T1 and T2 relaxometry of monocrystalline iron oxide nanoparticles (MION-46L): theory and experiment.
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Contrast Media↗
Biomedical subjects
R A Brooks
Publications and source records attributed to R A Brooks.
Hepatic hemosiderosis in non-human primates: quantification of liver iron using different field strengths.
Using a non-human primate model of idiopathic hemochromatosis, hemosiderin-induced T2 shortening of the liver was assessed at nine different field strengths over a range of 0.05 to 1.5 Tesla. The 1/T2 values increased linearly with field strength, with all specimens having approximately the same zero-field intercept. The slope of the field increase, termed "field-dependent T2 proton relaxation enhancement (PRE)", appeared to be proportional to the chemically determined tissue iron content, viz. 10.8 s-1T-1(mg Fe/g wet tissue)-1. The correlation between iron content and field-dependent T2 PRE (r = 0.94) was better than the correlation between iron content and 1/T2 values obtained at single field strengths. For livers containing > or = 2 mg Fe/g wet weight, biexponential T2 relaxation behavior emerged at higher field strengths, with the short T2 component (intracellular water) exhibiting a linear dependence of 1/T2 on field, while T2 of the long component (extracellular/sinusoidal water) was nearly field-independent. After maceration of the specimens, all T2 relaxation curves became monoexponential, including those for high iron content at high field strengths. The present data suggest that the use of double-field MR imaging to assess the field-dependent T2 PRE has potential for specific quantification of (liver) tissue iron stores.
Animals↗
The relation between brain iron and NMR relaxation times: an in vitro study.
T1 and T2 relaxation times and iron concentrations were measured in 24 specimens of gray matter from fresh human and monkey brains at magnetic fields from 0.05 to 1.5 Tesla. Three different effects were found that correlate with iron content: a T1-shortening that falls off somewhat at high fields, a T2-shortening that is field-independent and thus important at low fields, and a contribution to 1/T2 that increases linearly with field strength. This linear field dependence has been seen only in ferritin and other ferric oxyhydroxide particles. Our results are in agreement with in vivo MRI studies and are generally consistent with values for ferritin solution, except for differences such as clustering of ferritin in tissue. A cerebral cavernous hemangioma specimen showed similar T2-shortening, but with a 2.7 times larger magnitude, attributed to larger clusters of hemosiderin in macrophages. The dependence on interecho time 2 tau was measured in three brains; 1/T2 increased significantly for tau up to 32 ms, as expected from the size of the ferritin clusters. These findings support the theory that ferritin iron is the primary determinant of MRI contrast in normal gray matter.
Adult↗
T1 and T2 of ferritin solutions: effect of loading factor.
Proton magnetic relaxation times T1 and T2 were measured at field strengths from 0.05 T to 1.5 T in solutions of ferritin with loading factors from 90 to 3600 iron atoms per molecule. 1/T2 increased linearly with field strength, as previously observed, and the slope per unit iron was approximately the same in all samples. This latter finding indicates that the field dependence of T2 may be used as a measure of ferritin-bound iron, regardless of loading factor. A possible explanation is presented, based on the presumed antiferromagnetic structure of the ferritin core and the linear dependence of 1/T2 on core magnetization. A nonzero contribution to 1/T2 in the limit of low field and a contribution to 1/T1 were also found, both of which increase linearly with loading factor for constant protein concentration; these effects represent quantum mechanical dipole-dipole relaxation of water protons either by iron atoms on the surface of the core or by the iron core itself. Finally, the extrapolated intercept at LF = 0 for both 1/T1 and 1/T2 indicates a contribution from a small number of iron ions bound to the protein shell. These results may help in the use of MRI to measure brain iron and possibly even ferritin loading factor.
Animals↗
Determination of spatial patterns of DNA damage and repair in intestinal crypts by multi-cell gel electrophoresis.
We have developed a method to quantitate DNA strand breaks as a measure of DNA damage and repair in intact, isolated intestinal crypts. The assay is a modified form of the single-cell gel electrophoresis or 'comet' assay. By maintaining the spatial relationship between the cells we were able to characterise the repair response and the susceptibility to DNA damage of cells as a function of their position in the crypt. All cells were equally repair competent over the first 30 minutes of the repair of UV-C and gamma-radiation induced lesions. DNA damage was equally distributed following gamma-radiation but following incubation with the topoisomerase II inhibitor etoposide, damage was greater in the lower crypt with an unusual component to the comet tall which was tapered, implying an incremental change in susceptibility by cell position. This tapered component of the comet tail resolved rapidly after removal of etoposide. The pattern of damage produced by hydrogen peroxide was dose dependent with lower doses producing more strand breaks in the base of the crypt-an effect lost at higher doses. The assay has the ability to detect differences between cells in their susceptibility to DNA damage and their subsequent repair response which may vary with their proliferative or differentiative status.
