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The apparent diffusion coefficient (ADC) is analyzed for the case of oscillating diffusion-sensitizing gradients in the high-frequency regime. We provide a concise derivation of the analytical expression for the ADC for an arbitrary number of gradient oscillations N and initial phase φ. It is demonstrated that an ultimate goal - to determine the surface-to-volume ratio (S/V) from MR measurements by using oscillating gradients - can be achieved with cosine-type gradients (φ = 0) for an arbitrary N. However, to determine S/V employing gradients with φ ≠ 0 (including the sine-type gradients) and arbitrary N additionally requires prior knowledge of the time-dependent diffusion coefficient D(t). The latter is rarely known a priori but can be estimated under certain limiting conditions: (i) in the short time regime, when the total diffusion time of the measurements, t, is smaller than the characteristic diffusion time of the microstructural system of interest, an analytical expression for D(t) is available (Mitra's expression) and this allows S/V to be determined in the short time regime with sine-type gradients; (ii) in the important case of purely restricted diffusion, D(t) → 0 at sufficiently long time, the signal becomes independent of φ and behaves as for the cosine-type gradients, thus, allowing determination of S/V.

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Diffusion of spins between physical or virtual, communicating compartments having different states of longitudinal magnetization leads to diffusion-driven longitudinal relaxation. Herein, in two model systems, the effects of diffusion-driven longitudinal relaxation are explored experimentally and analyzed quantitatively. In the first case, longitudinal relaxation in a single slice of a water phantom is monitored spectroscopically as a function of slice thickness. In the second case, mimicking vascular flow/diffusion effects, longitudinal relaxation is monitored in a two-compartment, semi-permeable fiber phantom. In both cases, apparent longitudinal relaxation, though clearly multi-exponential, is well-modeled as bi-exponential.

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Two semipermeable, hollow fiber phantoms for the validation of perfusion-sensitive magnetic resonance methods and signal models are described. Semipermeable hollow fibers harvested from a standard commercial hemodialysis cartridge serve to mimic tissue capillary function. Flow of aqueous media through the fiber lumen is achieved with a laboratory-grade peristaltic pump. Diffusion of water and solute species (e.g., Gd-based contrast agent) occurs across the fiber wall, allowing exchange between the lumen and the extralumenal space. Phantom design attributes include: i) small physical size, ii) easy and low-cost construction, iii) definable compartment volumes, and iv) experimental control over media content and flow rate.

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The most common MR-based approach to noninvasively measure brain temperature relies on the linear relationship between the (1)H MR resonance frequency of tissue water and the tissue's temperature. Herein we provide the most accurate in vivo assessment existing thus far of such a relationship. It was derived by acquiring in vivo MR spectra from a rat brain using a high field (11.74 Tesla [T]) MRI scanner and a single-voxel MR spectroscopy technique based on a LASER pulse sequence. Data were analyzed using three different methods to estimate the (1)H resonance frequencies of water and the metabolites NAA, Cho, and Cr, which are used as temperature-independent internal (frequency) references. Standard modeling of frequency-domain data as composed of resonances characterized by Lorentzian line shapes gave the tightest resonance-frequency versus temperature correlation. An analysis of the uncertainty in temperature estimation has shown that the major limiting factor is an error in estimating the metabolite frequency. For example, for a metabolite resonance linewidth of 8 Hz, signal sampling rate of 2 Hz and SNR of 5, an accuracy of approximately 0.5 degrees C can be achieved at a magnetic field of 3T. For comparison, in the current study conducted at 11.74T, the temperature estimation error was approximately 0.1 degrees C.

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Quantitative characterization of the intracellular water (1)H MR signal from cultured cells will provide critical biophysical insight into the MR signal from tissues in vivo. Microbeads provide a robust immobilization substrate for the many mammalian cell lines that adhere to surfaces and also provide sufficient cell density for observation of the intracellular water MR signal. However, selective observation of the intracellular water MR signal from perfused, microbead-adherent mammalian cells requires highly effective suppression of the extracellular water MR signal. We describe how high-velocity perfusion of microbead-adherent cells results in short apparent (1)H MR longitudinal and transverse relaxation times for the extracellular water in a thin slice selected orthogonal to the direction of flow. When combined with a spin-echo pulse sequence, this phenomenon provides highly effective suppression of the extracellular water MR signal. This new method is exploited here to quantify the kinetics of water exchange from the intracellular to extracellular spaces of HeLa cells. The time constant describing water exchange from intracellular to extracellular spaces, also known as the exchange lifetime for intracellular water, is 119 +/- 14 ms.

