A new method for radiochemical separation of arsenic from irradiated germanium oxide.

Radioarsenic labelled radiopharmaceuticals could be a valuable asset to Positron Emission Tomography (PET). In particular, the long half-lives of (72)As (T(1/2)=26 h) and (74)As (T(1/2)=17.8 d) allow to investigate slow physiological or metabolical processes, like the enrichment and distribution of antibodies in tumor tissue. This work describes the direct production of no-carrier-added (nca) arsenic isotopes *As, with *=71, 72, 73, 74 or 77, the reaction to [*As]AsI(3) and its radiochemical separation from the irradiated solid germanium oxide via polystyrene-based solid-phase extraction. The germanium oxide target, irradiated at a cyclotron or a nuclear reactor, is dissolved in concentrated HF and Ge is separated almost quantitatively (99.97%) as [GeF(6)](2-). [*As]AsI(3) is formed by addition of potassium iodide. The radiochemical separation yield for arsenic is >90%. [*As]AsI(3) is a versatile radioarsenic labelling synthon.

A fully coupled binary biochemical reactive-diffusion model with analytic solution.

Coupled multicomponent biochemical reactive diffusion underlies a variety of biological signalling processes and pharmacokinetic applications, such as paracrine signalling involving "cocktails" comprised of growth promoter/inhibitor factors and proteases associated with tumor angiogenesis, invasion and metastasis, extravascular drug delivery, and polymeric controlled-release drug codelivery design. Here, we present a model and develop a new analytic solution to illustrate the spatiotemporal behavior associated with fully coupled binary biochemical reactive diffusion. The complete coupling renders the solution appreciably more complex in structure and behavior than solutions for unicomponent or partially coupled models. Concentration behavior is illustrated by the computational simulation of binary-species tumor angiogenesis factor reactive-diffusion in the extravascular tissue matrix. The computational results indicate that (a) steady-state concentration profiles are achieved within 1 h of a change in factor production; (b) in the steady state, the spatial profiles of the two components tend to be similar; (c) exceedingly steep concentration gradients, involving several orders-of-magnitude differences in concentration over a few tenths of a millimeter, can occur in the vicinity of boundary sources due to inter-species reaction; (d) the concentration profiles of the two species differ from unicomponent predictions due to the simultaneous mass interchange between the two species. The analytic solution predictions are also used to provide a first-ever validation of a time-dependent, binary-component Crank-Nicholson numerical solution. The ability to quantitatively model interacting and often strongly varying concentration levels as a function of time and position can serve as a powerful complementary tool to experimental analyses for assessing disease state and interventional pharmacological efficacy, especially when the spatial scales on which in vivo behavior occurs taxes the limits of imaging capabilities.

Bone material ultrasound velocity is predictive of whole bone strength.

In humans, bone strength is assessed indirectly by the noninvasive measurement of structure or mass. Recent clinical application of an ultrasonic critical-angle reflectometry technique (UCR) has demonstrated the measurement of the regional and directional distribution of mechanical stiffness. This study investigates the specific question: are these measurements of a local material level property predictive of the strength of whole bone? Maximum values of pressure wave velocity and breaking strength were recorded at two locations (midshaft and base of neck) on rat femurs from growing rats. The results demonstrate a strong empirical relationship between material-level ultrasound (US) velocity and whole bone mechanical strength. However, the US velocity at a specific bone site can be used to assess bone strength at that site only, explaining discrepancies in other published studies that negate a relationship between strength and US velocity. The results indicate an important role for US velocity measurement in clinical evaluation of bone health.

Tumor oximetry: demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning prostate R3327-AT1 rat tumor.

PURPOSE: We have developed an enhanced approach to measuring regional oxygen tension (pO(2)) dynamics in tumors. The technique is demonstrated in a group of 8 Dunning prostate rat tumors (R3327-AT1) with respect to respiratory challenge. METHODS AND MATERIALS: Hexafluorobenzene was injected directly into the tumors of anesthetized rats. (19)F nuclear magnetic resonance echo planar imaging relaxometry was performed to obtain maps of regional tumor oxygenation under baseline conditions and when the inhaled gas was changed to oxygen or carbogen. RESULTS: Sequential pO(2) maps required 8 min, with a typical precision of 1-3 torr at 30-100 individual regions across a tumor. When rats breathed 33% oxygen, distinct heterogeneity was observed for baseline oxygenation in each tumor with pO(2) values ranging from hypoxic to greater than 100 torr. Larger tumors showed significantly lower baseline pO(2). Respiratory challenge with oxygen or carbogen produced significant increases in tumor oxygenation with a close correlation between the response to each gas at individual locations. Regions of both small and large tumors responded to respiratory challenge, but the rate was generally much faster in initially well-oxygenated regions. CONCLUSIONS: Regional pO(2) was assessed quantitatively and the response of multiple individual tumor regions observed simultaneously with respect to interventions.

