Phosphomonoesters Research Articles

Phosphomonoesters predict early mortality in porcine hemorrhagic shock.

Hemodynamic, laboratory, and tissue energetics were measured in a porcine model of hemorrhagic shock to evaluate variables as predictors of early mortality from shock. We hypothesized that elevated phosphomonoesters would predict early mortality in hemorrhagic shock. Pigs (n = 36) were subjected to 35% hemorrhage for 90 minutes in a 1.5-T nuclear magnetic resonance (NMR) magnet. Measurements included base deficit (BD); lactate; oxygen consumption/delivery; near-infrared spectroscopy of liver, stomach, and skeletal muscle tissue oxyhemoglobin saturation; and NMR spectroscopic measurements of high-energy phosphates of liver and skeletal muscle. Variables were compared between nonsurvivors and survivors to resuscitation after 90-minute measurements. Ninety-minute mortality was 25%. Muscle phosphomonoesters (PMEs) and oxygen consumption differed significantly between survivors and nonsurvivors at baseline. Regression analysis identified baseline muscle PME levels, baseline BD, and 30-minute BD as early predictors of mortality before resuscitation (r2 = 0.304). Baseline elevation in muscle PME levels predicts mortality in an animal model of severe hemorrhagic shock.

Mapping hypoxia-induced bioenergetic rearrangements and metabolic signaling by 18O-assisted 31P NMR and 1H NMR spectroscopy.

Brief hypoxia or ischemia perturbs energy metabolism inducing paradoxically a stress-tolerant state, yet metabolic signals that trigger cytoprotection remain poorly understood. To evaluate bioenergetic rearrangements, control and hypoxic hearts were analyzed with 18O-assisted 31P NMR and 1H NMR spectroscopy. The 18O-induced isotope shift in the 31P NMR spectrum of CrP, betaADP and betaATP was used to quantify phosphotransfer fluxes through creatine kinase and adenylate kinase. This analysis was supplemented with determination of energetically relevant metabolites in the phosphomonoester (PME) region of 31P NMR spectra, and in both aromatic and aliphatic regions of 1H NMR spectra. In control conditions, creatine kinase was the major phosphotransfer pathway processing high-energy phosphoryls between sites of ATP consumption and ATP production. In hypoxia, creatine kinase flux was dramatically reduced with a compensatory increase in adenylate kinase flux, which supported heart energetics by regenerating and transferring beta- and gamma-phosphoryls of ATP. Activation of adenylate kinase led to a build-up of AMP, IMP and adenosine, molecules involved in cardioprotective signaling. 31P and 1H NMR spectral analysis further revealed NADH and H+ scavenging by alpha-glycerophosphate dehydrogenase (alphaGPDH) and lactate dehydrogenase contributing to maintained glycolysis under hypoxia. Hypoxia-induced accumulation of alpha-glycerophosphate and nucleoside 5'-monophosphates, through alphaGPDH and adenylate kinase reactions, respectively, was mapped within the increased PME signal in the 31P NMR spectrum. Thus, 18O-assisted 31P NMR combined with 1H NMR provide a powerful approach in capturing rearrangements in cardiac bioenergetics, and associated metabolic signaling that underlie the cardiac adaptive response to stress.

Protective role of cyclosporine in experimental unilateral blunt testicular trauma: evaluation by 31P MR spectroscopy.

Magnetic resonance (MR) imaging is a useful tool to study the anatomy of the testis while 31P magnetic resonance spectroscopy (MRS) provides a non-invasive alternative method to demonstrate the metabolic status of testes. This study was designed to test whether the protective role of cyclosporine in experimental unilateral blunt testicular trauma (UBTT) could be assessed by 31P MRS. Male Wistar rats (n = 30) aged 20 days were randomised into group I (sham surgery), group II (UBTT) and group III (UBTT and cyclosporine for 7 days). Contralateral testicles of 5 rats from each group was evaluated by 31P MRS at 30 and 60 days of age and phosphomonoesters (PM), phosphodiesters (PD), and adenosine triphosphate (ATP) levels were measured. At 60 days of age the PM/ATP ratio was 0.32+/-0.08 in group I whereas it was 0.68+/-0.31 in the group II (p<0.05). Group III rats showed PM, PD and PM/ATP ratios similar to the controls. In conclusion, it is observed that UBTT causes contralateral testicular damage which could be prevented by short-term cyclosporine treatment and 31P MRS is an excellent modality for such an evaluation.

