Biomedical subjects

Atle Bjørnerud

Publications and source records attributed to Atle Bjørnerud.

16 recordsLinked to original sources

PubMed2006

Clearance of iron oxide particles in rat liver: effect of hydrated particle size and coating material on liver metabolism.

OBJECTIVES: We sought to evaluate the effect of the particle size and coating material of various iron oxide preparations on the rate of rat liver clearance. MATERIALS AND METHODS: The following iron oxide formulations were used in this study: dextran-coated ferumoxide (size = 97 nm) and ferumoxtran-10 (size = 21 nm), carboxydextran-coated SHU555A (size = 69 nm) and fractionated SHU555A (size = 12 nm), and oxidized-starch coated materials either unformulated NC100150 (size = 15 nm) or formulated NC100150 injection (size = 12 nm). All formulations were administered to 165 rats at 2 dose levels. Quantitative liver R2* values were obtained during a 63-day time period. The concentration of iron oxide particles in the liver was determined by relaxometry, and these values were used to calculate the particle half-lives in the liver. RESULTS: After the administration of a high dose of iron oxide, the half-life of iron oxide particles in rat liver was 8 days for dextran-coated materials, 10 days for carboxydextran materials, 14 days for unformulated oxidized-starch, and 29 days for formulated oxidized-starch. CONCLUSIONS: The results of the study indicate that materials with similar coating but different sizes exhibited similar rates of liver clearance. It was, therefore, concluded that the coating material significantly influences the rate of iron oxide clearance in rat liver.

Animals↗

PubMed2006

Magnetic resonance imaging of the Harderian gland in piglets.

The main purpose of the present study was to investigate the value and effectiveness of functional and morphological magnetic resonance imaging (MRI), in order to assess the extent of brain injury in a hypoxic-ischaemic piglet model, and further to validate that the ischaemic injury was successfully induced. In this way, we also characterized the Harderian gland. MRI was performed at 1.5 T in anaesthetized piglets (n = 10, 12-36 h of age). Magnetic resonance perfusion and diffusion imaging were performed at different time points, before, during and after the induction of hypoxia-ischaemia. The effects following bilateral clamping of the carotid arteries were also assessed by contrast-enhanced magnetic resonance angiography. Morphological assessment included T1- and T2-weighted imaging, and fat-suppressed T1-weighted imaging before and after contrast medium enhancement. Morphological MRI revealed a prominent, well-defined structure located at the eyeball. Magnetic resonance angiography reconstructed with volume rendering showed this structure to be partially enclosed by large venous sinuses. At dissection, when compared with the magnetic resonance images, the deep gland of the third eyelid, the Harderian gland, corresponded to this structure both in topography and in size. By contrast, the lacrimal gland proper presented as a small, soft and pale structure that was difficult to distinguish from the surrounding connective tissue. At histological examination, the Harderian gland consisted mainly of compact areas of tubuloacinar glands with abundant eosinophilic granules. The present MRI demonstration of the Harderian gland was an accidental finding during an investigation to assess the extent of brain injury in a hypoxic-ischaemic piglet model. The combination of MRI and histology made it possible to detect and describe the Harderian gland in pig. It has generally been studied in rodents and lower vertebrates and is reported to possess various endocrine and exocrine functions.

Animals↗

PubMed2005

Intravascular contrast agent-enhanced MRI measuring contrast clearance and tumor blood volume and the effects of vascular modifiers in an experimental tumor.