Bone phenotype of the aromatase deficient mouse.

Estrogens are important for normal bone growth and metabolism. The mechanisms are incompletely understood. Thus, we have undertaken characterization of the skeletal phenotype of aromatase (ArKO) deficient mice. No abnormalities have been noted in skeletal patterning in newborns. Adult ArKO mice show decreased femur length and decreased peak Bone Mineral Density (BMD) with accelerated bone loss by 7 months of age in females. Magnetic resonance microscopy (MR) and microCT (microCT) imaging disclosed decreased cancellous connectivity and reduced cancellous bone volume in ArKO females. Bone formation rate (BFR) is increased in ArKO females and decreased in ArKO males. Estradiol therapy reverses these changes. This anabolic effect of estradiol in the male skeleton is supported by 18-F- Positron Emission Tomography (PET) imaging, which clearly demonstrates decreased spinal uptake, but marked increase after estradiol therapy. Serum IGF-1 levels are high in young female ArKO mice but low in young ArKO males. The reduced BMD in ArKO females, despite the presence of elevated serum IGF 1, suggests that other mechanism(s) are operative. There is increased B-cell lymphopoiesis in adult female ArKO bone marrow cells. These results show that ArKO mice show the effects of estrogen deficiency on bone growth, mass, metabolism, microarchitecture and the hematopoietic microenvironment.

Regional tumor oxygenation and measurement of dynamic changes.

We recently described a novel approach to measuring regional tumor oxygen tension using (19)F pulse burst saturation recovery (PBSR) nuclear magnetic resonance (NMR) echo planar imaging (EPI) relaxometry of hexafluorobenzene. We now compare oxygen tension measurements in a group of size-matched R3327-AT1 Dunning prostate rat tumors made using this new method with those using a traditional polarographic method: the Eppendorf histograph. Similar oxygen tension distributions were found using the two methods, and both techniques showed that tumors with volume greater than 3.5 cm(3) were significantly (P < 0.0001) less well oxygenated than smaller tumors (volume less than 2 cm(3)). Using the (19)F EPI approach, we also examined the response to respiratory challenge. Increasing the concentration of inspired oxygen from 33% to 100% O(2) produced a significant increase (P < 0.0001) in tumor oxygenation for a group of small tumors. In contrast, no change was observed in the mean pO(2) for a group of large tumors. Consideration of individual tumor regions irrespective of tumor size showed a strong correlation between the maximum pO(2) observed when breathing 100% O(2) compared with mean baseline pO(2). These results further demonstrate the usefulness of (19)F EPI to assess changes in regional tumor oxygenation.

High cervical disc herniation and Brown-Sequard syndrome. A case report and review of the literature.

We describe a rare herniation of the disc at the C2/C3 level in a 73-year-old woman. It caused hemicompression of the spinal cord and led to the Brown-Sequard syndrome. The condition was diagnosed clinically and by MRI six months after onset. Discectomy and fusion gave complete neurological resolution.

Bone material elasticity in a murine model of osteogenesis imperfecta.

To investigate the source of bone brittleness in the disease osteogenesis imperfecta (OI), biomechanical properties have been measured in the femurs from a homozygous (oim/oim) mutant mouse model of OI, its heterozygous littermates, and wild-type animals. The novel technique of ultrasound critical-angle reflectometry (UCR) was used to determine bone material elasticity matrix from measurements of the pressure and shear wave velocity at different orientations about selected points of the bone specimens. This nondestructive method is the only available means for obtaining measurements of this nature from a single surface. The ultrasound pressure wave velocity showed an increased isotropy in the homozygous compared to the wild-type specimens. This was reflected in a significant decrease in the principal elastic modulus measured along the length of the oim/oim bones (E33) while the modulus along the width (E11) did not change significantly, compared to wild-type specimens. The Poisson's ratio, v12, also had a significantly increased value in oim/oim bones. Measurements of these parameters in heterozygous animals generally fell between those from homozygous and control mice. The differences in the elasticity components in oim/oim bones indicate an altered stress distribution and a modified elastic response to loads, compared to normal bone.

