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Biomedical subjects

B D Ross

Publications and source records attributed to B D Ross.

196 records · Page 11Linked to original sources
PubMedDate not supplied

The biochemistry of living tissues: examination by MRS.

MRS defines the molecular state of water, the chemical environment of cells and tissues and the qualitative and quantitative state of intermediary metabolism. Because cancer has disordered physiology, obvious differences in MR spectra can be observed. However, the detailed understanding of the biochemistry of cancer will also emerge from careful, quantitative multinuclear MR. The intermediary metabolism of ATP, the Krebs cycle, creatine, cholines and lipids, is discussed. Finally, the biochemical challenge posed by oncogenes may be amenable to MR analyses.

Body Water↗
PubMedDate not supplied

A 15N NMR study of in vivo cerebral glutamine synthesis in hyperammonemic rats.

Rats were given intravenous 15NH4+ infusion at a rate of 2.2 or 5.5 mmol/h/kg body wt to induce hyperammonemia, as animal models of hepatic encephalopathy. Its effect on cerebral amino acid metabolism was studied in vivo by 15N NMR spectroscopy at 20.27 MHz for 15N. Cerebral [gamma-15N]glutamine (present at a tissue concentration of 4-9 mumol/g) and [alpha-15N]glutamate/glutamine (6 mumol/g) were clearly observed in living rats within 9-18 min. In portacaval-shunted rats, final cerebral [gamma-15N]glutamine concentrations were higher than those in controls after the same infusion period, presumably because decreased 15NH4+ removal in the liver led to increased 15NH3 diffusion into the astrocytes. In control rats, cerebral [gamma-15N]glutamine pool increased at a rate of 1.7 mumol/h/g when blood ammonia concentration was 0.8 mM. 15N enrichment in gamma-15N was 71%. From these observations, in vivo activity of glutamine synthetase in rat brain was estimated to be 3.5 mumol/h/g. Comparison with reported optimum in vitro activity suggests that in situ concentrations of some substrates and cofactors limit the activity of glutamine synthetase in vivo.

Ammonia↗
PubMedDate not supplied

Applications of magnetic resonance in model systems: cancer therapeutics.

The lack of information regarding the metabolism and pathophysiology of individual tumors limits, in part, both the development of new anti-cancer therapies and the optimal implementation of currently available treatments. Magnetic resonance [MR, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electron paramagnetic resonance (EPR)] provides a powerful tool to assess many aspects of tumor metabolism and pathophysiology. Moreover, since this information can be obtained nondestructively, pre-clinical results from cellular or animal models are often easily translated into the clinic. This review presents selected examples of how MR has been used to identify metabolic changes associated with apoptosis, detect therapeutic response prior to a change in tumor volume, optimize the combination of metabolic inhibitors with chemotherapy and/or radiation, characterize and exploit the influence of tumor pH on the effectiveness of chemotherapy, characterize tumor reoxygenation and the effects of modifiers of tumor oxygenation in individual tumors, image transgene expression and assess the efficacy of gene therapy. These examples provide an overview of several of the areas in which cellular and animal model studies using MR have contributed to our understanding of the effects of treatment on tumor metabolism and pathophysiology and the importance of tumor metabolism and pathophysiology as determinants of therapeutic response.

Animals↗
PubMedDate not supplied

Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging.

Current assessment of orthotopic tumor models in animals utilizes survival as the primary therapeutic end point. In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating antineoplastic therapies. Using human tumor cell lines constitutively expressing luciferase, the kinetics of tumor growth and response to therapy have been assessed in intraperitoneal, and subcutaneous, and intravascular cancer models. However, use of this approach for evaluating orthotopic tumor models has not been demonstrated. In this report, the ability of BLI to noninvasively quantitate the growth and therapeutic-induced cell kill of orthotopic rat brain tumors derived from 9L gliosarcoma cells genetically engineered to stably express firefly luciferase (9LLuc) was investigated. Intracerebral tumor burden was monitored over time by quantitation of photon emission and tumor volume using a cryogenically cooled CCD camera and magnetic resonance imaging (MRI), respectively. There was excellent correlation (r=0.91) between detected photons and tumor volume. A quantitative comparison of tumor cell kill determined from serial MRI volume measurements and BLI photon counts following 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment revealed that both imaging modalities yielded statistically similar cell kill values (P=.951). These results provide direct validation of BLI imaging as a powerful and quantitative tool for the assessment of antineoplastic therapies in living animals.