PURPOSE: To examine the feasibility of using the MRI blood pool agent NC100150 for evaluation of tumor blood volume (TBV) estimates by both dynamic contrast-enhanced MRI (DCE-MRI) and susceptibility contrast MRI assays in an experimental tumor. Contrast agent clearance (K(trans); depends on perfusion and permeability) from the DCE-MRI time curves was estimated, and changes in TBV and K(trans) were measured after administration of two drugs that reduce perfusion by different mechanisms. METHODS AND MATERIALS: The DCE-MRI experiments were simulated with expected physiologic values for the C3H mouse mammary carcinoma. The C3H tumor was examined by DCE-MRI and susceptibility contrast MRI with NC100150 (NC100150 Injection, Clariscan; Amersham Health, Oslo, Norway) after treatment with either hydralazine or combretastatin (Oxigene, Boston, MA). RESULTS: Simulations showed that reliable estimates of changes in TBV and K(trans) could be performed with DCE-MRI. Hydralazine was shown to reduce TBV as measured by both assays and to reduce K(trans). Dynamic contrast-enhanced MRI also suggested that TBV and K(trans) were reduced in combretastatin-treated tumors, and the TBV reduction was confirmed by susceptibility contrast MRI. Data suggested the drug to affect mainly the total TBV, whereas microvessels as such seemed less altered. CONCLUSION: The study supports the use of the combined DCE-MRI and susceptibility contrast MRI assay with a blood pool agent in characterizing tumors and their response to treatment.

Animals↗

PubMed2004

Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging.

The purpose of this study was to determine the cellular distribution and degradation in rat liver following intravenous injection of superparamagnetic iron oxide nanoparticles used for magnetic resonance imaging (NC100150 Injection). Relaxometric and spectrophotometric methods were used to determine the concentration of the iron oxide nanoparticles and their degradation products in isolated rat liver parenchymal, endothelial and Kupffer cell fractions. An isolated cell phantom was also constructed to quantify the effect of the degradation products on the loss of MR signal in terms of decreased transverse relaxation times, T2*. The results of this study show that iron oxide nanoparticles found in the NC100150 Injection were taken up and distributed equally in both liver endothelial and Kupffer cells following a single 5 mg Fe/kg body wt. bolus injection in rats. Whereas endothelial and Kupffer cells exhibited similar rates of uptake and degradation, liver parenchymal cells did not take up the NC100150 Injection iron oxide particles. Light-microscopy methods did, however, indicate an increased iron load, presumably as ferritin/hemosiderin, within the hepatocytes 24 h post injection. The study also confirmed that compartmentalisation of ferritin/hemosiderin may cause a significant decrease in the MRI signal intensity of the liver. In conclusion, the combined results of this study imply that the prolonged presence of breakdown product in the liver may cause a prolonged imaging effect (in terms of signal loss) for a time period that significantly exceeds the half-life of NC100150 Injection iron oxide nanoparticles in liver.

Animals↗

PubMed2004

Morphological and hemodynamic magnetic resonance assessment of early neonatal brain injury in a piglet model.

PURPOSE: To investigate the utility of functional and morphological magnetic resonance imaging (MRI) to assess the extent of brain injury in a hypoxia-ischemia (HI) piglet model and further to validate that the desired ischemic injury was successfully induced. MATERIALS AND METHODS: MRI was performed at 1.5 T in anesthetized piglets (N = 10, age = 12-36 hours). Relative cerebral blood flow (rCBF), time-to-peak (TTP) contrast, and apparent diffusion coefficient (ADC) were estimated at different time points pre-, during, and post-HI. The effect following bilateral clamping of the carotid arteries was assessed by contrast-enhanced MR angiography (MRA) and phase contrast MR angiography (PCA) (N = 4). RESULTS: A linear correlation was observed between relative cerebral perfusion reduction and cerebral ADC during HI (r(2) = 0.85, P < 0.05). There was no correlation between rCBF reduction during 30 minutes of HI and cerebral ADC after 30 or 150 minutes of reperfusion/reoxygenation (RR). CONCLUSION: The combination of morphological and functional (perfusion and diffusion) MRI enabled consistent assessment of both the presence and absence of complete occlusion as well as the functional significance of the occlusion.

Animals↗

PubMed2004

Long-term imaging effects in rat liver after a single injection of an iron oxide nanoparticle based MR contrast agent.