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The (1)H MR signal arising from flowing extracellular media in a perfused, microbead-adherent cultured cell system can be suppressed with a slice-selective, spin-echo pulse sequence. The signal from intracellular water can, thus, be selectively monitored. Herein, this technique was combined with pulsed field gradients (PFGs) to quantify intracellular water diffusion in HeLa cells. The intracellular water MR diffusion-signal attenuation at various diffusion times was well described by a biophysical model that characterizes the incoherent displacement of intracellular water as a truncated Gaussian distribution of apparent diffusion coefficients (ADCs). At short diffusion times, the water "free" diffusion coefficient and the surface-to-volume ratio of HeLa cells were estimated and were, 2.0 +/- 0.3 microm(2)/ms and 0.48 +/- 0.1 microm(-1) (mean +/- SD), respectively. At long diffusion times, the cell radius of 10.1 +/- 0.4 microm was inferred and was consistent with that measured by optical microscopy. In summary: 1) intracellular water "free" diffusion in HeLa cells was rapid, two-thirds that of pure water; and 2) the cell radius inferred from modeling the incoherent displacement of intracellular water by a truncated Gaussian distribution of ADCs was confirmed by independent optical microscopy measures.

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It has been generally found that solid tumours in vivo are more susceptible to destruction by heat than normal tissues. Hyperthermia has, thus, been employed in the treatment of cancer either applied alone or in combination with other modalities such as chemotherapy and radiotherapy. However, the critical mechanism(s) by which heat sensitizes and kills cells in the solid tumour remains poorly defined. Magnetic resonance spectroscopic monitoring of tumour metabolism during application of hyperthermia may provide important insight into the response to hyperthermic challenge. The implementation of dual antenna-coil methodology that provides for NMR spectroscopic monitoring (31P at 121 MHz) concomitant with applied 4 MHz RF hyperthermia in murine tumours is described herein, in some detail. This technology, which does not require advanced (and expensive) magnetic resonance imaging systems, should be readily adaptable by other laboratories with an interest in murine tumour models.

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The local magnetization distribution M(x,t) and the net MR signal S arising from a one-dimensional periodic structure with permeable barriers in a Tanner-Stejskal pulsed-field gradient experiment are considered. In the framework of the narrow pulse approximation, the general expressions for M(x,t) and S as functions of diffusion time and the bipolar field gradient strength are obtained and analyzed. In contrast to a system with impermeable boundaries, the signal S as a function of the b-value is modeled well as a bi-exponential decay not only in the short-time regime but also in the long-time regime. At short diffusion times, the local magnetization M(x,t) is strongly spatially inhomogeneous and the two exponential components describing S have a clear physical interpretation as two "population fractions" of the slow- and fast-diffusing quasi-compartments (pools). In the long-diffusion time regime, the two exponential components do not have clear physical meaning but rather serve to approximate a more complex functional signal form. The average diffusion propagator, obtained by means of standard q-space analysis procedures in the long-diffusion time regime is explored; its structure creates the deceiving appearance of a system with multiple compartments of different sizes, while in reality, it reflects the permeable nature of boundaries in a system with multiple compartments all of the same size.

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Described herein are the initial findings from an 'in-magnet' 31P NMR compatible hyperthermia system capable of concurrently heating and monitoring the metabolic response of murine tumours; the murine radiation induced fibrosarcoma (RIF-1) was employed for these studies. At thermal doses sufficient to raise tumour temperature to 41.5 and 43 degrees C for a period of 30 min, a marked and rapid decrease in nucleoside triphosphate concentration and in pH was observed during the heating period, while inorganic phosphate concentration increased significantly but more gradually. These 31P NMR determined metabolic indices remained depressed/elevated throughout a 1.5 h post-hyperthermia monitoring period. Importantly, these metabolic indices correlated significantly with specific growth delay. This suggests a possible role for NMR spectroscopy in early assessment, and perhaps control, of therapeutic response to hyperthermia.

