Muscle Sympathetic Nerve Activity Is Associated with Liver Insulin Sensitivity in Obese Non-Diabetic Men.

Introduction: Muscle sympathetic nerve activity (MSNA) may play a role in insulin resistance in obesity. However, the direction and nature of the relationship between MSNA and insulin resistance in obesity remain unclear. We hypothesized that resting MSNA would correlate inversely with both muscle and liver insulin sensitivity and that it would be higher in insulin-resistant vs. insulin-sensitive subjects. Materials and methods: Forty-five non-diabetic obese subjects were studied. As no significant relationships were found in women, the data presented in on 22 men aged 48 ± 12 years. Two-step (15 and 80 mU/m2/min) hyperinsulinaemic-euglycaemic clamps were performed using deuterated glucose to determine liver and muscle insulin sensitivity. Clinical and metabolic parameters were assessed. MSNA was measured via a microelectrode inserted percutaneously into the common peroneal nerve. Results: MSNA burst frequency correlated inversely with liver insulin sensitivity (r = -0.53, P = 0.02) and positively with the hepatokines C-reactive protein (CRP) and fibroblast growth factor (FGF)-19 (r = 0.57, P = 0.006, and r = -0.47, P = 0.03, respectively). MSNA burst frequency was lower in Liversen compared to Liverres (27 ± 5 vs. 38 ± 2 bursts per minute; P = 0.03). Muscle insulin sensitivity was unrelated to MSNA. Discussion: Sympathetic neural activation is related to liver insulin sensitivity and circulating hepatokines CRP and FGF-19 in non-diabetic obese men. These results suggest a potential hepato-endocrine-autonomic axis. Future studies are needed to clarify the influence of MSNA on liver insulin sensitivity in men.

Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma.

PURPOSE: There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1 -weighted oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme. METHODS: Preclinical evaluation was performed in a subcutaneous murine human glioma xenograft (U87MG). Animals underwent OE-MRI followed by dynamic contrast-enhanced MRI (DCE-MRI) and histological measurement including reduced pimonidazole adducts and CD31 staining. Area under the curve (AUC) was measured for the R1 curve for OE-MRI and the gadolinium concentration curve for DCE-MRI. Clinical evaluation in five patients used analogous imaging protocols and analyses. RESULTS: Changes in AUC of OE-MRI (AUCOE ) signal were regionally heterogeneous across all U87MG tumors. Tumor regions with negative AUCOE typically had low DCE-MRI perfusion, had positive correlation with hypoxic area (P = 0.029), and had negative correlation with vessel density (P = 0.004). DCE-MRI measurements did not relate to either hypoxia or vessel density in U87MG tumors. Clinical data confirmed comparable signal changes in patients with glioblastoma. CONCLUSION: These data support further investigation of T1 -weighted OE-MRI to identify regional tumor hypoxia. The quantification of AUCOE has translational potential as a clinical biomarker of hypoxia.

Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology.

BACKGROUND: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). METHODS: Eleven Fontan subjects (32+/-2 years, mean+/-SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET); six underwent 20 weeks of high-intensity resistance training; others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. RESULTS: In the trained state, muscle strength increased by 43% (p=0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p<0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, p<0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p=0.01) and during moderate-intensity exercise (by 16 ml, p=0.04); inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). CONCLUSIONS: Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation.

Physiological and performance responses to a preseason altitude-training camp in elite team-sport athletes.

PURPOSE: Little research has been done on the physiological and performance effects of altitude training on team-sport athletes. Therefore, this study examined changes in 2000-m time-trial running performance (TT), hemoglobin mass (Hbmass), and intramuscular carnosine content of elite Australian Football (AF) players after a preseason altitude camp. METHODS: Thirty elite AF players completed 19 days of living and training at either moderate altitude (~2130 m; ALT, n = 21) or sea level (CON, n = 9). TT performance and Hbmass were assessed preintervention (PRE) and postintervention (POST1) in both groups and at 4 wk after returning to sea level (POST2) in ALT only. RESULTS: Improvement in TT performance after altitude was likely 1.5% (± 4.8-90%CL) greater in ALT than in CON, with an individual responsiveness of 0.8%. Improvements in TT were maintained at POST2 in ALT. Hbmass after altitude was very likely increased in ALT compared with CON (2.8% ± 3.5%), with an individual responsiveness of 1.3%. Hbmass returned to baseline at POST2. Intramuscular carnosine did not change in either gastrocnemius or soleus from PRE to POST1. CONCLUSIONS: A preseason altitude camp improved TT performance and Hbmass in elite AF players to a magnitude similar to that demonstrated by elite endurance athletes undertaking altitude training. The individual responsiveness of both TT and Hbmass was approximately half the group mean effect, indicating that most players gained benefit. The maintenance of running performance for 4 wk, despite Hbmass returning to baseline, suggests that altitude training is a valuable preparation for AF players leading into the competitive season.