PURPOSE: To investigate the duration of liver R2* enhancement and pharmacokinetics following administration of an iron oxide nanoparticle in a rat model. MATERIALS AND METHODS: Rats were injected with 0, 1, 2, or 5 mg Fe/kg of NC100150 Injection, and quantitative in vivo 1/T2* liver measurements were obtained between 1 and 133 days after injection. The concentration of NC100150 Injection was determined by relaxometry methods in ex vivo rat liver homogenate. RESULTS: At all dose levels, 1/T2* remained greater than control values up to 63 days after injection. In the highest dose group, 1/T2* was above control levels during the entire 133 day time-course investigated. There were no quantifiable amounts of NC100150 Injection present 63 days after injection in any of the dose groups. The half-life of NC100150 Injection in rat liver was dose dependent. For the lowest dose group, the degradation of the particles could be defined by a mono-exponential function with a half-life of eight days. For the 2 and 5 mg Fe/kg dose groups, the degradation was bi-exponential with a fast initial decay of seven to eight days followed by a slow terminal decay of 43-46 days. CONCLUSION: NC100150 Injection exhibits prolonged 1/T2* enhancement in rat liver. The liver enhancement persisted at time points when the concentration of iron oxide particles present in the liver was below method detection limits. The prolonged 1/T2* enhancement is likely a result of the particle breakdown products and the induction of ferritin and hemosiderin with increasing iron cores/loading factors.

Analysis of Variance↗

PubMed2004

Novel pH-sensitive paramagnetic liposomes with improved MR properties.

The use of paramagnetic pH-sensitive liposomes was recently suggested as a new approach for monitoring pathologic changes in pH by MRI. Such liposomes must be stable in blood and selectively release the encapsulated paramagnetic agent when exposed to lower pH in the target tissue. In the present study, different liposomal systems were formulated and characterized by relaxometry, cryo-transmission electron microscopy (cryo-TEM), and MRI. The pH-sensitive system dipalmitoylphosphatidylethanolamine/palmitic acid (DPPE/PA) liposomal GdDTPA-BMA, which was previously shown to be unstable in blood, was modified to improve its stability. The incorporation of cholesterol into the DPPE/PA liposomes significantly increased their stability in blood, but the pH sensitivity was diminished. Polyethylene glycol (PEG)-modified DPPE/PA liposomes were pH-insensitive in buffer, and unstable in blood. However, exchanging PA with the double-chained amphiphile dipalmitoylglycerosuccinate (DPSG) yielded liposomes with improved properties. DPPE/DPSG liposomal GdDTPA-BMA was stable in blood at physiological pH, and displayed a marked pH sensitivity. The pH sensitivity was not diminished after preincubation in blood, contrary to what has been reported for analogues containing unsaturated lipids. The potential of this system for monitoring pH was demonstrated in an in vitro MRI phantom study.

Blood↗

PubMed2004

Experimental application of thermosensitive paramagnetic liposomes for monitoring magnetic resonance imaging guided thermal ablation.

The use of a liposomal paramagnetic agent with a T(1)-relaxivity that increases markedly at temperatures above the phase transition temperature (T(m)) of the liposomal membrane was evaluated during magnetic resonance imaging (MRI) guided hyperthermia ablation. A neodymium-yttrium aluminum garnet (Nd-YAG) laser unit and a radiofrequency ablation system were used for tissue ablation in eight rabbit livers in vivo. One ablation was made in each animal prior to administration of the liposomal agent. Liposomes with a T(m) of 57 degrees C containing gadodiamide (GdDTPA-BMA) were injected iv, and two additional ablations were performed. T(1)-weighted scans were performed in heated tissue, after tissue temperature had normalized, and 15-20 min after normalization of tissue temperature. Increase in signal intensity (DeltaSI) for ablations prior to injection of the agent was 13.0% (SD = 5.7) for the laser group and 9.1% (SD = 7.9) for the radiofrequency group. Signal intensity after administration of the agent unrelated to heating was not statistically significant (DeltaSI = 1.4%, P = 0.35). For ablations made after injection of the agent, a significant increase was found in the laser (DeltaSI = 34.5%, SD = 11.9) and radiofrequency group (DeltaSI = 21.6%, SD = 22.7). The persistent signal enhancement found in areas exposed to a temperature above the threshold temperature above T(m) allows thermal monitoring of MRI guided thermal ablation.

