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In vivo P-31-MR-spectroscopy of focal hepatic lesions. Effectiveness of tumor detection in clinical practice and experimental studies of surface coil characteristics and localization technique.

RATIONALE AND OBJECTIVES: The influence of partial tumor sampling in a volume of interest (VOI) on the ratios of phosphorus metabolites was examined by localized phosphorus magnetic resonance spectroscopy (P-31-MRS). Experiments were performed to investigate the characteristics of the surface coil used and precession of spatial localization. METHODS: A total of 24 patients with liver metastases and 20 volunteers were studied by P-31-MRS. Patients were divided in two groups: VOI < 50% (n = 8) and VOI > 50% (n = 16) occupied by tumor. For evaluation of the surface coil and localization method (image selected in vivo spectroscopy), phantom studies were performed. RESULTS: Superficial focal liver tumors were detectable with a surface coil at a distance within the coil radius. The image selected in vivo spectroscopy permitted the study of phosphorus metabolism in a defined VOI, phosphomonoester/beta-adenosine triphosphate and phosphodiester/beta-adenosine triphosphate were elevated significantly in spectra of both patient groups. CONCLUSIONS: Detection of small tumor volumes within a VOI filled by less than 50% of the tumor is possible, with results statistically different from that in normal volunteers.

Adult↗

In situ Raman microspectroscopic identification and localization of carotenoids: approach to monitoring of UV-B irradiation stress on Antarctic fungus.

The in situ Raman microspectroscopic properties of an Antarctic fungus are investigated to assess the nature and the spatial localization of the main chromophores and to study their spectral changes under enhanced UV-B irradiation. The Raman spectroscopic features of spores in situ are consistent with those of carotenoid-like pigments. In particular, the Raman shifts seem to be related either to the frequency modes of long conjugated double-bond carotenoids or to protein bound beta-carotene. The spectroscopic analysis at different spore depths clearly shows the strongest Raman signal arises from cell wall and membrane structures. The intensity of such a signal shows a drastic reduction upon UV-B irradiation without any significant frequency change. The use of Raman microspectroscopy for nondestructively monitoring the UV-B effects on Arthrobotrys ferox spores is also discussed.

Antarctic Regions↗

Partial wavelet encoding: a new approach for accelerating temporal resolution in contrast-enhanced MR imaging.

We propose a new approach using wavelet encoding to improve temporal resolution in contrast-enhanced magnetic resonance (MR) imaging. Exploiting the unique property of wavelets localized in space and frequency, we construct an efficient encoding scheme to capture signal changes due to contrast agent uptake, which in general is spatially localized with low- and mid-range frequency components. On the basis of space-frequency analysis, we describe mathematical formulations of our method and discuss its theoretical advantages over Fourier-based phase-encoding methods (the keyhole and reduced-encoding imaging by generalized-series reconstruction [RIGR] techniques). The results obtained in computer simulations and a phantom study demonstrate the feasibility and practical advantages of our approach.

Computer Simulation↗

Fast proton spectroscopic imaging using steady-state free precession methods.

Various pulse sequences for fast proton spectroscopic imaging (SI) using the steady-state free precession (SSFP) condition are proposed. The sequences use either only the FID-like signal S(1), only the echo-like signal S(2), or both signals in separate but adjacent acquisition windows. As in SSFP imaging, S(1) and S(2) are separated by spoiler gradients. RF excitation is performed by slice-selective or chemical shift-selective pulses. The signals are detected in absence of a B(0) gradient. Spatial localization is achieved by phase-encoding gradients which are applied prior to and rewound after each signal acquisition. Measurements with 2D or 3D spatial resolution were performed at 4.7 T on phantoms and healthy rat brain in vivo allowing the detection of uncoupled and J-coupled spins. The main advantages of SSFP based SI are the short minimum total measurement time (T(min)) and the high signal-to-noise ratio per unit measurement time (SNR(t)). The methods are of particular interest at higher magnetic field strength B(0), as TR can be reduced with increasing B(0) leading to a reduced T(min) and an increased SNR(t). Drawbacks consist of the limited spectral resolution, particularly at lower B(0), and the dependence of the signal intensities on T(1) and T(2). Further improvements are discussed including optimized data processing and signal detection under oscillating B(0) gradients leading to a further reduction in T(min).

