Injection rate, scanning position, and values of parameters on pulmonary computed tomography perfusion in normal Beagles.

OBJECTIVE: This study evaluated the effects of scanning position and contrast medium injection rate on pulmonary CT perfusion (CTP) images in healthy dogs. ANIMALS: 7 healthy Beagles. METHODS: Experiments involved 4 conditions: dorsal and sternal recumbency at 2.5 mL/s (first) and sternal recumbency with additional rates of 1.5 and 3.5 mL/s (second). Various parameters, including the initial time of venous enhancement (Tv), peak time of arterial enhancement (PTa), and peak enhancement values of the artery, were measured. The PTa to Tv interval was calculated. Perfusion mapping parameters (pulmonary blood flow, pulmonary blood volume, mean transit time, time to maximum, and time to peak) were determined in different lung regions (left and right dorsal, middle, and ventral). RESULTS: There are significant variations in most perfusion mapping parameters based on the pulmonary parenchymal location. Dorsal recumbency had a lower peak value of arterial enhancement than sternal recumbency. Pulmonary blood flow in the dorsal region and mean transit time and time to maximum in all regions showed no significant differences based on position. Pulmonary blood volume and time to peak varied with scanning position. The PTa to Tv interval did not differ based on the injection rate, but the injection time at 1.5 mL/s was longer than at other rates. All perfusion mapping parameters of the ventral region increased with higher injection rates. CLINICAL RELEVANCE: The recommended CTP imaging approach in dogs is a low injection rate of 1.5 mL/s in the sternal recumbency. This study provides reference ranges for perfusion parameters based on the pulmonary parenchymal location, contributing to the acquisition and application of pulmonary CTP images for differential diagnosis in small-breed dogs.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50-130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Stem cell restores thalamocortical plasticity to rescue cognitive deficit in neonatal intraventricular hemorrhage.

Severe neonatal intraventricular hemorrhage (IVH) patients incur long-term neurologic deficits such as cognitive disabilities. Recently, the intraventricular transplantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (MSCs) has drawn attention as a therapeutic potential to treat severe IVH. However, its pathological synaptic mechanism is still elusive. We here demonstrated that the integration of the somatosensory input was significantly distorted by suppressing feed-forward inhibition (FFI) at the thalamocortical (TC) inputs in the barrel cortices of neonatal rats with IVH by using BOLD-fMRI signal and brain slice patch-clamp technique. This is induced by the suppression of Hebbian plasticity via an increase in tumor necrosis factor-α expression during the critical period, which can be effectively reversed by the transplantation of MSCs. Furthermore, we showed that MSC transplantation successfully rescued IVH-induced learning deficits in the sensory-guided decision-making in correlation with TC FFI in the layer 4 barrel cortex.

Physical exercise enhances adult cortical plasticity in a neonatal rat model of hypoxic-ischemic injury: Evidence from BOLD-fMRI and electrophysiological recordings.

Neuroplasticity is considered essential for recovery from brain injury in developing brains. Recent studies indicate that it is especially effective during early postnatal development and during the critical period. The current study used functional magnetic resonance imaging (fMRI) and local field potential (LFP) electrophysiological recordings in rats that experienced neonatal hypoxic-ischemic (HI) injury during the critical period to demonstrate that physical exercise (PE) can improve cortical plasticity even when performed during adulthood, after the critical period. We investigated to what extent the blood oxygen level-dependent (BOLD)-fMRI responses were increased in the contralesional spared cortex, and how these increases were related to the LFP electrophysiological measurements and the functional outcome. The balance of excitation and inhibition was assessed by measuring excitatory and inhibitory postsynaptic currents in stellate cells in the primary somatosensory (S1) cortex, which was compared with the BOLD-fMRI responses in the contralesional S1 cortex. The ratio of inhibitory postsynaptic current (IPSC) to excitatory postsynaptic current (EPSC) at the thalamocortical (TC) input to the spared S1 cortex was significantly increased by PE, which is consistent with the increased BOLD-fMRI responses and improved functional outcome. Our data clearly demonstrate in an experimental rat model of HI injury during the critical period that PE in adulthood enhances neuroplasticity and suggest that enhanced feed-forward inhibition at the TC input to the S1 cortex might underlie the PE-induced amelioration of the somatosensory deficits caused by the HI injury. In summary, the results of the current study indicate that PE, even if performed beyond the critical period or during adulthood, can be an effective therapy to treat neonatal brain injuries, providing a potential mechanism for the development of a potent rehabilitation strategy to alleviate HI-induced neurological impairments.

Enhancement of Glucose Uptake by Meso-Dihydroguaiaretic Acid through GLUT4 Up-Regulation in 3T3-L1 Adipocytes.

Type 2 diabetes is characterized by insulin resistance, which leads to increased blood glucose levels. Adipocytes are involved in the development of insulin resistance, resulting from the dysfunction of the insulin signaling pathway. In this study, we investigated whether meso-dihydroguaiaretic acid (MDGA) may modulate glucose uptake in adipocytes, and examined its mechanism of action. MDGA enhanced adipogenesis through up-regulation of peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α in 3T3-L1 adipocytes partially differentiated with sub-optimal concentrations of insulin. MDGA also increased glucose uptake by stimulating expression and translocation of glucose transporter 4 (GLUT4) in adipocytes. These results suggest that MDGA may increase GLUT4 expression and its translocation by promoting insulin sensitivity, leading to enhanced glucose uptake.

Spatiotemporal microstructural white matter changes in diffusion tensor imaging after transient focal ischemic stroke in rats.