A quantitative comparison of the influence of individual versus population-derived vascular input functions on dynamic contrast enhanced-MRI in small animals.

For quantitative analysis of dynamic contrast enhanced magnetic resonance imaging data, the time course of the concentration of the contrast agent in the blood plasma, or vascular input function (VIF), is required. We compared pharmacokinetic parameters derived using individual and population-based VIFs in mice for two different contrast agents, gadopentetate dimeglumine and P846. Eleven mice with subcutaneous 4T(1) breast cancer xenografts were imaged at 7 T. A precontrast T(1) map was acquired along with dynamic T(1) -weighted gradient echo images before, during, and after a bolus injection of contrast agent delivered via a syringe pump. Each animal's individual VIF and derived population-averaged VIF were used to extract parameters from the signal-time curves of tumor tissue at both the region of interest and voxel level. The results indicate that for both contrast agents, K(trans) values estimated using population-averaged VIF have a high correlation (concordance correlation coefficient > 0.85) with K(trans) values estimated using individual VIF on both a region of interest and voxel level. This work supports the validity of using of a population-based VIF with a stringent injection protocol in preclinical dynamic contrast enhanced magnetic resonance imaging studies.

Use of dynamic susceptibility-contrast MRI (DSC-MRI) to assess perfusion changes in the ipsilateral brain parenchyma from glioblastoma.

INTRODUCTION: We investigated the effect of increased tumor perfusion using dynamic susceptibility-contrast magnetic resonance imaging (DSC-MRI) in glioblastoma (GBM) patients on the surrounding ipsilateral brain tissue with respect to perfusion of the normal, unaffected contralateral brain and of the tumor. MATERIAL AND METHODS: DSC-MRI was performed in 11 patients with glioblastoma using a multislice T2*-weighed EPI sequence (TR/TE = 2,000/62 ms; FOV 240 mm; matrix 128 x 128; slice thickness 6 mm) on a standard clinical 1.5 Tesla scanner during intravenous injection of 40 cc Gadolinium-DTPA at a flow rate of 5 cc/s. Maps for relative regional cerebral blood volume (rCBV) and relative regional cerebral blood flow (rCBF) were created and relative values analyzed in relation to the arterial input. RESULTS: Relative CBV and CBF were significantly higher in gray matter than in the respective white matter (paired t-test; P < 0.001) with a high correlation for both perfusion parameters between the gray and the white matter in both ipsilateral and contralateral brain (P < 0.001). The highest values for rCBV and rCBF were found in solid tumor tissue with a significant positive correlation between tumor and the adjacent gray matter (for both rCBV and rCBF; P < 0.001). CONCLUSION: In GBM patients there is increased metabolism and thus increased rCBV and rCBF within the tumor. This increased perfusion of the tumor is not at the expense of perfusion of the ipsilateral normal brain parenchyma and in fact, the rCBV and rCBF values are linked to tumor-induced changes in rCBV and rCBF.

Retinal folding in the term rabbit fetus-Developmental abnormality or fixation artifact?

UNLABELLED: Preclinical reproductive toxicology studies must be performed to provide information on the risk of causing fetal harm in pregnant patients. These studies detect fetal malformations, which may or may not be drug-related adverse events. In the rabbit fetus, "slight retinal folding" is commonly observed; there is anecdotal evidence that these folds may be caused by routine (Bouin's fluid) fixation. This study used magnetic resonance imaging (MRI) to assess rabbit retinal architecture in fresh specimens, which was then reassessed following Bouin's fluid fixation. A total of 30 fetuses from 5 litters were imaged. No retinal folding was detected in fresh specimens but it was observed in a majority of fetuses post-fixation. The use of Davidson's fixative followed by Bouin's fluid showed a markedly lower incidence of "slight retinal folding". CONCLUSION: slight retinal folds in the rabbit fetus are likely artifactual and can be reduced using Davidson's fixation prior to Bouin's.

Vessel wall damage caused by cerebral protection devices: ex vivo evaluation in porcine carotid arteries.