Membrane phospholipid abnormalities of basal ganglia in never-treated schizophrenia: a 31P magnetic resonance spectroscopy study

Background Studies in schizophrenia using in vivo 31P magnetic resonance spectroscopy (MRS) have mostly focused on the association cortices, including the frontal and temporal lobes. Striatum has also been implicated in schizophrenia, although neuroleptic exposure in the patients is a potential confound limiting interpretation of earlier studies. We examined membrane phospholipid abnormality in the basal ganglia using 31P MRS in neuroleptic-naive schizophrenia patients. Methods Never-treated, DSM-IV schizophrenia patients ( n = 20) and age- and gender-matched healthy control subjects ( n = 30) underwent in vivo 1-D 31P MRS of both basal ganglia using an image-selected technique on a 1.5-T magnetic resonance imaging scanner. A neuroradiologist blind to clinical data measured the phosphomonoester (PME) and phosphodiester (PDE) from the spectra. Results The schizophrenia patients showed significantly and bilaterally elevated levels of PME/PDE ratios in basal ganglia as compared with control subjects. There were no significant differences in the ratios between the two sides in either patient or control groups. Phosphomonoester/phosphodiester ratio did not correlate with illness duration. Lower Positive and Negative Syndrome Scale scores were associated with lower PME/PDE ratio. Conclusions The basal ganglia of never-treated schizophrenia patients show features suggestive of reduced breakdown and/or increased synthesis of membrane phospholipids. Lack of correlation between illness duration and the membrane phosphorus moiety ratio may be consistent with a nonprogressive, possibly neurodevelopmental etiopathogenesis.

The relationship of in vivo31P MR spectroscopy to histology in chronic hepatitis C

Liver biopsy remains the gold standard for characterizing diffuse liver disease and is associated with significant morbidity and, rarely, mortality. Our aim was to investigate whether a noninvasive technique, in vivo phosphorus 31 ( 31P)-magnetic resonance spectroscopy (MRS), could be used to assess the severity of hepatitis C virus (HCV)-related liver disease. Fifteen healthy controls and 48 patients with biopsy-proven HCV-related liver disease were studied prospectively. Based on their histologic fibrosis (F) and necroinflammatory (NI) scores, patients were divided into mild hepatitis (F ≤ 2/6, NI ≤ 3/18), moderate/severe hepatitis (3 ≤ F < 6 or NI ≥ 4/18), and cirrhosis (F = 6/6). Hepatic 31P MR spectra were obtained using a 1.5-T spectroscopy system. Quantitation of the 31P signals was performed in the time domain using the Advanced MAgnetic RESonance algorithm. There was a monotonic increase in the mean ± 1 standard error phosphomonoester (PME) to phosphodiester (PDE) ratios for the control, mild disease, moderate disease, and cirrhosis groups: 0.15 ± 0.01, 0.18 ± 0.02, 0.25 ± 0.02, 0.38 ± 0.04, respectively (ANOVA, P < .001). An 80% sensitivity and specificity was achieved when using a PME/PDE ratio less than or equal to 0.2 to denote mild hepatitis and a corresponding ratio greater than or equal to 0.3 to denote cirrhosis. No other significant spectral changes were observed. In conclusion, 31P MRS can separate mild from moderate disease and these 2 groups from cirrhosis. The ability to differentiate these populations of patients has therapeutic implications and 31P MRS, in some situations, would not only complement a liver biopsy but could replace it and be of particular value in assessing disease progression. (H epatology 2003;37:788-794.)

Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study.