Regional tumor oxygen tension: fluorine echo planar imaging of hexafluorobenzene reveals heterogeneity of dynamics.

PURPOSE: Therapeutic success could be enhanced if therapy were tailored to the characteristics of specific tumors. We have been developing novel approaches to measuring tumor oxygen tension in vivo, and recently reported a method based on 19F nuclear magnetic resonance (NMR) spin lattice echo planar imaging (EPI) relaxometry of hexafluorobenzene (HFB). We have now examined the feasibility of monitoring dynamic changes in regional tumor oxygenation in response to respiratory challenge. Preliminary data in one tumor show distinct differences before and subsequent to irradiation. METHODS AND MATERIALS: Dunning prostate adenocarcinoma R3327-AT1 was grown in the form of pedicles on the foreback of male Copenhagen rats. When the tumors reached approximately 1 cm diameter, HFB (40 microl) was administered by direct intratumoral injection deliberately dispersed to interrogate both central and peripheral regions. Local pO2 was determined using pulse burst saturation recovery 19F NMR EPI on the basis of the spin lattice relaxation rate. RESULTS: Interrogation of both central and peripheral regions of tumors showed bimodal distribution for oxygenation, including many voxels with pO2 < 15 torr. Altering the inspired gas to 100% O2 produced significant elevation for regions with initially high pO2 (P < 0.01), but the temporal course of dynamic changes varied for each voxel. Many voxels with low pO2 showed little response. Following irradiation (20 Gy), tumor oxygenation was significantly elevated and remained high for at least 10 h. CONCLUSION: We believe this method provides a valuable new approach to investigate tumor oximetry that may extend our understanding of tumor physiology, and could have prognostic value.

Development of novel 19F NMR pH indicators: synthesis and evaluation of a series of fluorinated vitamin B6 analogues.

We have synthesized a series of novel fluorinated vitamin B6 analogues (6-fluoropyridoxol derivatives) as potential 19F NMR pH indicators for use in vivo. Modifications included addition of aldehyde, carboxyl or aminomethyl groups at the 4- or 5-ring position, and examination of a trifluoromethyl moiety as an internal chemical shift standard. The variation in chemical shift with respect to acid-base titration showed pKa values in the range 7.05-9.5 with a chemical shift sensitivity in the range 7.4-12 ppm. Several of the molecules readily cross cell membranes providing estimates of both intra- and extra-cellular pH in whole blood. 6-Fluoropyridoxamine (6-FPAM) exhibits a pKa = 7.05, which is closer to normal physiological pH than the parent molecule 6-fluoropyridoxol (6-FPOL) (pKa = 8.2), and should thus, be useful for precise and accurate measurements of pH in vivo. Enhanced spectral resolution for 6-FPAM over 6-FPOL is demonstrated in whole blood and the perfused rat heart.

SPECT electronic collimation resolution enhancement using chi-square minimization.

An electronic collimation technique is developed which utilizes the chi-square goodness-of-fit measure to filter scattered gammas incident upon a medical imaging detector. In this data mining technique, Compton kinematic expressions are used as the chi-square fitting templates for measured energy-deposition data involving multiple-interaction scatter sequences. Fit optimization is conducted using the Davidon variable metric minimization algorithm to simultaneously determine the best-fit gamma scatter angles and their associated uncertainties, with the uncertainty associated with the first scatter angle corresponding to the angular resolution precision for the source. The methodology requires no knowledge of materials and geometry. This pattern recognition application enhances the ability to select those gammas that will provide the best resolution for input to reconstruction software. Illustrative computational results are presented for a conceptual truncated-ellipsoid polystyrene position-sensitive fibre head-detector Monte Carlo model using a triple Compton scatter gamma sequence assessment for a 99mTc point source. A filtration rate of 94.3% is obtained, resulting in an estimated sensitivity approximately three orders of magnitude greater than a high-resolution mechanically collimated device. The technique improves the nominal single-scatter angular resolution by up to approximately 24 per cent as compared with the conventional analytic electronic collimation measure.

Analytic treatment of resolution precision in electronically collimated SPECT imaging involving multiple-interaction gamma rays.