Animals↗

Detection of tumor response to radiation therapy by in vivo proton MR spectroscopy.

PURPOSE: These studies were performed to investigate the effects of radiation on levels of metabolites such as lactate and choline compounds detected by 1H magnetic resonance spectroscopy (MRS). The purpose was to determine the ability of spatially localized 1H MRS to detect tumor response to radiation therapy. METHODS AND MATERIALS: Proton spectroscopic images were obtained from RIF-1 tumors with voxel spatial resolutions of 8-16 mm3 before and at 24 and 48 h following 2, 4, and 20 Gy of gamma-radiation. RESULTS: Lactate levels decreased significantly for all doses by 48 h. Tumors irradiated with 2 and 4 Gy showed a significant decrease by 48 h, but not at 24 h. A group of sham-irradiated control animals demonstrated no significant changes in lactate over the period of observation. CONCLUSIONS: Changes in lactate observed in this study are consistent with an increased blood flow observed in previous studies (15) in the same tumor model following 20 Gy X-irradiation. These studies point to the feasibility of detecting response to clinical doses of fractionated radiation therapy by 1H MRS.

Hydrogen↗

Ran localizes around the microtubule spindle in vivo during mitosis in Drosophila embryos.

The GTPase Ran regulates multiple cellular functions throughout the cell cycle, including nucleocytoplasmic transport, nuclear membrane assembly, and spindle assembly. Ran mediates spindle assembly by affecting multiple spindle assembly pathways: microtubule dynamics, microtubule motor activity, and spindle pole assembly. Ran is predicted to facilitate spindle assembly by remaining in the GTP-bound state around the chromatin in mitosis. Here, we directly test the central tenet of this hypothesis in vivo by determining the cellular localization of Ran pathway components in Drosophila embryos. We find that, during mitosis, RCC1, the nucleotide exchange factor for Ran, is associated with chromatin, while Ran and RanL43E, an allele locked in the GTP-bound state, localize around the spindle. In contrast, nuclear proteins redistribute throughout the embryo upon nuclear envelope breakdown (NEB). Thus, in vivo RanGTP has the correct spatial localization within the cell to modulate spindle assembly.

Animals↗

Exploring the local conformational space of a membrane protein by site-directed spin labeling.

Molecular modeling based on a hybrid evolutionary optimization and an information condensation algorithm, called GHOST, of spin label ESR spectra was applied to study the structure and dynamics of membrane proteins. The new method is capable of providing detailed molecular information about the conformational space of the spin-labeled segment of the protein in a membrane system. The method is applied to spin-labeled bacteriophage M13 major coat protein, which is used as a model membrane protein. Single cysteine mutants of the coat protein were labeled with nitroxide spin labels and incorporated in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers. The new computational method allows us to monitor distributions of local spatial constraints and molecular mobility, in addition to information about the location of the protein in a membrane. Furthermore, the results suggest that different local conformations may coexist in the membrane protein. The knowledge of different local conformations may help us to better understand the function-structure relationship of membrane proteins.

Algorithms↗

Decoding the neural substrates of reward-related decision making with functional MRI.

Although previous studies have implicated a diverse set of brain regions in reward-related decision making, it is not yet known which of these regions contain information that directly reflects a decision. Here, we measured brain activity using functional MRI in a group of subjects while they performed a simple reward-based decision-making task: probabilistic reversal-learning. We recorded brain activity from nine distinct regions of interest previously implicated in decision making and separated out local spatially distributed signals in each region from global differences in signal. Using a multivariate analysis approach, we determined the extent to which global and local signals could be used to decode subjects' subsequent behavioral choice, based on their brain activity on the preceding trial. We found that subjects' decisions could be decoded to a high level of accuracy on the basis of both local and global signals even before they were required to make a choice, and even before they knew which physical action would be required. Furthermore, the combined signals from three specific brain areas (anterior cingulate cortex, medial prefrontal cortex, and ventral striatum) were found to provide all of the information sufficient to decode subjects' decisions out of all of the regions we studied. These findings implicate a specific network of regions in encoding information relevant to subsequent behavioral choice.