In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo (31)P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo (31)P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

NMR studies of the relationship between the changes of membrane lipids and the cisplatin-resistance of A549/DDP cells

Changes of membrane lipids in cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells during the apoptotic process induced by a clinical dose of cisplatin (30 μM) were detected by 1H and 31P-NMR spectroscopy and by membrane fluidity measurement. The apoptotic phenotypes of the two cell lines were monitored with flow cytometry. The assays of apoptosis showed that significant apoptotic characteristics of the A549 cells were induced when the cells were cultured for 24 hours after treatment with cisplatin, while no apoptotic characteristic could be detected for the resistant A549/DDP cells even after 48 hours. The results of 1H-NMR spectroscopy demonstrated that the CH2/CH3 and Glu/Ct ratios of the membrane of A549 cells increased significantly, but those in A549/DDP cell membranes decreased. In addition, the Chol/CH3 and Eth/Ct ratios decreased for the former but increased for the latter cells under the same conditions. 31P-NMR spectroscopy indicated levels of phosphomonoesters (PME) and ATP decreased in A549 but increased in A549/DDP cells after being treated with cisplatin. These results were supported with the data obtained from 1H-NMR measurements. The results clearly indicated that components and properties of membrane phospholipids of the two cell lines were significantly different during the apoptotic process when they were treated with a clinical dose of cisplatin. Plasma membrane fluidity changes during cisplatin treatment as detected with the fluorescence probe TMA-DPH also indicate marked difference between the two cell lines. We provided evidence that there are significant differences in plasma membrane changes during treatment of cisplatin sensitive A549 and resistant A549/DDP cells.

Energy metabolism and cerebral blood flow during cytotoxic brain edema induced by 6-aminonicotinamide.

We investigated the progression of cytotoxic brain edema induced by 6-aminonicotinamide (6-ANA), a potent antimetabolite of nicotinamide, by measuring the time courses of changes in brain tissue water state (with MRI), histology (with H&E staining), energy metabolism (with 31P-NMR), brain hemoglobin concentration (with near-infrared spectroscopy; NIRS), cerebral blood flow and volume (CBF. CBV), mean arterial blood pressure (MABP), and brain activity (with EEG) up to 10 hours (h). Change in cerebrovascular autoregulation was also investigated. 6-ANA (120 mg/kg) was administered intraperitoneally to 30 male Wistar rats (250-350 g). After 10 h, the T2-weighted signal intensity was increased (p < 0.05), and H&E staining showed severe vacuolation of glial cells. ATP production/consumption and intracellular pH were well maintained up to 10 h, while the intensity of the phosphomonoesters (PME) signal was significantly increased (p < 0.05). Oxygen consumption gradually decreased from 4 to 10 h. CBF and MABP were all significantly increased (by 2.5-fold for CBF) (p < 0.05). Theta and delta wave amplitudes were reduced at 10 h. In summary, 6-ANA (120 mg/kg) induced cytotoxic brain edema from 4 to 10 h. Energy balance and brain activity were well maintained up to 10 h, though cerebrovascular autoregulation was impaired.

Magnetic Resonance Spectroscopy of cancer—practicalities of multi-centre trials and early results in non-Hodgkin's lymphoma

This review describes problems and solutions encountered in large scale multicentre trials of Magnetic Resonance Methods for monitoring cancer. It is illustrated with reference to the Multi-Institutional Group on Magnetic Resonance Spectroscopy (MRS) Applications to Cancer which was set up to perform a trial of 31P MRS for monitoring non-invasively chemotherapy of solid tumours. 31P MR spectra of non-Hodgkin's lymphoma (NHL) pre- and posttreatment, across nine Institutions, were acquired on either General Electric (GE) or Siemens 1.5T Clinical MR instruments. Development of the trial protocol, design of the Radio Frequency (RF) coils and Quality Control procedures necessary to ensure that the datasets acquired at each centre were comparable, are described. The data revealed that phosphomonoesters (PME)/nucleotide triphosphates (NTP) ratio decreased significantly after treatment in the Complete ( P<0.001) and Partial ( P<0.05) Responders but not in the Non-Responders ( P>0.1). In addition, the PME/NTP ratio in the pre-treatment spectra correlated with the subsequent outcome of treatment indicating that PME/NTP levels are significant predictors of long-term clinical response and time-to-treatment failure in NHL.

