Positive and negative values of %E(2) suggest tidal overdistension or tidal recruitment, respectively. In addition, the linear respiratory system elastance was calculated. Comparisons among variables at each PEEP value, Vt setting, ventilatory mode, and regression model considering or not considering flow-dependencies were performed with the Wilcoxon-sign rank test for paired samples (P < 0.05). Multiple comparisons were corrected with the Bonferroni method. The relative change in the estimated noisy variance was used as an index of the goodness of fit of the models. VDSCM including the flow-dependent parameter significantly improved estimated noisy variance in almost all experimental conditions (11.2 to 71.4, smallest of the lower and highest of the upper 95% confidence intervals). No differences in %E(2) were observed between VCV and PCV, at comparable Vt and PEEP levels, when flow-dependencies were included in the regression model. The negligence of the flow-dependent parameter systematically led to an underestimation of %E(2) in PCV compared to VCV mode (all P < 0.02). At a given Vt, %E(2) was negative at a PEEP of 0 cm H(2)O and significantly increased with PEEP, being almost 0 at a PEEP of 5 cm H(2)O. At a given level of PEEP, %E(2) significantly increased with Vt. The distension index %E(2), derived from the VDSCM considering flow-dependencies, seems able to identify tidal recruitment/overdistension induced by Vt and PEEP independent of flow waveform in healthy lung-anesthetized patients.

Parametric [11C]flumazenil images

This [11C]flumazenil (FMZ) study evaluates the performance of various parametric analysis methods and their ability to detect statistically significant group differences. Dynamic 60-min FMZ scans were performed in eight healthy and nine individuals with major depressive disorder. Parametric volume of distribution (VT) images were generated using a basis function method (BFM) implementation of the single tissue compartment model (1T) and Logan plot analysis, both with a metabolite-corrected arterial plasma input function. Parametric binding potential (BP ND) images were generated using multilinear reference tissue methods (MRTM0-4), reference Logan and receptor parametric mapping (RPM1-2), with pons as a reference region. Standardized uptake value (SUV) and SUV ratio-to-pons (SUVr) images were calculated over the time interval 30-40 and 20-60 min postinjection. The resulting VT, BP ND, SUV and SUVr values were compared with nonlinear regression values, using both the 1T model and the simplified reference tissue model. Statistical parametric mapping (SPM5) was used to detect group differences, with an emphasis on the bilateral parahippocampal gyri. BFM was more accurate than Logan, but showed more variability. Both RPM methods and MRTM2 showed the best average correlation with the simplified reference tissue model. In using SPM, SUV and SUVr images provided the best contrast between groups in the parahippocampal gyri, but provided large underestimation and overestimation in quantitative comparisons. BFM and RPM methods allowed for the determination of perfusion effects. Parametric Logan VT, MRTM2 and RPM1-2 BP ND methods allow the best quantitative comparison of FMZ binding between groups and show good discriminating performance in SPM analysis.

Volume-Independent Elastance

A decremental positive end-expiratory pressure (PEEP) trial after full lung recruitment allows for the adjustment of the lowest PEEP that prevents end-expiratory collapse (open-lung PEEP). For a tidal volume (Vt) approaching zero, the PEEP of minimum respiratory system elastance (PEEP(minErs)) is theoretically equal to the pressure at the mathematical inflection point (MIP) of the pressure-volume curve, and seems to correspond to the open-lung PEEP in a decremental PEEP trial. Nevertheless, the PEEP(minErs) is dependent on Vt and decreases as Vt increases. To circumvent this dependency, we proposed the use of a second-order model in which the volume-independent elastance (E1) is used to set open-lung PEEP. Pressure-volume curves and a recruitment maneuver followed by decremental PEEP trials, with a Vt of 6 and 12 mL/kg, were performed in 24 Wistar rats with acute lung injury induced by intraperitoneally injected (n = 8) or intratracheally instilled (n = 8) Escherichia coli lipopolysaccharide. In 8 control animals, the anterior chest wall was surgically removed after PEEP trials, and the protocol was repeated. Airway pressure (Paw) and flow (F) were continuously acquired and fitted by the linear single-compartment model (Paw = Rrs·F + Ers·V + PEEP, where Rrs is the resistance of the respiratory system, and V is volume) and the volume-dependent elastance model (Paw = Rrs·F + E1 + E2·V·V + PEEP, where E2·V is the volume-dependent elastance). From each model, PEEPs of minimum Ers and E1 (PEEP(minE1)) were identified and compared with each respective MIP. The accuracy of PEEPminE1 and PEEPminErs in estimating MIP was assessed by bias and precision plots. Comparisons among groups were performed with the unpaired t test whereas a paired t test was used between the control group before and after chest wall removal and within groups at different Vts. All P values were then corrected for multiple comparisons by the Bonferroni procedure. In all experimental groups, PEEPminErs, but not PEEPminE1, tended to decrease as Vt increased. The difference between MIP and PEEPminE1 exhibited a lower bias compared with the difference between MIP and PEEPminErs (P < 0.001). The PEEPminE1 was always significantly higher than the PEEPminErs (7.7 vs 3.8, P < 0.001) and better approached MIP (7.7 vs 7.3 cm H2O with P = 0.04 at low Vt, and 7.8 vs 7.1 cm H2O with P < 0.001 at high Vt). PEEPminE1 better identifies the open-lung PEEP independently of the adjusted Vt, and may be a practical, more individualized approach for PEEP titration.

Calcium buffering and clearance in spider mechanosensory neurons

Spider VS-3 mechanoreceptor neurons have a low-voltage-activated Ca2+ current that raises intracellular calcium concentration [Ca2+] when they are depolarized by agonists of GABAA receptors or fire action potentials. The Ca2+ rise produces negative feedback by modulating the mechanoreceptor current and regulates Ca2+- and voltage-activated K+ currents. However, nothing is known about Ca2+ buffering in VS-3 neurons. Dynamic changes in VS-3 neuron intracellular [Ca2+] were measured using the fluorescent Ca2+ indicator Oregon Green BAPTA-1 (OG488) to understand Ca2+ buffering and clearance. Intracellular OG488 concentration increased slowly over more than 2 h as it diffused through a sharp intracellular microelectrode and spread through the cell. This slow increase was used to measure endogenous Ca2+ buffering and clearance by the added buffer technique, with OG488 acting as both added exogenous buffer and Ca2+ indicator. [Ca2+] was raised for brief periods by regular action potential firing, produced by pulsed electric current injection through the microelectrode. The resulting rise and fall of [Ca2+] were well fitted by the single compartment model of Ca2+ dynamics. With earlier ratiometric [Ca2+] estimates, these data gave an endogenous Ca2+ binding ratio of 684. Strong Ca2+ buffering may assist these neurons to deal with rapid changes in mechanical inputs.