Adult↗

Enhancement of inferior temporal neurons during visual discrimination.

1. Previous results have shown that spatially directed attention enhances the stimulus-elicited responses of neurons in some areas of the brain. In the inferior temporal (IT) cortex, however, directing attention toward a stimulus mildly inhibits the responses of the neurons. Inferior temporal cortex is involved in pattern discrimination, but not spatial localization. If enhancement signifies that a neuron is participating in the function for which that part of cortex is responsible, then pattern discrimination, not spatial attention, should enhance responses of IT neurons. The influence of pattern discrimination behavior on the responses of IT neurons was therefore compared with previously reported suppressive influences of both spatial attention and the fixation point. 2. Single IT neurons were recorded from two monkeys while they performed each of five tasks. One task required the monkey to make a pattern discrimination between a bar and a square of light. In the other four tasks the same bar of light appeared, but the focus of spatial attention could differ, and the fixation point could be present or absent. Either attention to (without discrimination of) the bar stimulus or the presence of the fixation point attenuated responses slightly. These two suppressive influences produced a greater attenuation when both were present. 3. The visual conditions and motor requirements when the bar stimulus appeared in the discrimination task were identical to those of the trials in the stimulus attention task. However, one-half of the responsive neurons showed significantly stronger responses to the bar stimulus when it appeared in the discrimination task than when it appeared in the stimulus attention task. For most of these neurons, discrimination just overcame the combined effect of the two suppressive influences. For six other neurons, the response strength was significantly greater during the discrimination task than during any other task. 4. The monkeys achieved an overall correct performance rate of 90% in both the discrimination and stimulus attention tasks. To achieve this performance in the discrimination task they adopted a strategy in which they performed one trial type, bar stimulus attention trials, perfectly (100%) and the other trial type, pattern trials, relatively poorly (84% correct).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Discrimination of compound gratings: spatial-frequency channels or local features?

Models based on spatial-frequency channels and local features provide alternative explanations for suprathreshold pattern discrimination. We compared psychophysical discrimination data with the predictions of the Wilson and Gelb channel model and three local-feature models. The features were peak-valley local contrast, peak-peak local contrast, and luminance gradients. We measured visual sensitivity for discriminating compound gratings (F + 3F or F + 5F, in peaks-add or peaks-subtract phases) whose component contrasts were yoked together so that a contrast increment in one component was accompanied by an equal decrement in the other. The Wilson and Gelb model accounted for the results with peaks-add gratings, but failed to predict those with peaks-subtract gratings. None of the local-feature models explained the results by themselves. Most of the data fell close to an envelope composed of the lowest thresholds of the three feature-detector models, although there were important exceptions. Our findings are consistent with the view that suprathreshold pattern discrimination is mediated by mechanisms responsive to spatially localized features and that more than one type of feature is used.

Computer Simulation↗

Surface coil spectroscopic imaging: time and spatial evolution of lactate production following fluid percussion brain injury.

Detailed temporal and spatial distributions of lactate production are presented for graded fluid-percussion brain injury in the rat. A one-dimensional proton spin-echo spectroscopic imaging (1D SESI) technique, performed with a surface coil, is presented and evaluated. This technique, which represents a practical compromise, provides spatially localized proton nuclear magnetic resonance (NMR) brain spectra from a series of small voxels (less than 0.15 cm3) in less than 10 min, thus enabling both spatial and temporal monitoring of lactate production. These high-resolution lactate maps are correlated with hyperintense regions observed in T2-weighted images taken 10 h after impact, which, in turn, correlate with histology. The data demonstrate that, following severe trauma there is delayed production and propagation of lactate to regions of the brain that are remote from the trauma site. The extent of lactate production depends on the severity of impact. More significantly, the data show that following severe trauma, local lactate concentrations exceed 15 mumol/g, the concentration that has been claimed as the threshold for brain injury. Therefore high lactate levels cannot be ruled out a priori as a possible factor in brain injury following severe head trauma.

Animals↗

Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves.