Animals↗
T1 and T2 alterations in the brains of patients with hepatic cirrhosis.
PURPOSE: To determine whether previously reported T1-weighted MR hyperintensities in the brains of patients with hepatic cirrhosis are accompanied by changes in T2. METHODS: We measured T1 and T2 in the brains of 10 patients with chronic liver disease and 7 age-matched healthy volunteers, using classic spin-echo sequences with multiple saturation recovery times and multiple echoes. RESULTS: Both T1 and T2 were shortened in the basal ganglia, cortex, and white matter of the patients, with the greatest shortening in the globus pallidus, where 1/T1 was increased by 0.76 s-1 or 74% and 1/T2 by 1.45 s-1 or 11%. CONCLUSIONS: The T1 changes were accompanied by T2 changes of greater magnitude that were not as visible because T2 is normally much shorter than T1, especially in the globus pallidus.
Adult↗
Magnetic resonance imaging of brain iron in health and disease.
Brain iron is a major contributor to magnetic resonance imaging (MRI) contrast in normal gray matter, and its role in the pathogenesis of different neurological disorders has also become apparent. Non-heme brain iron is present in the brain mainly in the form of ferritin. The unique magnetic properties of ferritin determine different signal changes on both T1- and T2-weighted images, and the T2 relaxation rates have a linear dependence on applied field strength. This finding is typical for ferric oxyhydroxide cores. The resulting T2-shortening also depends on echo-spacing used in the imaging sequence as well as on the water diffusion coefficient and the size of the ferritin cluster. Quantitation of non-heme brain iron by MRI aids in the diagnosis and monitoring of different neurological diseases.
Brain↗
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a potent mutagen in the mouse small intestine.
Mutations in long lived stem cells are critical events in carcinogenesis. The Dlb-1 assay detects intestinal stem cell mutation at the Dlb-1 locus in Dlb-1a/b heterozygous mice by visualizing mutated clones of epithelial cells in situ which do not bind the lectin Dolichos biflorus agglutinin. We have used this assay to show that the food-derived heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent intestinal mutagen when administered either i.p. or p.o. This contrasts with the inactivity of the structurally related mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the assay which we have described previously. Immunocytochemical localization of the P-450 enzyme CYP1A2, which is responsible for the primary activation of these mutagens, shows that in untreated mice it is present in liver hepatocytes and in occasional villus epithelial cells but is absent from the target intestinal stem cell population. In addition, liver microsomes, unlike intestinal microsomes, were able to convert PhIP to the proximate mutagen N-hydroxy-PhIP. CYP1A2 immunoreactivity in beta-napthoflavone-induced animals was elevated in liver hepatocytes and increased to a lesser extent in duodenal villus epithelial cells. Treatment with beta-napthoflavone produced an unexpected 46% decrease in the number of Dlb-1 mutations in response to PhIP. Following treatment with PhIP, there was no difference in the number of Dlb-1 locus mutations between the proximal and distal ends of the small intestine in uninduced animals, indicating that the bile duct is unlikely to be responsible for transport of mutation inducing metabolites of PhIP to the small intestine. Our results demonstrate that metabolic activation of an indirect acting genotoxic agent can occur at a site other than the target tissue, and absence of the enzymes required for activation of a mutagen does not necessarily protect that tissue from its genotoxic effects.
Animals↗
Magnetoferritin. Biomineralization as a novel molecular approach in the design of iron-oxide-based magnetic resonance contrast agents.
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Apoferritins↗
A study of the effects of human blood derivatives and individual growth factors on [3H]thymidine uptake in bovine retinal pericytes and endothelial cells.