Biliary drainage for obstructive jaundice enhances hepatic energy status in humans: a 31-phosphorus magnetic resonance spectroscopy study.

Biliary obstruction impairs liver function although the pathophysiological mechanism is incompletely understood. The aim of this study was to examine serial changes in liver metabolism in patients with obstructive jaundice using image guided in vivo 31-phosphorus magnetic resonance spectroscopy ((31)P MRS). This technique allows repeated and non-invasive assay of organ energy metabolism and phospholipid biochemistry. We studied 10 patients presenting with obstructive jaundice secondary to extrahepatic localised malignancy. There were eight men and two women, median age 72 years (range 54-94), six with cholangiocarcinoma (all Bismuth type 1) and four with carcinoma of the head of the pancreas. Ten healthy volunteers (median age 24 years (range 21-26)) were studied for comparison. Hepatic metabolism in jaundiced patients was measured by (31)P MRS at presentation and again after a one week period of biliary drainage. Conventional liver function tests were also recorded. Compared with controls, liver spectra from jaundiced patients contained an excess of phosphomonoester (PME) metabolites (PME/total phosphate median 10.3% (interquartile range 8.7-11.5) in controls, 15.4% (13.1-17.7) in jaundiced cases; p<0.01). Biliary decompression was achieved in all patients (five with internal stents and five by external drainage catheters), and plasma biochemistry improved predictably (bilirubin 176 micromol/l (158-351) at presentation, 110 micromol/l (42-241) after drainage for one week; p<0.01). Enhancement of hepatic energy status, measured by the ratio of adenosine triphosphate (ATP) to inorganic phosphate (Pi), was observed in all cases after relief of biliary obstruction (ATP/Pi 1.4 (1.17-1.69) at presentation, 1.97 (1.4-2.48) after drainage; p<0.01) and was independent of the route of bile drainage. Hepatic phosphodiester (PDE) content was decreased after relief of obstruction (PDE/total phosphate 25.2% (20.5-27.4) at presentation, 19.8% (16.6-24.5) after drainage; p<0.01). This change was probably due to a reduction in the contribution from bile contents to this resonance as a strong PDE signal was also detectable in spectra obtained from separate bile specimens. Obstructive jaundice produces alterations in liver phosphoester biochemistry, most likely reflecting disturbances in phospholipid metabolism. Relief of biliary obstruction is associated with a measurable increase in hepatic energy status. Bile may contribute to the phosphodiester signal of the 31-phosphorus liver spectrum and changes in these resonances must therefore be interpreted with caution and in relation to the clinical situation. Monitoring of liver metabolism by (31)P MRS may allow clinicians to refine the selection and timing of therapeutic options in jaundiced patients.

31P-spectroscopy of frontal lobe in schizophrenia: alterations in phospholipid and high-energy phosphate metabolism

Studies using 31P-magnetic resonance spectroscopy (MRS) reported on abnormalities in frontal lobe metabolism in schizophrenia. The most consistent findings were a reduction in the resonances of phosphomonoesters (PME) and/or increased phosphodiesters (PDE), which are, respectively, the precursors and the metabolites of membrane phospholipids, thus suggesting an accelerated phospholipid metabolism in the disease. Other studies reported increased high-energy phosphates (ATP—adenosine triphosphate and PCr—phosphocreatine) in schizophrenia, reflecting decreased use of energy in the frontal lobe. We investigated 53 schizophrenic patients (DSM-IV) and 35 healthy controls. Eighteen from these patients were drug naı̈ve and the remaining 35 were drug-free for an average of 6 months. Phospholipid metabolism and high-energy phosphates were assessed in the left frontal lobe using 31P-MRS. Psychopathological evaluation was done with the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms Rating Scale (NSRS). Neuropsychological evaluation was performed with the Wisconsin Card Sorting Test (WCST), Stroop Test and Wechsler Adult Intelligence Scale. Drug-naı̈ve patients showed reduced PDE in the left frontal lobe compared to controls and to previously medicated patients ( p<0.05). No differences among the three groups were found regarding the other spectroscopy parameters. In healthy controls, but not in schizophrenics, a negative (and probably physiological) correlation was found between PME and PDE ( p<0.01). In schizophrenic patients, ATP was correlated with negative symptoms and with neuropsychological impairment ( p<0.01). The lack of a correlation between PME and PDE, as well as the reduction of PDE in schizophrenia, suggest a disrupted phospholipid metabolism in the disease, albeit on a contrary direction of that reported in literature. The relationships of ATP with negative symptoms and neuropsychological deficit suggest an alteration of energetic demand in the frontal lobe of schizophrenic patients, which is in line with the hypofrontality hypothesis of the disease.