Animals↗

PubMed2004

The utility of superparamagnetic contrast agents in MRI: theoretical consideration and applications in the cardiovascular system.

This review will discuss the in vivo physical chemical relaxation properties of superparamagnetic iron oxide particles. Various parameters such as size, magnetization, compartmentalization and water exchange effects and how these alter the behavior of the iron oxide particles in an in vitro vs an in vivo situation with special reference to the cardiovascular system will be exemplified. Furthermore, applications using iron oxide particles for vascular, perfusion and viability imaging as well as assessment of the inflammatory status of a given tissue will be discussed.

Animals↗

PubMed2004

In and ex vivo MR evaluation of acute myocardial ischemia in pigs by determining R1 in steady state after the administration of the intravascular contrast agent NC100150 injection.

RATIONALE AND OBJECTIVES: To study the dose response in perfused and nonperfused myocardium by measuring relaxation rate (R1) in a steady-state situation after injection of the intravascular contrast agent NC100150 Injection in pigs and whether the dose response differs in vivo and ex vivo. MATERIALS AND METHODS: The left anterior descending artery was occluded. R1 was measured using a Look-Locker sequence for 2 dose groups (2 mg Fe/kg bw, n = 4, and 5 mg Fe/kg bw, n = 5) and a control group (n = 3). RESULTS: A significant increase in R1 was found in perfused myocardium after contrast agent injection, in contrast to nonperfused myocardium. There was a significantly larger difference in R1 between perfused and nonperfused myocardium in the 5 mg Fe/kg bw dose group compared with the other 2 groups. The difference in R1 between perfused and nonperfused myocardium was significantly higher in vivo than ex vivo. CONCLUSION: A nearly linear R1 dose response was found in perfused myocardium in vivo. The dose response ex vivo was less steep possibly due to larger water exchange limitations.

Animals↗

PubMed2003

Quantification of breast tumor microvascular permeability with feruglose-enhanced MR imaging: initial phase II multicenter trial.

PURPOSE: To investigate use of the macromolecular contrast agent feruglose for differentiating and grading of human benign and malignant breast tumors on the basis of their microvascular characteristics. MATERIALS AND METHODS: Sixty-three women with 63 primary breast lesions were examined with dynamic T1-weighted gradient-echo magnetic resonance (MR) imaging after intravenous injection of feruglose. A two-compartment unidirectional kinetic model applied to the dynamic data yielded estimates of the endothelial transfer coefficient, KPS, and the fractional plasma volume of the tumors. These MR imaging-derived parameters were correlated with the histologic tumor grade and quantified according to the Scarff-Bloom-Richardson (SBR) score by means of Pearson product moment correlation analyses. Differences between malignant and nonmalignant breast lesions with respect to KPS for feruglose were evaluated by means of the chi2 test and by calculating the sensitivity, specificity, and positive and negative predictive values. RESULTS: Histologic analysis revealed 26 benign and 37 malignant tumors. A moderate yet statistically significant correlation between KPS and SBR score was found (R = 0.496, P <.001). No significant correlation was observed between fractional plasma volume and SBR score (R = 0.085, P =.507). The KPS values were zero for 19 (73%) of the 26 benign tumors and were greater than zero for 27 (73%) of the 37 carcinomas. This distribution was significantly different (chi2 = 13.035, P =.001). With the criterion KPS > 0 in carcinomas, sensitivity was 0.73, specificity was 0.73, and the positive predictive value was 0.79. CONCLUSION: Quantitative measures of tumor microvascular permeability can be used for breast tumor characterization. The probability of breast tumor microvascular hyperpermeability to be associated with malignancy is 79%.

