Decreased phosphorus metabolite concentrations and alkalosis in chronic cerebral infarction.

A study was performed to determine quantitatively the alterations in phosphorus metabolite concentrations and pH in regions of the human brain damaged by chronic stroke. Image-guided phosphorus-31 magnetic resonance spectroscopy was performed on the brains of eight healthy subjects and six patients with cerebral infarction of more than 3 months duration. Phosphorus metabolite concentrations in infarcted regions were reduced 8%-67%. Significant decreases occurred in phosphomonoester (PME), phosphodiester (PDE), and adenosine triphosphate (ATP) concentrations, while inorganic phosphate (Pi) and phosphocreatine (PCr) concentrations showed smaller, nonsignificant decreases. The PCr/ATP ratio was significantly increased, while the ATP/Pi ratio was somewhat lower. The phospholipid ratio PDE/PME was also significantly increased, while the ratios of phospholipid (PME, PDE) to phosphate (PCR, Pi) metabolites were significantly decreased. The pH of the infarcted region indicated significantly more alkalinity than in the normal brain. The results suggest that chronic stroke is associated with significant changes in brain metabolite concentrations and pH that are different from those reported for other brain diseases.     

Clinical magnetic resonance spectroscopy of brain, heart, liver, kidney, and cancer. A quantitative approach

Clinical studies using 31P and 1H MRS with a whole body 2.0 T MRI/MRS system are described. In most cases, techniques to quantitate absolute molar concentrations of metabolites in various organs were used. In the brain, AIDS, chronic stroke, and white matter lesions were associated with alterations of brain 31P metabolites. Epilepsy was associated with increased pH in the seizure focus. In the heart, dilated cardiomyopathy was associated with increased PDE/ATP while PCr/ATP was unchanged. In the liver, alcoholic hepatitis and cirrhosis were associated with diminished hepatic ATP while alcoholic hepatitis had increased pH and cirrhosis had decreased pH. This allowed differentiation of normal liver, alcoholic hepatitis, and alcoholic cirrhosis without biopsy. In the prostate, malignancy was associated with increased PME/ATP and decreased PCr/ATP. The PME/PCr was greatly increased in malignant prostate with no overlap in normals. Other cancers outside the brain had increased PME and effective treatment was often associated with diminished PME. 1H MRS of the brain was performed using ISIS and outer volume suppression pulses for volume localization. Excellent high resolution 1H water-suppressed spectra were obtained at echo times as short as 30 ms, showing well resolved peaks for lactate, N-acetylaspartate, glutamate, choline, creatinine, and inositol. 1H MRS demonstrated that the uptake of ethanol by the brain was slower than the rise of ethanol in blood. 31P spectroscopic imaging of the brain with resolution of 2.25 x 2.25 x 2.5 cm produced metabolic images and high resolution spectra from desired regions of interest.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of prostate cancer, benign prostatic hyperplasia and normal prostates using transrectal 31phosphorus magnetic resonance spectroscopy: a preliminary report.

We assessed the ability of 31phosphorus (31P) transrectal magnetic resonance spectroscopy to characterize normal human prostates as well as prostates with benign and malignant neoplasms. With a transrectal probe that we devised for surface coil spectroscopy we studied 15 individuals with normal (5), benign hyperplastic (4) and malignant (6) prostates. Digital rectal examination, transrectal ultrasonography and magnetic resonance imaging were used to aid in accurate positioning of the transrectal probe against the region of interest within the prostate. The major findings of the in vivo studies were that normal prostates had phosphocreatine-to-adenosine triphosphate (ATP) ratios of 1.2 +/- 0.2, phosphomonoester-to-beta-ATP ratios of 1.1 +/- 0.1 and phosphomonoester-to-phosphocreatine ratios of 0.9 +/- 0.1. Malignant prostates had phosphocreatine-to-beta-ATP ratios that were lower (0.7 +/- 0.1) than those of normal prostates (p less than 0.02) or prostates with benign hyperplasia (1.1 +/- 0.2, p less than 0.01). Malignant prostates had phosphomonoester-to-beta-ATP ratios (1.8 +/- 0.2) that were higher than that of normal prostates (p less than 0.02). Using the phosphomonoester-to-phosphocreatine ratio, it was possible to differentiate metabolically malignant (2.7 +/- 0.3) from normal prostates (p less than 0.001), with no overlap of individual ratios. The mean phosphomonoester-to-phosphocreatine ratio (1.5 +/- 0.5) of prostates with benign hyperplasia was midway between the normal and malignant ratios, and there was overlap between individual phosphomonoester-to-phosphocreatine ratios of benign prostatic hyperplasia glands with that of normal and malignant glands. To verify the in vivo results, we performed high resolution magnetic resonance spectroscopy on perchloric acid extracts of benign prostatic hyperplasia tissue obtained at operation and on a human prostatic cancer cell line DU145. The extract results confirmed the differences in metabolite ratios observed in vivo. We conclude that transrectal 31P magnetic resonance spectroscopy can characterize metabolic differences between the normal and malignant prostate.     