PURPOSE: To determine the extent of vessel wall damage caused by cerebral protection devices designed for carotid angioplasty by using ex vivo porcine carotid arteries. MATERIALS AND METHODS: The local animal experimentation committee did not require its approval for this study. With a benchtop vascular model (flow rate, 470 mL/min; dicrotic pulsatile flow, 76 pulses per minute; pressure, 115/67 mm Hg [mean pressure, 91 mm Hg]) into which 85 porcine internal carotid arteries (ICAs) were inserted, five different protection devices (Angioguard [Cordis/Johnson & Johnson, Miami, Fla], Filterwire EX [Boston Scientific, Natick, Mass], Trap [Microvena, White Bear Lake, Minn], Neuroshield [Abbott Laboratories, Redwood City, Calif], and Percusurge [Abbott Laboratories]) were evaluated. Adverse movement (1 cm up, 2 cm down, and 1 cm up again) of the activated devices (deployed filters or inflated balloons [Percusurge only]) was simulated, and the device was retrieved. For each of these steps (deployment, movement, retrieval) the amount of debris from the vessel wall in the effluent of the ICA was determined by using a 100-microm filter. The Mann-Whitney test was used to test for differences, and a correction for multiple comparisons was made. P < .05 was considered to indicate a significant difference. The authors attempted to determine whether there was a notable association between the total amount of debris captured and the classification of damage at microscopy. Carotid arteries were analyzed histologically with light and scanning electron microscopy. RESULTS: All examined protection devices caused dislodged debris, which was captured in the effluent filter. There were significant differences among the devices in terms of the total amount of debris captured in the filters (lowest amounts of debris, 4.75 mg [Angioguard] and 5.02 mg [Filterwire EX]; highest amount, 7.51 mg [Trap]; P < or = .001 for all). All devices caused histologically visible wall damage, with the degree of intimal denudation correlating with the mass of the debris. The Trap device caused the most severe intimal and subintimal wall damage. Adverse movement resulted in no increased debris dislodgment as compared with the debris dislodged during deployment and retrieval of the devices. CONCLUSION: On the basis of the data obtained, cerebral protection devices themselves have a potential influence on embolization rates by causing debris to be dislodged during carotid stent placement.

Comparison of 4 cerebral protection filters for carotid angioplasty: an in vitro experiment focusing on carotid anatomy.

PURPOSE: To assess the influence of internal carotid artery (ICA) tortuosity on the effectiveness of 4 cerebral protection filters in an in vitro bench-top model. METHODS: To simulate the anatomical arterial variants, 3 open flow models were constructed: one with normal carotid anatomy, 1 representing a mildly tortuous ICA, and a third imitating a severely tortuous ICA. Polyvinyl alcohol particles (150-1000 microm) served as the embolic material; the emboli were divided into 3 groups according to size: small (150-250 microm), medium (355-500 microm), and large (710-1000 microm). Five milligrams of each size group were injected separately into the ICA proximal to each of 4 protection filters: AngioGuard, FilterWire EX, TRAP, and NeuroShield. Emboli that were not caught by the protection system or were washed into the external carotid artery (ECA) ran into an effluent filter and were weighed and classified according to size. RESULTS: In 240 test runs, the FilterWire EX presented the lowest weight of emboli in the ICA effluent under all anatomical conditions: normal anatomy 0.39 mg (2.58%), mild tortuosity 0.45 mg (2.99%), and severe tortuosity 0.50 mg (3.33%) (p>0.05). The Angioguard system showed the worst results: normal 1.21 mg (98.03%), mild tortuosity 2.54 mg (16.84%), and severe tortuosity 3.14 mg (20.91%) (p<0.001) compared to the FilterWire EX and the NeuroShield systems. The only protection device displaying no significant differences in all of the 3 emboli sizes was the FilterWire EX (p>0.05). Relevant differences in effectiveness in mildly and severely tortuous ICAs were apparent among the other devices. For all emboli sizes, the differences of the AngioGuard and TRAP systems were highly significant (p<0.001). There was no significant difference between the FilterWire EX and the NeuroShield. CONCLUSIONS: The only protection device showing no significant decrease in efficacy in the tortuous ICA models was the FilterWire EX. In both tested anatomical variants, the protection systems ranked in the same order of effectiveness. None of the tested devices prevented embolization completely.

Volumetric interpolated contrast-enhanced MRA for the diagnosis of pulmonary embolism in an ex vivo system.