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The spatial distribution of the transverse nuclear spin magnetization, appearing in a single compartment with impermeable boundaries in a Stejskal-Tanner gradient pulse MR experiment, is analyzed in detail. At short diffusion times the presence of diffusion-restrictive barriers (membranes) reduces effective diffusivity near the membranes and leads to an inhomogeneous spin magnetization distribution (the edge-enhancement effect). In this case, the signal reveals a quasi-two-compartment behavior and can be empirically modeled remarkably well by a biexponential function. The current results provide a framework for interpreting experimental MR data on various phenomena, including water diffusion in giant axons, metabolite diffusion in the brain, and hyperpolarized gas diffusion in lung airways.

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Oocytes of Xenopus laevis are large, single cells that provide a promising model system for the exploration of the MR biophysics fundamental to more complex living systems. Previous studies have generally employed 2D spin-echo sequences with an image slice thickness greater than the thickness of the cellular volumes of interest. Also, the large cytoplasmic lipid signal has typically been ignored. This study describes separate, high-resolution 3D measurements of the water and lipid spin densities, T(1) and T(2) relaxation time constants, and the water apparent diffusion rate constant (ADC) in the Xenopus oocyte without significant partial volume artifacts. The lipid spin-density and values for water MR properties varied monotonically from the vegetal to animal poles, indicating that the border between the poles is not sharply demarcated. Regional water MR property values correlated with lipid signal intensity. Lipid-specific imaging is shown for which water suppression is achieved via high diffusion weighting in the imaging sequence.

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BACKGROUND AND PURPOSE: (23)Na MRI may offer new insight into the evaluation of tissue injury. We performed a direct, longitudinal, morphological comparison of (1)H T2 relaxation, (1)H apparent diffusion coefficient (ADC), (23)Na content, and histopathology after cerebral ischemia to address the hypotheses that (a) (23)Na MRI is unique in comparison to (1)H MRI, and (b) accumulation of (23)Na is an unambiguous marker for dead tissue. METHODS: Rats underwent 30 minutes of focal ischemia. MRIs of (1)H T2, (1)H ADC, and (23)Na content were acquired from 12 hours up to 1, 2, or 14 days after reperfusion. On excision, brains were stained with triphenyltetrazolium chloride (TTC). RESULTS: In all cases, the region of abnormality increased in size for 2 days. On day 5, both (1)H T2 and ADC temporarily appeared normal despite the presence of TTC-defined infarction. By comparison, the volume of tissue exhibiting abnormally intense (23)Na signal mirrored the TTC-defined infarct at all time points. CONCLUSIONS: Regions of high (23)Na content correlate well with the TTC-defined infarct and may be a quantitative in vivo marker for dead tissue. In contrast, the dynamics of the (1)H T2 and ADC make it difficult to interpret these images without additional information because they may appear normal despite infarction. Neither type of (1)H image delineates dead tissue, and none of these methods predicts the potential infarct size at early time points.

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Accurate knowledge of the magnetic properties of human blood is required for the precise modeling of functional and vascular flow-related MRI. Herein are reported determinations of the relaxation parameters of blood, employing in vitro samples that are well representative of human blood in situ. The envelope of the blood (1)H(2)O free-induction decay signal magnitude during the first 100 msec following a spin echo at time TE is well- described empirically by an expression of the form, S(t) = S(o). exp[-R(*)(2). (t - TE) - AR*. (t - TE)(2)]. The relaxation parameters AR* and R(*)(2) increase as a function of the square of the susceptibility difference between red blood cell and plasma and depend on the spin-echo time. The Gaussian component, AR*, should be recognized in accurate modeling of MRI phenomena that depend upon the magnetic state of blood. The magnetic susceptibility difference between fully deoxygenated and fully oxygenated red blood cells at 37 degrees C is 0.27 ppm, as determined independently by MR and superconducting quantum interference device (SQUID) measurements. This value agrees well with the 1936 report of Pauling and Coryell (Proc Natl Acad Sci USA 1936;22:210-216), but is substantially larger than that frequently used in MRI literature. Magn Reson Med 45:533-542, 2001.

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The apparent diffusion coefficients (ADCs) of a series of markers concentrated in the extracellular space of normal rat brain were measured to evaluate, by inference, the ADC of water in the extracellular space. The markers (mannitol, phenylphosphonate, and polyethylene glycols) are defined as "compartment selective" because tissue culture experiments demonstrate some leakage into the intracellular space, making them less "compartment specific" than commonly believed. These primarily extracellular markers have ADCs similar to those of intracellular metabolites of comparable hydrodynamic radius, suggesting that water ADC values in the intra- and extracellular spaces are similar. If this is the case, then it is unlikely that a net shift of water from the extra- to the intracellular space contributes significantly to the reduction in water ADC detected following brain injury. Rather, this reduction is more likely due primarily to a reduction of the ADC of intracellular water associated with injury.