Comparison of 31P MRS and 1H MRI at 1.5 and 2.0 T

The goals of this study were to compare 31P magnetic resonance spectroscopy (MRS) and 1H magnetic resonance imaging (MRI) of human subjects and phantoms at 1.5 and 2.0 T. The 31P signal-to-noise (S/N) ratios in phantom standards and in localized volumes in human brain and liver were compared at 1.5 and 2.0 T. In addition, T1 values for 31P resonances in human brain, 31P linewidths of metabolites in human brain and liver, 1H S/N in a phantom standard, and MR image quality in human head and body were compared at the two field strengths. The results of our study showed that at the higher strength field, (1) in vivo 31P MRS studies benefited from up to 32% improvement in S/N; (2) in vivo 31P MRS studies also benefited from increased spectral dispersion; (3) the quality of MR head images remained comparable; and (4) body images showed some decrease in image quality due to increased chemical shift, and flow and motion artifacts.     

Workshop: Use of “read-across” for chemical safety assessment under REACH

Read-across has generated much attention, since it may be used as an alternative approach for addressing the information requirements under REACH. Experience in the application of “read-across” has undoubtedly been gained within the context of the 2010 registrations (>1000 tonnes/annum). Industry, European Chemicals Agency (ECHA) and EU Member States all conceptually accept read-across approaches but difficulties still remain in applying them consistently in practice. A workshop on the ‘Use of Read-Across for Chemical Safety Assessment under REACH’, organised by ECHA with the active support of Cefic LRI was held on the 3rd October 2012 to gain insight on how ECHA evaluates read-across justifications, to share Industry experiences with read-across approaches and to discuss practical strategies to help develop scientifically valid read-across for future submissions.     

P-31 MR spectroscopy of normal human brain and brain tumors

Image-guided phosphorus-31 magnetic resonance (MR)-localized image-selected in vivo spectroscopy was performed on normal human brain and brain tumors. Peak area ratios, absolute molar concentrations of metabolites, and pH were determined. T1 values in normal brain were measured. The most important finding was that the metabolite concentrations detectable with MR spectroscopy in brain tumors were reduced from 20% to 70%. Phosphomonoesters, phosphodiesters, and phosphocreatine (PCr) showed the greatest decreases, while inorganic phosphate (Pi) showed the least change. The PCr-Pi ratio was significantly reduced in tumors. The pH of brain tumors (7.12 +/- 0.03) was more alkaline than that of normal brain (6.99 +/- 0.01). The authors conclude that the metabolite concentrations and pH in human brain tumors differ significantly from those in normal brain. These differences may be ultimately useful in characterizing tumors in man.     

P-31 spectroscopy study of response of superficial human tumors to therapy

Studies were performed to characterize phosphorus-31 magnetic resonance (MR) spectra obtained from 10 superficial human tumors outside the brain and to determine whether P-31 MR spectroscopy could allow detection of a response to therapy before a change in tumor size was measured. The ratio of phosphomonoester to adenosine triphosphate peak intensities (PME/ATP) was unusually large in all tumors studied. The average PME/ATP in lymphomas (1.8 +/- 0.5) was greater than in nonlymphoma cancers (1.1 +/- 0.15). The average PME/ATP for all tumors studied (1.4 +/- 0.5) was much greater than that of underlying skeletal muscle (0.23 +/- .09). Eight of the tumors were studied before and after therapy. Responders were distinguished from nonresponders on the basis of changes in tumor size. PME/ATP decreased during therapy in three lymphomas that responded to therapy. In an adenocarcinoma and Ewing sarcoma that did not respond to therapy, PME/ATP increased. PME/ATP remained constant in two squamous cell carcinomas that responded to therapy and decreased in one squamous cell carcinoma that decreased in size by 40% but was classified as a nonresponder. Changes in PME/ATP did not always parallel changes in tumor size during therapy. In two patients, a decrease in PME/ATP preceded a decrease in tumor size. In four patients, PME/ATP increased transiently during periods when tumor size remained constant.     