PURPOSE: To implement a three-dimensional gradient-recalled echo (GRE) volumetric interpolated breath-hold examination (VIBE) sequence for pulmonary contrast-enhanced MRA (CE-MRA) in an experimental setup. MATERIALS AND METHODS: Eight porcine lungs were intubated, inflated inside a chest phantom, and examined at 1.5 T during slow perfusion (2-300 mL/minute). Three-dimensional-MRA was performed with and without contrast agent using three-dimensional-GRE (VIBE) with TR/TE = 4.5/1.9 msec, TA = 23 seconds, FOV = 390 mm, FA = 12 degrees /30 degrees, as well as a standard three-dimensional-GRE sequence and T2 fast spin-echo (FSE) sequences. Four of the eight lungs were embolized with autologous blood clots. By consensus readings, two observers evaluated the detectability of peripheral vessels, signal intensity over vessels and lung, and visualization of emboli. Digital subtraction angiograms served as a control to document vessel patency. RESULTS: Prior to contrast administration, three-dimensional-VIBE/12 degrees yielded the best results for lung parenchyma signal and visualization of small vessels (third-order, P < 0.01); however, no emboli were detected (due to lack of contrast). After administration of contrast agent, three-dimensional-GRE (VIBE) at FA = 30 degrees provided significantly better results (fifth-order branches, documentation of subsegmental occlusions [fourth order], P < 0.01). T2-FSE images documented water uptake into the lungs. Digitally subtracted angiography (DSA) confirmed the patency of seventh-order branches. CONCLUSION: This ex vivo study confirms the potential advantages of using a dual MR investigation for pulmonary embolism, combining three-dimensional-GRE (VIBE) at FA = 12 degrees to image lung parenchyma and at FA = 30 degrees for CE-MRA..

Comparison of various cerebral protection devices used for carotid artery stent placement: an in vitro experiment.

PURPOSE: To compare the effectiveness of five basic cerebral protection devices designed for carotid angioplasty in an in-vitro bench-top model. MATERIALS AND METHODS: Simulation of embolization from carotid angioplasty (n = 180) was performed with polyvinyl alcohol (PVA) particles (Contour; 150-1,000- micro m) in an open flow model simulating the aortic arch with a carotid bifurcation made from elastic silicone tubes. Particles (150-250 micro m [small], 355-500 micro m [medium], 710-1,000 micro m [large]; 5 mg each) were injected separately into the internal carotid artery (ICA) proximal to the placed protection device. Five devices were tested: the Angioguard (AG), Filter Wire EX (EX(A), EX(B)), Trap, Neuroshield (NS), and GuardWire Plus (GW). Particles getting past the protection device or flowing into the external carotid artery (ECA) were caught in a filter at the end of both arteries and their weight was determined. RESULTS: For small, medium, and large particles, the lowest weight of emboli in the effluent of the ICA was obtained with the NS (0.28 mg, 0.18 mg, and 0.07 mg, respectively; P <.001 compared to all other devices except the GW for small particles only). The GW had the highest embolization rate into the ECA for all particle sizes. When combining the particle weights for the different protection devices, the NS showed the lowest weight of emboli into the ICA filter (0.53 mg/3.5%; P <.001 compared to all [>1.1 mg/7.0%]). The GW revealed the highest weight of emboli into the ECA (1.2 mg/7.6%; P <.001 compared to all [<0.59 mg/0.09%]). Effectiveness of the EX(B) device was enhanced when circumferentially deployed under direct view (EX(B), 0.39 mg/2.58%; EX(A), 1.18 mg/7.81%; P <.001). CONCLUSIONS: In vitro, none of the tested devices or modifications has the ability to prevent embolization completely. An occlusion balloon leads to increased embolization into the ECA. The effectiveness of the EX might be enhanced with design improvements. During this evaluation, the NS was most effective for preventing PVA particle embolization of the three different particle groups within this in-vitro model.

Lung morphology: fast MR imaging assessment with a volumetric interpolated breath-hold technique: initial experience with patients.

PURPOSE: To prospectively evaluate the clinical feasibility of magnetic resonance (MR) imaging of the lungs with fast volumetric interpolated three-dimensional (3D) gradient-recalled-echo (GRE) sequences and to compare this examination with standard computed tomography (CT) in patients with lung abnormalities. MATERIALS AND METHODS: Twenty-five patients with different lung abnormalities were examined with 3D GRE MR imaging. The small pulmonary nodules in seven, TNM stage of large intrapulmonary tumors in eight, and benign bronchial disease in five patients were evaluated. MR imaging-based diagnoses were compared with diagnoses made at CT and at discharge from the hospital. Contingency tables and the McNemar test were used to evaluate the significance of differences between MR imaging- and CT-based diagnoses. RESULTS: The MR imaging- and CT-based diagnoses were identical in 24 of 25 patients. In the remaining patient, clinical findings confirmed the accuracy of the MR imaging finding of pleural empyema. Ten of 15 solid pulmonary nodules smaller than 10 mm in diameter were detected at MR imaging (P >.1). Tumor stages at MR imaging and CT were identical, but lymph node stages at the two examinations differed in two of eight patients owing to overestimation of lymph node size at MR imaging (P >.2). In the five patients with bronchiectasis, MR imaging depicted 26 of 33 affected lung segments; differences between MR imaging and CT findings of bronchial dilatation (P >.05) and bronchial wall thickening (P >.2) were not significant. Peribronchial fibrosis was overestimated at MR imaging owing to image artifacts (P <.05). CONCLUSION: Study results confirmed the feasibility of fast breath-hold 3D GRE MR imaging of the lung.