Pericytes disappear early, selectively and specifically from retinal capillaries in diabetic microangiopathy, but little is known of their growth and turnover in health and disease. We have studied the effects of human blood derivatives and of a panel of individual growth factors on [3H]thymidine incorporation in bovine retinal pericytes and endothelial cells. Human serum and platelet-rich plasma stimulated incorporation of the nucleotide in a dose-dependent manner in both cell types, and did so more potently than platelet-free plasma. Consistent and significant stimulation of DNA synthesis in pericytes was observed with basic fibroblast growth factor (ED50 = 1.8 x 10(-13) mol/l), acidic fibroblast growth factor (7.4 x 10(-12) mol/l), insulin-like growth factor 1 (8.6 x 10(-10) mol/l), insulin (158 microU/ml) and endothelin-1 (6.1 x 10(-10) mol/l). Transforming growth factor beta 1 inhibited DNA synthesis (ID50 = 3.6 x 10(-10) mol/l) and so did heparin (1.4 x 10(-6) mol/l) and low molecular weight heparin (2.9 x 10(-6) mol/l). Retinal endothelial cells were stimulated by basic fibroblast growth factor (3.2 x 10(-13) mol/l) and acidic fibroblast growth factor (1.3 x 10(-9) mol/l), and inhibited by transforming growth factor beta 1 (1.6 x 10(-12) mol/l). Neither cell type was stimulated by platelet-derived growth factor (A + B chain heterodimer), epidermal growth factor, growth hormone, or nerve growth factor (7S complex). The characteristics and active concentrations of the above growth factors suggest that none is solely responsible for the pericyte mitogenic activity of platelets, serum or plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
T1 and T2 of ferritin at different field strengths: effect on MRI.
Nuclear magnetic relaxation times T1 and T2 were measured in ferritin solutions at field strengths from 0.04 to 1.5 T. T1 was relatively constant, but 1/T2 increased linearly with field strength, in agreement with earlier MRI observations in the monkey brain. This finding supports the theory that ferritin is responsible for T2 shortening in brain nuclei containing iron. The linear dependence of 1/T2 on magnetic field is unique and not explained by present theories of the magnetic properties of ferritin.
Animals↗
Cerebellar diaschisis revisited: pontine hypometabolism and dentate sparing.
A unilateral supratentorial lesion may cause hypometabolism in the contralateral cerebellar hemisphere (crossed cerebellar diaschisis). We analyzed glucose metabolism, measured by PET-FDG, in the posterior fossa in 67 patients (78 PET studies) with primary unilateral supratentorial brain tumors selected for visually obvious metabolic asymmetry in the cerebellar hemispheres. We found that glucose utilization was 17% lower in the contralateral cerebellar cortex (compared with the ipsilateral one), consistent with the selection criterion, and 19% lower in the ipsilateral pons, wherein lie the first order synapses of the corticopontocerebellar pathway. This finding helps to validate the prevalent view that cerebellar diaschisis is due to interruption of afferent input from the corticopontocerebellar pathway. However, glucose metabolism in the contralateral dentate nucleus was relatively preserved--only 2% less than the ipsilateral dentate. This "dentate sparing" suggests preservation of afferent input to the largest of the deep cerebellar nuclei from the Purkinje cells in the cortex, despite interruption of the major excitatory input to the Purkinje cells.
Adolescent↗
PET-fluorodeoxyglucose of cranial and spinal neuromas.
Five patients with eighth nerve, one with ninth nerve and one with cervical neuromas were studied with PET and [18F] fluorodeoxyglucose (FDG). Four of the patients had had surgery prior to the PET study, and six patients had subsequent surgery. All tumors were well-visualized on the PET images. Only one patient with bilateral acoustic neuroma exhibited tumor recurrence or growth after the PET study; these two lesions showed the highest FDG uptakes in the PET studies (tumor-to-cerebellum ratio of 0.93-0.98). All other tumors were relatively hypometabolic (tumor-cerebellum ratios of 0.43-0.65) and showed no tumor growth or recurrence during follow-up periods ranging from 5 to 8 yr. These results suggest that PET-FDG may be of value in the evaluation of cranial and spinal schwannomas.
Adolescent↗
Characterization of release of basic fibroblast growth factor from bovine retinal endothelial cells in monolayer cultures.
Release of basic fibroblast growth factor (bFGF) was investigated in bovine retinal endothelial cells (BREC) maintained in monolayer culture. Confluent cells released bFGF into serum-free culture medium or medium containing 5% serum at rates of up to 105.2 and 61.3 pM/day respectively. bFGF release coincided with a decrease in monolayer cell number and increases in lactate dehydrogenase (LDH) concentration and cells and cell-debris particles in the medium, which suggested that cell damage and lysis were responsible for growth-factor release. Maximum bFGF release at 24 h (230 +/- 10 pM) occurred when the cells were treated with lipopolysaccharide (10 micrograms/ml), which also produced the greatest changes in parameters of cell damage. Sub-confluent cells showed little overt damage at 24 h, but released bFGF (78 +/- 20 pM) along with LDH, indicating that some cell lysis had occurred. Insulin-like growth factor 1 (IGF-1) was also released into serum-free culture medium at a rate of 0.34 nM/day, but not into medium containing serum or when the cells were treated with lipopolysaccharide. This implies that the mechanism of IGF-1 release is different from that of bFGF and is not related to cell damage. Culture medium conditioned by BREC stimulated the proliferation of these cells, as measured by an increase in their incorporation of [methyl-3H]thymidine from 7550 +/- 479 to 10467 +/- 924 d.p.m. These results demonstrate that bFGF is released from damaged BREC and that medium conditioned by these cells can stimulate retinal-endothelial-cell proliferation. This strengthens the case for an involvement of this growth factor in retinal neovascularization.