The widely applied single-interaction analytic expression characterizing the energy resolution component of the angular resolution precision for an electronically collimated point source is extended to include multiple-interaction Compton scatter sequences as well as sequences terminated by photoelectric absorption. The analytic formulation is developed using the statistical variance of the mean for components comprising composite, multivariate resolution precision estimators. It is demonstrated that enhanced resolution precision in the incident interaction scatter angle is attained when use is made of information from multiple interactions. An improvement in the resolution precision of up to approximately 40% is observed for triple Compton scatter. Comparison of the analytic estimates with Monte Carlo/chi-square results shows good agreement.

Regional tumor oximetry: 19F NMR spectroscopy of hexafluorobenzene.

PURPOSE: An accurate method for monitoring oxygen tension (pO2) of individual tumors could be valuable for optimizing treatment plans. We have recently shown that 19F nuclear magnetic resonance (NMR) spin-lattice relaxometry of hexafluorobenzene (HFB) provides a highly sensitive indicator of tumor oxygenation. We have now refined the methodology to provide enhanced precision, and applied the method to investigate dynamic changes in tumor oxygenation. METHODS AND MATERIALS: Dunning prostate adenocarcinoma R3327-AT1 was grown in the form of pedicles on the foreback of male Copenhagen rats. When the tumors reached approximately equal to 1 cm diameter, HFB (20 microl) was administered, either centrally or peripherally, by direct intratumoral (i.T) injection. Local pO2 was determined using pulse-burst saturation recovery (PBSR) 19F NMR spectroscopy on the basis of the spin-lattice relaxation rate, R1. RESULTS: Interrogation of the central region of tumors provided typical values in the range pO2 = 1.4-6.4 mmHg, with a typical stability of +/-2 mmHg over a period of 20 min, when rats breathed 33% O2. Altering the inhaled gas to oxygen or carbogen (95% O2/5% CO2) produced no significant change. In contrast, interrogation of tumor periphery indicated baseline pO2 in the range 7.9-78.9 mmHg. Altering inspired gas produced significant changes (p < 0.0001) with O2 or carbogen, although the change was generally greater with carbogen. In each case, pO2 returned to baseline within 16 min of returning the inhaled gas to baseline. CONCLUSION: We believe this method provides a valuable new approach with the requisite precision and accuracy to investigate tumor pO2.

Simultaneous intracellular and extracellular pH measurement in the heart by 19F NMR of 6-fluoropyridoxol.

6-Fluoropyridoxol (6-FPOL) was evaluated as a simultaneous indicator of intracellular and extracellular pH and, hence, pH gradient in perfused rat hearts. After infusion, 19F NMR spectra rapidly showed two well-resolved peaks assigned to the intracellular and extracellular compartments, and pH was calculated on the basis of chemical shift with respect to a sodium trifluoroacetate standard. To demonstrate use of this molecule, dynamic changes in myocardial pH were assessed with a time resolution of 2 min during respiratory and metabolic alkalosis or acidosis and ischemia. For a typical heart, intracellular pH (pHi) = 7.14+/-0.01 and extracellular pH (pHe) = 7.52+/-0.02. In response to metabolic alkalosis, pHi remained relatively constant and the pH gradient increased. In contrast, respiratory challenge caused a significant increase in pHi. Independent measurements using pH electrodes and 31P NMR confirmed validity of the 19F NMR results.

Bone elasticity and ultrasound velocity are affected by subtle changes in the organic matrix.

The mechanical competence of bone can be studied through the measurement of the components of its material elasticity, a property which can vary both in magnitude and in dependence upon orientation (anisotropy). While it is known that the elasticity is largely determined by the mineral constituents of the bone matrix, it is nonetheless clear that it must be also dependent upon the remaining constituents of bone material. In this work, the influence of organic components on the elasticity is explored by altering specific constituents of the bone matrix to varying degrees. This study addresses two questions: first, are the resulting changes in elasticity strongly or weakly dependent upon direction, and second, are they substantially dependent upon the nature and magnitude of the induced matrix alteration? To answer these questions, we performed different chemical manipulations of the bone matrix and measured the changes in elasticity and velocity using the technique of ultrasound critical angle reflectometry. Altering the properties of the organic matrix resulted in substantial and complex changes in the elasticity of bone. The observed changes were strongly dependent upon direction, could not be explained by changes in density alone, and varied strongly with the specific chemical treatment of the matrix. Immersion in urea selectively affected protein components of the organic matrix and resulted in reversible changes in velocity and elasticity, while removal of collagen caused anisotropic decreases and removal of all organic matter caused a collapse of all components of the elasticity. In conclusion, this study confirms that the organic matrix exerts a profound influence on the elasticity and indicates that the measurement of elastic properties at multiple directions is necessary in the assessment of bone mechanical competence.