Animals↗
PubMedDate not supplied

Clinical magnetic susceptibility mapping of the brain.

A field mapping technique was used to detect changes in the local magnetic field in 14 tumors, five hematomas, one lacunar infarct, and two cases of multiple sclerosis. These changes were attributed to variations in the tissue susceptibility. A partial or complete rim of changed susceptibility was detected at the margin of five of the tumors and localized changes were seen within two of the tumors. All five hematomas displayed susceptibility effects. These were seen at the rim of the hematoma in all cases but central effects were also seen in four cases. One area of probable lacunar infarction also displayed susceptibility effects. The effects described may be due to the paramagnetic contribution of species such as deoxyhemoglobin, methemoglobin, free ferric iron, hemosiderin, and other breakdown products of blood. Local field inhomogeneities due to changes in tissue susceptibility have implications for magnetic resonance (MR) image interpretation and the performance of MR spectroscopy.

Brain Diseases↗
PubMedDate not supplied

Clinical use of rapid T2 weighted partial saturation sequences in MR imaging.

Rapid T2 dependent field echo [partial saturation (PS)] sequences were used in 38 patients with brain tumors, intracerebral hematomas, and cerebral infarction as well as other neurological and abdominal disease. Reduction in the radiofrequency excitation angle (alpha) from 90 to 30 degrees produced an increase in lesion contrast as did change of echo time (TE) from 33 to 59 or 120 ms using repetition time (TR) values in the range of 120-500 ms. The PS sequence showing most lesion contrast was compared with conventional spin echo (SE 1,500/80 and SE 1,500/120) and inversion recovery (IR 1,500/500/44 and IR 1,500/100/44) sequences. Although PS sequences with TE = 39 ms were usually inferior to conventional SE sequences, those with TE = 59 or 120 ms were comparable and in some cases (particularly hematomas) superior. The PS sequences with alpha of approximately 30 degrees, TR of 80-250 ms, and TE of 60-120 ms offer considerable savings in time compared with conventional sequences although more work will be required to explore the limits of this approach and to optimize sequences at different field strengths.

Brain Diseases↗
PubMedDate not supplied

Metabolic response of glioblastoma to adoptive immunotherapy: detection by phosphorus MR spectroscopy.

In a patient with cerebral glioblastoma, metabolic disturbances were detected within the tumor and in the surrounding brain. Within the volume occupied by the tumor, phosphocreatine (PCr)/adenosine triphosphate was reduced and inorganic phosphate/PCr elevated, indicative of tissue necrosis. Loss of total 31P signal was consistent with reduced metabolite content within the area of tumor defined by CT and magnetic resonance (MR). These studies were accomplished with 31P MR spectroscopy at 2 T, using a volume head coil and the technique of two-dimensional phase-encoding to map regional metabolism across the entire cerebral cortex in voxels of 30 cm3. Using the same method, only minor variations in 31P metabolism were noted in six normal controls. Treatment with locally placed Interleukin-2 activated lymphocytes resulted in changes in both MR and 31P MR spectroscopy in the region of the tumor.

Brain Neoplasms↗
PubMedDate not supplied

Direct 31P imaging in human limb and brain.