Animals↗
Computed tomography, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in multiple system atrophy and pure autonomic failure.
We studied 45 patients who had autonomic failure with computed tomography, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose to characterize the neuroimaging features of multiple system atrophy and pure autonomic failure and determine the utility of these techniques in distinguishing multiple system atrophy from pure autonomic failure. There were 30 patients with multiple system atrophy and 15 with pure autonomic failure. In the multiple system atrophy group, eight patients had mainly cerebellar signs, seven extrapyramidal and 15 had combinations of cerebellar and extrapyramidal signs. Cerebellar atrophy on computerized tomography and magnetic resonance imaging, signal hypointensity in the posterolateral putamen on magnetic resonance imaging and a generalized reduction in glucose utilization rate with positron emission tomography with [18F]fluorodeoxyglucose, were the main findings and were seen only in the patients with multiple system atrophy. Decreased glucose utilization (hypometabolism) was most prominent in the cerebellum, brainstem, striatum and frontal and motor cortices. These results indicate clear differences, using neuroimaging studies, between multiple system atrophy and pure autonomic failure.
Atrophy↗
Pituitary microadenomas: a PET study.
Twenty cases of surgically verified pituitary microadenoma (17 with Cushing disease and three with acromegaly) were studied with positron emission tomography (PET) with use of fluorine-18-2-fluorodeoxyglucose (FDG). The diagnostic results were compared with those of other modalities, namely, computed tomography (CT), magnetic resonance (MR) imaging, and, in the cases of Cushing disease, simultaneous bilateral inferior petrosal sinus sampling (SIPS). The PET results showed 12 positive readings and one questionable reading, compared with seven positive readings and one questionable reading for CT (18 cases studied) and 13 positive and two questionable MR imaging readings. PET complemented MR imaging, in the sense that five of the positive PET readings were negative or questionable at MR imaging. PET studies of 20 healthy control subjects showed no false-positive cases, whereas other studies of healthy subjects with contrast material-enhanced CT and MR imaging have yielded, respectively, 20% and 15% positive readings, with findings suggestive of silent or occult adenomas.
Adenoma↗
Role of iron and ferritin in MR imaging of the brain: a study in primates at different field strengths.
The authors measured in vivo signal intensity on magnetic resonance (MR) images and postmortem iron concentrations in the brains of three young and two old rhesus monkeys. T2-weighted MR imaging was done at 0.5, 1.5, 2.0, and 4.7 T. Relative assessment of iron concentration was made from the optical density of brain sections stained with the Perls' method intensified with diaminobenzidine. MR imaging and optical density measurements were made in the centrum semiovale (white matter) and in four gray matter areas: the insular cortex, caudate nucleus, putamen, and globus pallidus, the latter three of which accumulate significant iron deposits with age. High optical density and decreased signal intensity were found in these areas, and the inverse correlation between gray matter/white matter signal ratio and optical density was in good agreement with the theory of T2 shortening caused by diffusion of water through magnetic inhomogeneities. However, the dependence of T2 shortening on field strength was not quadratic, as expected for paramagnetic iron, but instead showed a marked leveling off at higher field strengths. This magnetic "saturation" is explainable by antiferromagnetism and superparamagnetism of the ferritin core and has been observed in ferritin solutions at low temperatures. Similar observations at body temperature are needed before the iron-ferritin explanation for T2 shortening can be considered proved.
Aging↗
On the origin of paramagnetic inhomogeneity effects in blood.
Hydrogen, sodium, and fluorine (added F-) NMR spectra of venous and oxygenated blood were measured. The fluorine resonance was seen as a single peak in both samples, and all three resonances exhibited the same deoxy-oxy shift. Because F- exchanges slowly across the red cell membrane, and because sodium is 95% extracellular, these results suggest that the intra-extracellular field difference delta B is less than 0.1 ppm. A small value of delta B tends to rule out transmembrane exchange as an important contributor to relaxation in MRI of blood and hematomas. However, the broadening of the resonances with deoxygenation, by 0.3-0.4 ppm, indicates that both intra- and extracellular gradients are of comparable and sufficient magnitude to produce the T2-weighted hypointensity seen in clinical magnetic resonance images of hematomas at high fields.
Blood↗