Characterization of the integrity of three-dimensional trabecular bone microstructure by connectivity and shape analysis using high-resolution magnetic resonance imaging in vivo.

Bone mineral density and bone structure are the main determinants of bone strength in osteoporosis. In this study we used high-resolution magnetic resonance imaging to visualize the bone microstructure in the finger phalanges in vivo and to assess the topological three-dimensional connectivity of the trabecular network and the shape of the trabeculae as measures of bone quality. We visualized the phalanges of young and elderly healthy volunteers in vivo with a spatial resolution of 152 microm x 152 microm x 280 microm. Image processing software to quantify three measures of connectedness was developed and tested: connectivity, global connectivity density, and local connectivity density. Global three-dimensional connectivity ranged from 904 to 1,607 connections. Global connectivity density ranged from 2.9 to 4.7 connections per mm with large intersubject differences. We found a decrease of local connectivity density with growing distance from the joint ranging from 5.1 to 0.2 connections per mm. These preliminary results represent a quantitative description of the well-known rarefication of the trabecular network when moving from epiphysis to the diaphysis. Three-dimensional visualization showed a dense network consisting mostly of rod-like trabeculae at the epiphysis changing to a less dense network of a few plate-like structures near the medullary canal. An algorithm for the quantitative classification of trabecular architecture with regard to plate or rod-like shape was tested for feasibility. We conclude that in vivo assessment of three-dimensional properties of the trabecular network is possible in human phalanges. Determination of connectivity and shape will allow quantification of structural aspects of osteoporotic changes and may improve assessment of fracture risk.

Comparison and modification of two cerebral protection devices used for carotid angioplasty: in vitro experiment.

The effectiveness of two basic cerebral protection devices designed for carotid angioplasty with and without additional aspiration techniques was compared in an in vitro model. During carotid angioplasty, embolization was simulated by injecting polyvinyl alcohol particles of different sizes into the model system. None of the tested devices, all of which were positioned in the internal carotid artery, was able to completely prevent embolization. In the internal carotid artery, the rate of particle capture did not vary among protection devices. However, embolization into the external carotid artery was more frequent with use of the GuideWire, as compared with that with use of the Angioguard.

In vitro comparison of four cerebral protection filters for preventing human plaque embolization during carotid interventions.

PURPOSE: To evaluate in an in vitro bench-top model the efficacy of 4 filtration devices designed for cerebral protection during carotid angioplasty. METHODS: Embolization during carotid angioplasty was simulated with human plaque material (8 to 12 particles weighing 6.02 +/- 0.10 mg) in an open flow model with the aortic arch and carotid bifurcation made from elastic silicone tubes and saline used as the fluid medium. The 500 to 1500-microm particles were injected into the internal carotid artery (ICA) in front of the test protection device, which was deployed 5 cm distal to the bifurcation. Particles getting past the protection device or flowing into the external carotid artery (ECA) were caught in 100-microm filters and weighed. Ten trials were made on each of 4 devices: Angioguard, FilterWire EX, TRAP, and NeuroShield. All were deployed according to the manufacturers' directions except the FilterWire, which was manually repositioned in all tests to eliminate a gap between the filter and the tube wall. RESULTS: The lowest weight of missed particles in the effluent was obtained with the NeuroShield (0.05 +/- 0.04 mg, 0.8% of injected particle weight) and FilterWire (0.08 +/- 0.05 mg, 1.3%; p=0.254 compared to NeuroShield, p=0.006 versus TRAP). The weight of particles missed by the TRAP device (0.16 +/- 0.06 mg, 2.6%; p<0.001 versus NeuroShield and Angioguard, p<0.05 compared to FilterWire) was higher, and the largest amount of missed particles was observed with the Angioguard filter (0.27 +/- 0.06 mg, 4.4%; p<0.001 compared to all). NeuroShield and FilterWire were significantly different (p<0.001) compared to Angioguard and TRAP in a pairwise analysis. No embolization into the ECA occurred. CONCLUSIONS: In vitro, none of the tested devices had the ability to completely prevent embolization into the ICA. Comparing current designs, the NeuroShield filter and the FilterWire EX captured the highest percentage of human particles in this in vitro model, probably due to their larger filter volume.