OBJECTIVE: This article describes two methods for direct imaging of the 31P-metabolites phosphocreatine (PCr) and inorganic phosphate (Pi) and their application in human brain and muscle. MATERIALS AND METHODS: All studies were performed on a 1.5 T whole-body GE Signa scanner, using bird cage resonators double-tuned to 31P and 1H. The pulse sequence was based on a multiple slice, multiple echo imaging sequence. Selection of the PCr signal was achieved either by selective excitation or by the extensive chemical shift artifact in read direction. Examinations were done in two diabetic patients, in four patients with cerebral neoplasms, and in several healthy subjects. RESULTS: In calf muscle, images showed uniform distribution of PCr in normal muscle; deficits corresponded to bony structures and neurovascular bundles. Repeated exercise (dorsiflexion of the foot) led to selective loss of PCr in the anterior muscle compartment. A simultaneous increase in Pi appeared as a spatially distinct map. Diabetic patients showed more severe changes of PCr distribution in the calf muscle at rest and during much milder exercise. Direct imaging in the human brain with chemical shift selective excitation was completed in 5-30 min. In normal cerebral cortex, PCr was uniformly distributed around deficits marking the lateral ventricles. Tumors exhibiting moderate to severe depletion of PCr appeared as well defined deficits in the PCr image. CONCLUSION: Direct imaging of PCr and Pi, with or without selective excitation of PCr, was effective in the human brain and limb. The methods described should lead to greatly improved fast phosphorus imaging. Clinical utility in peripheral ischemia and in localized energy deficits in the brain of patients with tumor, stroke, and other pathologies is anticipated.

Aged↗
PubMedDate not supplied

Added value of automated clinical proton MR spectroscopy of the brain.

OBJECTIVE: A trial was conducted to establish the added diagnostic value of an automated proton MR spectroscopy (MRS) examination (PROBE). MATERIALS AND METHODS: The PROBE and MRS were compared for metabolite ratios of normal controls and 21 patients. In addition, PROBE was performed in either the occipital cortex (gray matter) or the parietal cortex (white matter) or, more rarely, within the confines of a focal lesion identified on MRI, using a GE Signa 1.5 T whole-body scanner, in 112 patients undergoing routine brain MRI. The trial was conducted in three different MR centers to establish percentage of positive findings with MRI vs. MRI plus MRS. RESULTS: Cerebral metabolite ratios (N-acetylaspartate/creatine, choline/creatine, myo-inositol/creatine) obtained by PROBE and MRS were similar. Metabolite profiles in dementia, head trauma, herpes encephalitis, hepatic and hypoxic encephalopathy, stroke, and tumor were identified using PROBE. The PROBE technique increased the number of positive findings ("added value") achieved by MRI; the added value was 28, 21, and 93% for the three trial sites. CONCLUSION: With only minor variations, PROBE reproduces the cerebral metabolite patterns obtained with MRS. It significantly increases the diagnostic yield of routine neuroimaging and might be incorporated as a standard sequence in a cost-effective manner.

Adult↗
PubMedDate not supplied

Short TE proton MRS and neurofibromatosis type 1 intracranial lesions.

PURPOSE: The intracranial lesions of neurofibromatosis type 1(NF-1) have variable pathology and growth based on molecular genetics. Because of this variable pathology and growth, the lesions are followed by sequential MRI. Our hypothesis was that MR spectroscopy (MRS) could provide a noninvasive neurochemical biopsy of NF-1 lesions, thereby distinguishing the different lesions, monitoring their variable growth, and having added value when compared with MRI. METHOD: Nineteen patients fulfilling the National Institutes of Health criteria for NF-1 were followed with sequential MRI and short TE proton MRS. MRI monitored the lesions by observing the area of prolonged T2, mass effect, and degree of enhancement. MRS monitored the lesions by following the level of neurons, cellularity, and a by-product of the inositol signaling pathway. A comparison was made between the MRI and MRS findings to determine if MRS provided added value. Sixty-nine spectra were obtained in 24 resions. RESULTS: MRI was able to identify hamartomas, gliomas, and indeterminate lesions. MRS was able to distinguish three distinct spectra when compared with the cellularity of normal deep white matter (DWM): a hamartoma spectrum with a choline/creatine (CHO/CRE) ratio below 1.5, a transitional spectrum with a CHO/CRE ratio above 1.5 and below 2.0, and a glioma spectrum with a CHO/CRE ratio above 2.0. On comparing MRS and MRI, MRS provided added value by identifying changes in cellularity while MR images were stable, identifying spectra that could distinguish hamartomas from gliomas, and identifying a transitional spectrum that could progress or regress into glioma or hamartoma spectrum. CONCLUSION: MRS was able to identify three distinct spectra in NF-1 lesions when compared with the cellularity of normal DWM, thereby providing a neurochemical means to characterize lesions.