Structural reorganization in white matter (WM) after stroke is a potential contributor to substitute or to newly establish the functional field on the injured brain in nature. Diffusion tensor imaging (DTI) is an imaging modality that can be used to evaluate damage and recovery within the brain. This method of imaging allows for in vivo assessment of the restricted movements of water molecules in WM and provides a detailed look at structural connectivity in the brain. For longitudinal DTI studies after a stroke, the conventional region of interest method and voxel-based analysis are highly dependent on the user-hypothesis and parameter settings for implementation. In contrast, tract-based spatial statistics (TBSS) allows for reliable voxel-wise analysis via the projection of diffusion-derived parameters onto an alignment-invariant WM skeleton. In this study, spatiotemporal WM changes were examined with DTI-derived parameters (fractional anisotropy, FA; mean diffusivity, MD; axial diffusivity, DA; radial diffusivity, RD) using TBSS 2 h to 6 weeks after experimental focal ischemic stroke in rats (N = 6). FA values remained unchanged 2-4 h after the stroke, followed by a continuous decrease in the ipsilesional hemisphere from 24 h to 2 weeks post-stroke and gradual recovery from the ipsilesional corpus callosum to the external capsule until 6 weeks post-stroke. In particular, the fibers in these areas were extended toward the striatum of the ischemic boundary region at 6 weeks on tractography. The alterations of the other parameters in the ipsilesional hemisphere showed patterns of a decrease at the early stage, a subsequent pseudo-normalization of MD and DA, a rapid reduction of RD, and a progressive increase in MD, DA and RD with a decreased extent in the injured area at later stages. The findings of this study may reflect the ongoing processes on tissue damage and spontaneous recovery after stroke.

Neuroplasticity for spontaneous functional recovery after neonatal hypoxic ischemic brain injury in rats observed by functional MRI and diffusion tensor imaging.

For infants and children, an incredible resilience from injury is often observed. There is growing evidence that functional recovery after brain injury might well be a consequence of the reorganization of the neural network as a process of neuroplasticity. We demonstrate the presence of neuroplasticity at work in spontaneous recovery after neonatal hypoxic ischemic (HI) injury, by elucidating a precise picture in which such reorganization takes place using functional MRI techniques. For all 12 siblings, 6 rats were subjected to severe HI brain injury and 6 rats underwent sham operation only. Severe HI brain injury was induced to postnatal day 7 (p7) Sprague-Dawley rats according to the Rice-Vannucci model (right carotid artery occlusion followed by 150min of hypoxia with 8% O2 and 92% of N2). Brain activation maps along with anatomical and functional connectivity maps related to the sensory motor function were obtained at adult (p63) using blood oxygen level dependent (BOLD)-functional MRI (fMRI), resting state-functional MRI (rs-fMRI) and diffusion tensor imaging (DTI); each of these MRI data was related to sensory motor functional outcome. In-depth investigation of the functional MRI data revealed: 1) intra-hemispheric expansion of BOLD signal activation in the contralesional undamaged hemisphere for ipsilesional forepaw stimuli to include the M2 and Cg1 in addition to the S1 and M1 wide spreading in the anterior and posterior directions, 2) inter-hemispheric transfer of BOLD signal activation for contralesional forepaw stimuli, normally routed to the injured hemisphere, to analogous sites in the contralesional undamaged hemisphere, localized newly to the M1 and M2 with a reduced portion of the S1, 3) inter-hemispheric axonal disconnection and axonal rewiring within the undamaged hemisphere as shown through DTI, and 4) increased functional interactions within the cingulate gyrus in the HI injured rats as shown through rs-fMRI. The BOLD signal amplitudes as well as DTI and rs-fMRI data well correlate with behavioral tests (tape to remove). We found that function normally utilizing what would be the injured hemisphere is transferred to the uninjured hemisphere, and functionality of the uninjured hemisphere remains not untouched but is also rewired in an expansion corresponding to the newly formed sensorimotor function from both the contralesional and the ipsilesional sides. The conclusion drawn from the data in our current study is that enhanced motor function in the contralesional hemisphere governs both the normal and damaged sides, indicating that active plasticity with brain laterality was spontaneously generated to overcome functional loss and established autonomously through normal experience via modification of neural circuitry for neonatal HI injured brain.

Cortical atrophy, reduced integrity of white matter and cognitive impairment in subcortical vascular dementia of Binswanger type.

AIMS: An association between white matter hyperintensities (WMH) and cognitive dysfunction has long been recognized. However, subjects with identically appearing WMH on magnetic resonance imaging present with a wide variance in cognitive function ranging from normal cognition to dementia. The aim of this study was to compare cortical atrophy and integrity of white matter of patients with subcortical vascular dementia of Binswanger type (SVaD-BT) with those of the normal cognition group with WMH (ncWMH). METHODS: Eleven patients with SVaD-BT and 11 age-, sex-, education- and grade of WMH-matched ncWMH underwent magnetic resonance imaging, including 3-D volumetric images for cortical atrophy and diffusion tensor imaging for integrity of white matter. RESULTS: Compared to ncWMH, SVaD-BT patients showed cortical atrophies in frontal (i.e. frontal pole, precentral gyrus and frontal medial cortex) and occipital areas (i.e. lingual gyrus) followed by atrophies in temporal (i.e. fusiform cortex and middle temporal gyrus) areas. Along with cortical atrophies, reduced integrity with low fractional anisotropy and high mean diffusivity values in genu and splenium of the corpus callosum were detected in SVaD-BT patients. CONCLUSIONS: Our findings suggest that cognitive decline from ncWMH to SVaD-BT may be associated with cortical atrophy and reduced integrity of white matter.