1. Seventy-one C polymodal nociceptors supplying glabrous and hairy skin in limbs of awake human volunteers were identified on the basis of cutaneous stimulus-response characteristics recorded intraneurally by microneurography (MNG). The large majority of such units were primarily detected during intraneural microstimulation (INMS) on the basis of subjective quality and cutaneous localization of evoked painful sensation. Electrophysiological studies were supplemented with rigorous psychophysical testing during microstimulation delivered at intraneural C recording sites. 2. The conduction velocity of single C nociceptor units could be shown to become transiently slowed following repetitive INMS at threshold intensity for conscious sensation. Such 'marking' witnessed that particular C units, identified by recording, had been effectively activated during INMS and psychophysical testing. 3. Cognitive attributes of sensations evoked from C recording sites by INMS at threshold intensity for perception were estimated psychophysically for subjective quality, temporal attributes and localized projection. There was remarkable matching of physiological unit type (C polymodal nociceptor) with subjective quality of evoked sensation (dull or burning pain). Further, there was remarkable spatial matching of receptive field of given C nociceptors with projected field of the pain sensation evoked from the C recording site by INMS delivered at threshold intensity for conscious sensation. 4. Dissociated A nerve fibre blocks caused by compression-ischaemia did not abolish the sensation of burning pain projected to hairy skin, evoked by INMS delivered at C recording sites. 5. While the double matching of (a) subjective quality and spatial localization with (b) objective physiological unitary type and receptor location, coupled with the results of A blocks, provide evidence that C nociceptor fibres can be fairly selectively activated during INMS, the results also attest that C polymodal nociceptors from human skin evoke delayed dull or burning pain, accurately projected to a defined locus in skin, even after spatial summation is reduced to a minimum.

Adult↗

VEGF-initiated blood-retinal barrier breakdown in early diabetes.

PURPOSE: The objectives of this study were to (1) determine whether endogenous vascular endothelial growth factor (VEGF) triggers diabetic blood-retinal barrier breakdown, and (2) identify the site as well as phenotype of the hyperpermeable diabetic retinal vessels. METHODS: Retinal VEGF mRNA levels were quantified in 1-week diabetic rats using the RNase protection assay. VEGF bioactivity was blocked via the systemic administration of a highly specific VEGF-neutralizing soluble Flt/F(c) construct (VEGF TrapA(40)). An inactive IL6 receptor/F(c) construct (IL6R Trap) was used as an isotype control. Blood-retinal barrier breakdown was quantified using the Evans blue technique and was spatially localized with fluorescent microspheres. RESULTS: Retinal VEGF mRNA levels in 1-week diabetic animals were 3.2-fold higher than in nondiabetic controls (P < 0.0001). Similarly, retinal vascular permeability in 8-day diabetic animals was 1.8-fold higher than in normal nondiabetic controls (P < 0.05). Diabetes-induced blood-retinal barrier breakdown was dose-dependently inhibited with VEGF TrapA(40), with 25 mg/kg producing complete inhibition of the diabetes-induced increases (P < 0.05). Blood-retinal barrier breakdown in diabetic animals treated with solvent alone or IL6R Trap did not differ significantly from untreated diabetic animals (P > 0.05). Spatially, early blood-retinal barrier breakdown was localized to the retinal venules and capillaries of the superficial retinal vasculature. CONCLUSIONS: Early blood-retinal barrier breakdown in experimental diabetes is VEGF dependent and is restricted, in part, to the venules and capillaries of the superficial inner retinal vasculature. VEGF inhibition should prove a useful therapeutic approach in the treatment of early diabetic blood-retinal barrier breakdown.

Animals↗

Developmental expression of the inositol 1,4,5-trisphosphate receptor and localization of inositol 1,4,5-trisphosphate during early embryogenesis in Xenopus laevis.

To study the role of inositol 1,4,5-trisphosphate (IP3) receptors during early embryogenesis in Xenopus, we examined the temporal-spatial localization of Xenopus IP3 receptor (XIP3R). XIP3R protein is enriched in the animal hemisphere of early cleavage stage embryos and becomes localized in the ectoderm and involuted mesoderm in gastrula stage embryos. Up to tailbud stages, expression of XIP3R is observed in the mesodermal tissues and in most subregions of the central nervous system. A quantitative analysis of endogenous IP3 mass during normal early embryogenesis revealed an increase in IP3 mass first observed at early gastrula stage of 10.5 with an enrichment in the ectoderm throughout the gastrula stages, implying a potential role during gastrulation.