Chronic hepatitis: in vivo proton MR spectroscopic evaluation of the liver and correlation with histopathologic findings.

To correlate the in vivo hydrogen 1 ((1)H) magnetic resonance (MR) spectroscopic features of the chronic hepatitis-involved liver with the histopathologic stages of fibrosis. Seventy-five patients with chronic hepatitis were examined with (1)H MR spectroscopy, which was performed in the right hepatic lobe. The peak areas of glutamine and glutamate complex (Glx), phosphomonoesters (PME), glycogen and glucose complex (Glyu), and lipid were measured on the liver spectra. The histopathologic features were correlated with the in vivo (1)H MR spectroscopic findings at each stage of chronic hepatitis. Fifteen healthy volunteers also were included as a control group. (1)H MR spectroscopy depicted Glx, PME, Glyu, and lipid in all livers. In the normal livers, the calculated mean (+/- SD) relative metabolite-to-lipid ratios of Glx, PME, and Glyu were 0.14 +/- 0.04, 0.03 +/- 0.01, and 0.21 +/- 0.04, respectively. The mean value of each metabolite-to-lipid ratio was significantly different between all stages of chronic hepatitis, and with the exception of the mean ratio at the interval between stages 0 and 1 (P > .05), the mean value increased significantly with increasing stage (P < .05). A pronounced peak was demonstrated at 3.9-4.1 ppm at (1)H MR spectroscopy of all stages of chronic hepatitis except stage 0. The increased Glx, PME, and Glyu levels relative to the lipid content with chronic hepatitis indicated the severity of fibrosis and thus were concordant with the histopathologic stages. In vivo (1)H MR spectroscopy might be a substitute for liver biopsy in the diagnosis and staging of chronic hepatitis.

Associations between central and peripheral measures of phospholipid breakdown revealed by cerebral 31-phosphorus magnetic resonance spectroscopy and fatty acid composition of erythrocyte membranes

1. Abnormal neuronal membrane phospholipid metabolism is increasingly recognized as being of central importance to a number of neuropsychiatric disorders. Currently, two important indices of membrane phospholipid metabolism tend to be measured: the ratio of the areas of the phosphomonoester (PME) and phosphodiester (PDE) peaks from in vivo cerebral phosphorus magnetic resonance spectroscopy ( 31P MRS) studies; and erythrocyte membrane fatty acid concentrations. Thus far, there have been no studies comparing these two indices to ascertain the extent to which they agree. 2. The authors measured these indices in nine normal adults. Spectral localization was achieved using four-dimensional chemical shift imaging methods and erythrocyte membrane fatty acid concentrations (from blood samples taken at the time of scanning) were measured using gas liquid chromatography. 3. Levels of PDE (an index of phospholipid catabolism), measured using cerebral 31P MRS, were significantly correlated with reduced concentrations of the highly unsaturated fatty acids docosahexaenoic acid (DHA) ( r = −0.68, p < 0.05) and eicosapentaenoic acid (EPA) ( r = −0.78, p < 0.02). No significant correlations were found between peripheral concentrations of any highly unsaturated fatty acids and PME levels, nor between their essential fatty acid precursors and either PDE or PME levels. Other 31-phosphorus metabolites also showed no significant correlations with the blood fatty acid measures. 4. The correlations between central measures of PDE and peripheral measures of DHA and EPA provide validation of cerebral 31P MRS as a non-invasive technique for the study of membrane phospholipid metabolism in vivo.