Adolescent↗
PubMedDate not supplied

Short-echo time proton MR spectroscopy in the presence of gadolinium.

PURPOSE: The purpose of this work was to quantify the impact of contrast agents on short-TE single-voxel 1H MR spectroscopy (MRS) diagnosis of recurrent brain tumors. METHOD: Short-TE 1H MRS was performed in 49 patients with biopsy-proven brain tumors and 14 control subjects. Eight patients (nine paired exams) were examined before and after administration of Gd-DTPA (interval approximately 5-7 min). RESULTS: Tumor spectra showed increased choline/creatine ratio (Cho/Cr; p < 0.009) and Cho concentrations (p < 0.02). Receiver operator characteristic for Cho/Cr = 0.93 differentiated 100% of tumors from control in the absence or presence of contrast agent. Repeated 1H MRS varied <3%. Cho T2 was significantly longer than Cr T2 (p < 0.02). CONCLUSION: Proton MRS with TE of 30 ms may safely be used in combined contrast-enhanced MRI/MRS protocols. Further study is required with long-TE MRS because of the prolonged T2 of Cho.

Adult↗
PubMedDate not supplied

Phosphate energy metabolism during domoic acid-induced seizures.

The effect of domoic acid-induced seizure activity on energy metabolism and on brain pH in mice was studied by continuous EEG recording and in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Mice were divided into ventilated (n = 6) and nonventilated (n = 7) groups. Baseline EEG was 0.1-mV amplitude with frequence of > 30-Hz and of 4-5 Hz. After intraperitoneal (i.p.) administration of domoic acid (6 mg/kg), electrographic spikes appeared at increasing frequency, progressing to high-amplitude (0.1-0.8 mV) continuous seizure activity (status epilepticus). In ventilated mice, the [31P]NMR spectra showed that high-energy phosphate levels and tissue pH did not change after domoic acid administration or during the intervals of spiking or status epilepticus. Nonventilated mice showed periods of EEG suppression accompanied by decreases in the levels of high-energy phosphate metabolites and in pH, corresponding to episodic respiratory suppression during the spiking interval. In all animals, status epilepticus was followed by a marked decrease in EEG amplitude that progressed rapidly to isoelectric silence. [31P]NMR spectra obtained after this were indicative of total energy failure and tissue acidosis. In a separate group of ventilated mice (n = 4), domoic acid-induced status epilepticus was accompanied initially by an increase in mean arterial blood pressure (MAP) that slowly returned to baseline level. Isoelectric silence was accompanied by a decrease in MAP to 75 +/- 8 mm Hg. These experiments suggest that domoic acid-induced seizures are not accompanied by an increase in substrate demand that exceeds supply.

Adenosine Triphosphate↗
PubMedDate not supplied

Early metabolic effects of hypotension on rat kidney.

Saturation-transfer phosphorus nuclear magnetic resonance (STNMR) has been applied to the rat kidney in vivo. The rate of renal metabolism determined by this method compares favorably with the renal oxygen consumption, assuming an ATP:oxygen ratio of 2. Hemorrhagic hypotension resulted in a 20% fall in renal blood flow and a significant fall in oxygen consumption. The rate of renal metabolism fell by 50%. This rate of ATP synthesis was below that required to maintain a normal [ATP], but renal [Pi] was not increased. When renal perfusion was reduced by 60%, intrarenal [Pi] rose. When [P1] was elevated, the method os STNMR no longer gave a reliable measure of the rate ATP synthesis, indicating that this new Pi pool was not in rapid chemical exchange with ATP. STNMR represents a useful noninvasive means of monitoring renal metabolic rate, with limitations due to insensitivity and the existence of multiple pools of intrarenal Pi.

Adenosine Diphosphate↗