Inhibition of tumor high-energy phosphate metabolism by insulin combined with rhodamine 123

The purpose of this study was to determine whether the energy metabolism of an experimental rodent sarcoma was selectively depressed by the combination of inhibition of glycolysis and respiration. In vivo phosphorus-31 nuclear magnetic resonance spectroscopy was used to monitor the response of tumor or brain high-energy phosphate compounds to insulin hypoglycemia, rhodamine 123, or both agents in fasting rats with subcutaneous methylcholanthrene-induced sarcomas. Insulin or rhodamine 123 alone produced a similar 50% to 60% reduction in tumor adenosine triphosphate (ATP) concentration compared with controls injected with saline solution (p less than 0.05, one-way analysis of variance [ANOVA]). The combination of insulin plus rhodamine 123 resulted in a 90% reduction of tumor ATP concentration, which was significantly different from the effect of either agent alone (p less than 0.05, one-way ANOVA). Brain phosphocreatine and ATP concentrations were unchanged by these agents. Administration of dimethyl sulfoxide (DMSO)/glycerol, the vehicle for rhodamine, produced a 35% reduction of tumor ATP, which was similar to the effect of insulin alone but significantly different from rhodamine. The combination of DMSO/glycerol plus insulin hypoglycemia resulted in a 70% reduction in tumor ATP, which was significantly elevated compared with the combination of rhodamine plus insulin. Glucose deprivation induced by insulin, and combined with the inhibition of oxidative phosphorylation, produces an additive depression of tumor energetics. The drug vehicle DMSO/glycerol significantly depresses tumor energy metabolism, presumably because of its DMSO component, which may explain the previously reported antineoplastic efficacy of this solvent. Combinations of inhibitors directed at different points of tumor metabolism produced an enhanced depression of tumor energetics, whereas host tissue was protected.     

Increased pH and Seizure Foci Inorganic Phosphate in Temporal Demonstrated by [31P]MRS

To investigate alterations of brain metabolism associated with temporal lobe epilepsy, [31P]MRS studies were performed on the anterotemporal lobes of patients with medically refractory complex partial seizures. Interictally, the pH was significantly more alkaline in the temporal lobe ipsilateral to the seizure focus (7.25 vs. 7.08, p less than 0.05), and the inorganic phosphorous concentration was greater on the side of the epileptogenic focus (1.9 vs. 1.1 mM, p less than 0.05). These changes in pH and inorganic phosphate may represent metabolic alterations secondary to seizures. Alternatively, because alkalosis enhances neural excitability and may enhance seizure activity, the increased pH of the seizure focus may provide insight into the pathophysiologic mechanism of epileptic seizures.     

Clinical MRS studies of the brain

Image-guided 31P and 1H magnetic resonance localized spectroscopy was performed on patients with brain tumors, temporal lobe epilepsy, chronic brain stroke, and deep white matter lesions. Absolute molar concentrations of metabolites, peak area ratios, and pH were obtained. The important findings were that 31P metabolite concentrations were significantly reduced in tumors, infarcts, and deep white matter lesions. Similarly, 1H metabolite intensities were reduced in chronic stroke. In the seizure foci of epilepsy patients, in tumors, and in chronic stroke, the pH was more alkaline than the normal pH. Peak area ratios were altered in tumors (reduction of phosphocreatine/inorganic phosphate (PCr/Pi) and in chronic stroke (large increases in Cr/NAA and Cho/NAA). Finally, the spectroscopic imaging technique offers a versatile alternative to the "single point" techniques, producing spectra or images of the spatial distribution of individual 31P metabolites.