Ultrasound critical-angle reflectometry (UCR): a new modality for functional elastometric imaging.

This paper discusses the measurement of velocity in a solid based on the analysis of the amplitude and phase of ultrasound waves reflected by a solid, a technique called ultrasound critical-angle reflectometry (UCR). To this end, the complete formulation of ultrasound wave reflection and refraction from a liquid-solid interface is described. Differences between this formulation and previously published ones are briefly discussed. Based on this analysis it is in particular possible to measure by this technique not only pressure but also, for the first time in such studies, shear wave velocities, an experimentally confirmed result. The measurement of the complete stiffness matrix of a transversely isotropic solid, specifically cortical bone, by applying UCR elastometry to any point on the solid's surface is demonstrated. Finally this method is extended to functional elastometric imaging. The techniques presented in this paper offer new opportunities for applications of UCR imaging to the assessment of bone metabolism, formation and disease and also the analysis of composite materials in general.

Connectivity in human cancellous bone by three-dimensional magnetic resonance imaging.

Bone architecture affects strength and resistance to fracture. Trabecular connectivity is now recognized as an important measure of bone quality, and could be useful as an indicator of the osteoporotic condition, as well as a tool for measuring the effectiveness of therapies. We have applied three-dimensional magnetic resonance imaging microscopy to human cancellous bone biopsies, and report the results of connectivity measurements. Sample heterogeneity was examined on the basis of connectivity density for subvolumes. The choice of examination volume had a significant effect on connectivity density measurements, but sample volumes greater than 100 mm3 were found to give stable results. Connectivity density was strongly correlated with nodal density, and two-dimensional estimates of connectivity, but not bone volume fraction. Repeat measurement at constant resolution (69 x 138 x 109 microns, signal-to-noise ratio of about 35) showed reproducibility of about 5% for connectivity density. Our most recent results have significantly enhanced resolution (69 x 69 x 43 microns); bone fraction remained constant, but apparent connectivity density is greater.

Regional tumor oxygen dynamics: 19F PBSR EPI of hexafluorobenzene.

We demonstrate a novel approach to measuring regional tumor oxygen tension using 19F pulse burst saturation recovery echo planar imaging (EPI) relaxometry of hexafluorobenzene. Hexafluorobenzene offers exceptional sensitivity to changes in oxygen tension, and has a single resonance making it ideal for imaging studies. By combining a pulse burst saturation recovery preparation sequence with EPI, the relaxation experiments were performed in approximately 20 min facilitating measurements of dynamic changes in pO2 accompanying interventions. Direct intratumoral administration of hexafluorobenzene permitted labeling of specific regions of interest, and imaging provided maps of pO2, confirming distinct intra tumoral heterogeneity. For a group of three Dunning prostate adenocarcinoma R3327-AT1 tumors interrogation of the central tumor region showed skewed pO2 distributions with considerable radiobiological hypoxia (approximately 90% voxels had pO2 < 15 torr) when rats breathed 33% O2. Altering the inspired gas to pure oxygen caused distributions to shift towards increased pO2 with significant increases in mean oxygen tension (p < 0.05) in two cases. Interrogation of both central and peripheral regions in a fourth tumor showed bimodal distribution for tumor oxygenation including approximately 75% voxels with pO2 > 15 torr. EPI allows the fate of individual voxels to be traced: upon altering the inspired gas to pure oxygen those voxels with baseline pO2 > 30 torr showed significant changes (p < 0.05), whereas those with pO2 < 16 torr showed minimal response. The precision of the measurements, together with the ability to simultaneously examine dynamic changes in multiple regions should provide a useful technique for investigating tumor hypoxia with respect to therapy.

Measurement of shear-wave velocity by ultrasound critical-angle reflectometry (UCR).

There exists a growing body of research that relates the measurement of pressure-wave velocity in bone to different physiological conditions and treatment modalities. The shear-wave velocity has been less studied, although it is necessary for a more complete understanding of the mechanical properties of bone. Ultrasound critical-angle reflectometry (UCR) is a noninvasive and nondestructive technique previously used to measure pressure-wave velocities both in vitro and in vivo. This note describes its application to the measurement of shear-wave velocity in bone, whether directly accessible or covered by soft tissue.