Animals↗

Spatio-temporal models with errors in covariates: mapping Ohio lung cancer mortality.

In estimating spatial disease patterns, as well as in related assessments of environmental equity, regional morbidity and mortality rate maps are widely used. Hierarchical Bayes methods are increasingly popular tools for creating such maps, since they permit smoothing of the fitted rates toward spatially local mean values, with more unreliable estimates (those arising in low-population regions) receiving more smoothing. In this paper we blend methods for spatial-temporal mapping with those for handling errors in covariates in a single hierarchical model framework. Estimated posterior distributions for the resulting highly-parameterized models are obtained via Markov chain Monte Carlo (MCMC) methods, which also play a key role in our approach to model evaluation and selection. We apply our approach to a data set of county-specific lung cancer rates in the state of Ohio during the period 1968-1988. Our model uses age-adjusted death rates, and incorporates recent information regarding smoking prevalence, population density, and the socio-economic status of the counties. This information is critical to understanding the role played by a certain depleted uranium fuel processing facility on the elevated lung cancer rates in the counties that neighbour it.

Adolescent↗

Local feature analysis: a statistical theory for reproducible essential dynamics of large macromolecules.

Multivariate statistical methods are widely used to extract functional collective motions from macromolecular molecular dynamics (MD) simulations. In principal component analysis (PCA), a covariance matrix of positional fluctuations is diagonalized to obtain orthogonal eigenvectors and corresponding eigenvalues. The first few eigenvectors usually correspond to collective modes that approximate the functional motions in the protein. However, PCA representations are globally coherent by definition and, for a large biomolecular system, do not converge on the time scales accessible to MD. Also, the forced orthogonalization of modes leads to complex dependencies that are not necessarily consistent with the symmetry of biological macromolecules and assemblies. Here, we describe for the first time the application of local feature analysis (LFA) to construct a topographic representation of functional dynamics in terms of local features. The LFA representations are low dimensional, and like PCA provide a reduced basis set for collective motions, but they are sparsely distributed and spatially localized. This yields a more reliable assignment of essential dynamics modes across different MD time windows. Also, the intrinsic dynamics of local domains is more extensively sampled than that of globally coherent PCA modes.

Bacteriophage T4↗

Cellular location of insulin-triggered signals and implications for glucose uptake.

Insulin stimulation of glucose uptake into muscle and fat cells requires movement of GLUT4-containing vesicles from intracellular compartments to the plasma membrane. Accordingly, insulin-derived signals must arrive at and be recognized by the appropriate intracellular GLUT4 pools. We describe the insulin signals participating in GLUT4 translocation, and review evidence that they are recruited to intracellular membranes in conjunction with cytoskeletal elements. Such segregation may facilitate the encounter between signals and target vesicles. In most animal and cellular models of insulin resistance, insulin-stimulated GLUT4 translocation to the plasma membrane is reduced. Insulin resistance caused by oxidative stress does not affect early insulin signals, rather their intracellular localization is altered. In this and several other insulin-resistant states, insulin-induced actin remodelling is concomitantly diminished. We summarize evidence suggesting that spatial localization of signals is critical for efficient insulin action, and that the cytoskeleton may act as a scaffold to promote efficient translocation of GLUT4 to the cell surface.

Animals↗

Evaluation of gustatory function after third molar removal.

The aim of this study was to determine the severity of taste changes after surgical removal of all four third molars in one session. Taste function in 27 patients was measured before and at 1 month and 6 months after surgery. In every patient all four third molars were removed using local anesthesia and sedation with midazolam and fentanyl. For testing gustatory function, two tests were administered: a whole-mouth, above threshold test and a spatial (localized) taste test. For this purpose, sucrose, NaCl, citric acid and quinine hydrochloride solutions were used. Taste intensity of quinine hydrochloride of the palate was significantly reduced 1 month after surgery (P < 0.05) but recovered and reach to preoperative values 6 months after surgery. The results showed that there were no significant changes in gustatory function after third molar surgery.

Adolescent↗