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The transcription factor early growth response protein 1 (EGR1) is overexpressed in a majority of human prostate cancers and is implicated in the regulation of several genes important for prostate tumor progression. Here we have assessed the effect of Egr1 deficiency on tumor development in two transgenic mouse models of prostate cancer (CR2-T-Ag and TRAMP). Using a combination of high-resolution magnetic resonance imaging and histopathological and survival analyses, we show that tumor progression was significantly impaired in Egr1-/- mice. Tumor initiation and tumor growth rate were not affected by the lack of Egr1; however, Egr1 deficiency significantly delayed the progression from prostatic intra-epithelial neoplasia to invasive carcinoma. These results indicate a unique role for Egr1 in regulating the transition from localized, carcinoma in situ to invasive carcinoma.

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A fundamental discovery of modern human brain imaging with positron-emission tomography that the blood flow to activated regions of the normal human brain increases substantially more than the oxygen consumption has led to a broad discussion in the literature concerning possible mechanisms responsible for this phenomenon. Presently no consensus exists. It is well known that oxygen delivery is not the only function of systemic circulation. Additional roles include delivery of nutrients and other required substances to the tissue, waste removal, and temperature regulation. Among these other functions, the role of regional cerebral blood flow in local brain temperature regulation has received scant attention. Here we present a theoretical analysis supported by empirical data obtained with functional magnetic resonance suggesting that increase in regional cerebral blood flow during functional stimulation can cause local changes in the brain temperature and subsequent local changes in the oxygen metabolism. On average, temperature decreases by 0.2 degrees C, but individual variations up to +/-1 degrees C were also observed. Major factors contributing to temperature regulation during functional stimulation are changes in the oxygen consumption, changes in the temperature of incoming arterial blood, and extensive heat exchange between activated and surrounding brain tissue.

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Global cardiac function has been studied in small animals with methods such as echocardiography, cine-magnetic resonance imaging (MRI), and cardiac catheterization. However, these modalities make little impact on delineation of pathophysiology at the tissue level. The advantage of tagged cine-MRI technique is that the twisting motion of the ventricle, referred to as torsion, can be measured noninvasively, reflecting the underlying shearing motion of individual planes of myofibrils that generate wall thickening and ventricular ejection. Thus we sought to determine whether the mechanism of ventricular ejection, as measured by torsion, was the same in both humans and mice. Nine mice and ten healthy humans were studied with tagged cine-MRI. The magnitude and systolic time course of ventricular torsion were equivalent in mouse and humans, when normalized for heart rate and ventricular length. The end-systolic torsion angle was 12.7 +/- 1.7 degrees in humans vs. 2.0 +/- 1.5 degrees in mice unnormalized and 1.9 +/- 0.3 degrees /cm vs. 2.7 +/- 2.3 degrees /cm when normalized for ventricular length). These results support the premise that ventricular torsion may be a uniform measure of normal ventricular ejection across mammalian species and heart sizes.

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An unusual strategy for performing magnetic resonance experiments is demonstrated. Instead of employing conventional radiofrequency transmitter fields to perturb spin state populations away from equilibrium, as is the basis of most magnetic resonance spectrometers today, technological advances now make possible fast switching of the magnetic field orientation to achieve the same effect. This is demonstrated with an electron spin resonance experiment where the magnetic field is switched 90 degrees nonadiabatically with a dead time of a few tens of nanoseconds and an electron free induction decay observed.

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Using magnetic resonance methods and a clinically relevant rodent model of sepsis, we have made in vivo measurements of increased intracellular calcium in a pathologic state in the CNS. The intracellular calcium concentration was increased nearly twofold in septic rat brain compared with controls (p < 0.0001). This result, in a fully intact functioning mammalian system, ties together a previous spectrum of indirect evidence from numerous laboratories suggesting an important role for elevated intracellular calcium in sepsis. In addition, levels of the proinflammatory cytokine tumor necrosis factor-a were elevated threefold in septic rat brain (p < 0.02), and electron microscopic examination revealed scattered injury in approximately 0.25% of glial cells. These findings are discussed in light of the current understanding of the pathophysiology of sepsis.

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