Adult↗

PubMed2003

Quantification of renal perfusion using an intravascular contrast agent (part 1): results in a canine model.

In this work absolute values of regional renal blood volume (rRBV) and flow (rRBF) are assessed by means of contrast-enhanced (CE) MRI using an intravascular superparamagnetic contrast agent. In an animal study, eight foxhounds underwent dynamic susceptibility-weighted MRI upon injection of contrast agent. Using principles of indicator dilution theory and deconvolution analysis, parametric images of rRBV, rRBF, and mean transit time (MTT) were computed. For comparison, whole-organ blood flow was determined invasively by means of an implanted flow probe, and the weight of the kidneys was evaluated postmortem. A mean rBV value of 28 ml/100 g was found in the renal cortex, with a corresponding mean rBF value of 524 ml/100 g/min and an average MTT of about 3.4 s. Although there was a systematic difference between the absolute blood flow values determined by MRI and the ultrasonic probe, a significant correlation (r(s) = 0.72, P < 0.05) was established. The influence of the arterial input function (AIF), T(1) relaxation effects, and repeated measurements on the precision of the perfusion quantitation is discussed.

Animals↗

PubMed2003

Assessment of myocardial blood volume and water exchange: theoretical considerations and in vivo results.

The measured signal response in contrast-enhanced myocardial perfusion imaging has been shown to be affected by the rate of water exchange between the intravascular and extravascular compartments, the effect being particularly significant when intravascular contrast agents are used. In the present study, the T(1) relaxation rates were measured in eight pigs in blood and myocardium using a Look-Locker sequence after repeated injections of the intravascular contrast agent NC100150. The selection of myocardial region of interest was automated based on a minimum chi-square method. The intra- and extravascular water exchange rates and the myocardial blood volume were calculated from the measured relaxation rates by applying a two-compartment water exchange limited model that accounts for biexponential longitudinal relaxation. The following (mean +/- SD) values were obtained for the exchange frequency (f), the extravascular residence time (tau(e)), the intravascular residence time (tau(i)) and blood volume (BV), respectively: f = 1.39 +/- 0.52 s(-1), tau(e) = 708 +/- 264 ms, tau(i) = 107 +/- 63 ms, and BV = 11.2 +/- 2.1 mL/100 g. The mean value of f was found to be about 15% higher if biexponential relaxation was not accounted for, supporting the hypothesis that significant biexponential relaxation in tissues with large blood volume can lead to an overestimation of water exchange rates unless corrected for.

Animals↗

PubMed2003

Macromolecular contrast medium (feruglose) versus small molecular contrast medium (gadopentetate) enhanced magnetic resonance imaging: differentiation of benign and malignant breast lesions.

RATIONALE AND OBJECTIVES: To compare the diagnostic performance of the blood pool agent feruglose and the standard extracellular contrast agent gadopentetate in their abilities to differentiate benign and malignant breast tumors. PATIENTS AND METHODS: Fourteen women, aged 35-77 years (mean, 55 years), with 19 breast lesions underwent dynamic fast field echo 14/1/30 degrees (TR/TE/alpha) magnetic resonance imaging of the breast after bolus injection of feruglose (Clariscan; Amersham Health, Amersham, UK: dose, 2 mg Fe/kg) and an additional, comparative gadopentetate (dose, 0.2 mmol gadolinium/kg)-enhanced fast field echo 10/4/30 degrees (TR/TE/alpha) magnetic resonance study within 1-11 days (mean, 4.8 days) before or after the feruglose study. All breast tumors were surgically excised within 1-6 days (mean, 2.5 days) after completion of the magnetic resonance studies. Data were analyzed by measuring quantitative enhancement data and qualitatively by categorizations of the shape of the tumor enhancement curves. Group differences between quantitative data of the two contrast agents and between benign and malignant tumors were evaluated using a two-tailed paired-sample t test. Differences in curve type distribution between benign and malignant tumors were tested with the chi2 test. RESULTS: Histopathology showed a spectrum of 10 benign and nine malignant breast lesions: five mastopathies, two fibroadenomas, two chronic inflammations, and one papillomatosis, as well as five invasive ductal carcinomas and four invasive lobular carcinomas. Substantial differences were observed between feruglose- and gadopentetate-enhanced images: the mean tumor deltaSI(%) peak enhancement and wash-in rate were significantly higher for gadopentetate- as compared with feruglose-enhanced images (P < .05). Using either contrast agent, morphologic enhancement characteristics showed a considerable overlap between benign and malignant breast lesions. However, the kinetic enhancement profiles of benign and malignant lesions were significantly different based on feruglose-enhanced data (chi2 = 9.017; P = .0027) but not gadopentetate-enhanced data (chi2 = 2.239; P = .3264). CONCLUSION: Compared with gadopentetate, the new blood pool agent feruglose provided an improved characterization of the evaluated breast lesions; however, at the cost of weaker overall tumor enhancement.

Adult↗

PubMed2002

Renal T(*)(2) perfusion using an iron oxide nanoparticle contrast agent--influence of T(1) relaxation on the first-pass response.

Quantitative perfusion measurements require accurate knowledge of the correlation between first-pass signal changes and the corresponding tracer concentration in tissue. In the present study, a detailed analysis of first-pass renal cortical changes in T(1) and T(*)(2) following bolus injection of the iron oxide nanoparticle NC100150 Injection was investigated in a pig model using a double-echo gradient-echo sequence. The estimated change in 1/T(*)(2) during first pass calculated from single-echo sequences was compared to the true double-echo-derived 1/T(*)(2) curves. Using a single-echo (TE = 6 ms) spoiled gradient-echo sequence, the first-pass 1/T(*)(2) response following a bolus injection of 1 mg Fe/kg of NC100150 Injection was significantly underestimated due to counteracting T(1) effects. Signal response simulations showed that the relative error in the first-pass response decreased with increasing TE and contrast agent dose. However, both the maximum TE and the maximum dose are limited by excessive cortical signal loss, and the maximum TE is further limited by high temporal resolution requirements. The problem of T(1) contamination can effectively be overcome by using a double-echo gradient-echo sequence. This yields a first-pass response that truly reflects the tissue tracer concentration, which is a critical requirement for quantitative renal perfusion assessment.

Animals↗

PubMed2002

Assessment of T1 and T2* effects in vivo and ex vivo using iron oxide nanoparticles in steady state--dependence on blood volume and water exchange.

Accurate knowledge of the relationship between contrast agent concentration and tissue relaxation is a critical requirement for quantitative assessment of tissue perfusion using contrast-enhanced MRI. In the present study, using a pig model, the relationship between steady-state blood concentration levels of an iron oxide nanoparticle with a hydrated diameter of 12 nm (NC100150 Injection) and changes in the transverse and longitudinal relaxation rates (1/T2* and 1/T1, respectively) in blood, muscle, and renal cortex was investigated at 1.5 T. Ex vivo measurements of 1/T2* and 1/T1 were additionally performed in whole pig blood spiked with different concentrations of the iron oxide nanoparticle. In renal cortex and muscle, 1/T2* increased linearly with contrast agent concentration with slopes of 101 +/-22 s(-1)mM(-1) and 6.5 +/-0.9 s(-1)mM(-1) (mean +/- SD), respectively. In blood, 1/T2* increased as a quadratic function of contrast agent concentration, with different quadratic terms in the ex vivo vs. the in vivo experiments. In vivo, 1/T1 in blood increased linearly with contrast agent concentration, with a slope (T1-relaxivity) of 13.9 +/- 0.9 s(-1)mM(-1). The achievable increase in 1/T1 in renal cortex and muscle was limited by the rate of water exchange between the intra- and extravascular compartments and the 1/T1-curves were well described by a two-compartment water exchange limited relaxation model.

Animals↗