Brain death-related energetic failure of the donor heart becomes apparent only during storage and reperfusion: an ex vivo phosphorus-31 magnetic resonance spectroscopy study on the feline heart

Background and Objective: Recently, we have shown, by using localized in vivo phosphorus-31 magnetic resonance spectroscopy ( 31P MRS) of the anterior left ventricular wall, that brain death (BD) is not associated with reduced myocardial energy status. In this study, we applied ex vivo 31P MRS of the entire heart to study the effects of BD on the energy status of the feline donor heart following explantation. Methods: We used cats (6 BD and 6 controls [C]) in a 26-hour protocol. After 2 hours of preparation, we induced BD by filling an intracranial balloon at t = 0 hour. At t = 6 hours, the hearts were arrested with St. Thomas’ Hospital cardioplegic solution, explanted, and stored in the same solution at 4°C in a 4.7 Tesla magnet for 17 hours. Subsequently, the hearts were reperfused in the Langendorff mode at 38°C for 1 hour. The first 5-minute 31P MRS spectrum was obtained 1 hour after crossclamping the aorta; we obtained subsequent spectra every hour during storage and every 5 minutes during reperfusion. At the end, the hearts were dried and weighed. Phosphocreatine (PCr), γ-adenosine triphosphate (γ-ATP), inorganic phosphate (Pi), and phosphomonoesters (PME), were expressed per g dry heart weight. The intracellular pH (pH i) and the PCr/ATP ratio were calculated. Results: During storage, we identified a significant but similar decrease of pH i, PCr/ATP ratio, and PCr in both groups. During reperfusion, pH i and PCr/ATP ratio recovered similarly in both groups, whereas the recovery of PCr in the BD group was significantly lower ( p < 0.05). The Pi and PME increased in both groups during storage but to a lesser extent in the BD group ( p < 0.05). This difference disappeared during reperfusion. The γ-ATP was already significantly lower in the BD group at the onset of storage, and this remained so throughout storage and reperfusion ( p < 0.05 vs C). Contractile capacity was lost in all hearts, except for 1 heart in the BD group. Conclusion: Brain death-related failure of the energetic integrity of the feline donor heart becomes apparent only when using 31P MRS during ischemic preservation and subsequent reperfusion.

Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled 31P magnetic resonance spectroscopy study

Background: The objective of our study was to evaluate whether lithium increases brain phosphomonoester (PME) levels in human subjects.Methods: Proton decoupled 31P magnetic resonance spectra were obtained from eight healthy volunteers before and after the administration of lithium carbonate, 450 mg b.i.d., for 7 and 14 days.Results: Pairwise comparisons of the mole percent PME revealed a significant increase from baseline at day 7 and day 14 of lithium administration.Conclusions: An increase in PME concentration with 7 and 14 days of lithium administration in the human brain in vivo was observed. Because the inositol-1-monophosphate contributes to the PME peak, this result suggests that some of the initial actions of lithium may occur through a reduction of myo-inositol, which in turn may initiate a cascade of secondary changes at different levels of signal transduction process and gene expression in brain, effects that are ultimately responsible for the therapeutic benefits of lithium.

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis

Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness.

Neurochemical Investigation of the Schizophrenic Brain by in Vivo Phosphorus Magnetic Resonance Spectroscopy

Abnormal phospholipid metabolisms may play important roles in the pathophysiology of schizophrenia. Phosphorus magnetic resonance spectroscopy (31P-MRS) offers a new method for studying phosphorus-related metabolism in vivo. A decrease in the level of phosphomonoesters (PME) and an increase in the level of phosphodiesters (PDE) has been demonstrated in the prefrontal lobe of neuroleptic-naive schizophrenic patients. Most of the studies in medicated schizophrenic patients have shown decreased PME and/or increased PDE. The decreased PME in the frontal lobe appears to be associated with negative symptoms and poor working memory performance. 1H-decoupled 31P-MRS revealed a reduction in the phosphocholine element of PME and an elevation in the mobile phospholipids of PDE in the prefrontal region of medicated schizophrenic patients. PDE were elevated in the temporal lobes of neuroleptic-naive schizophrenic patients, and this increase was partially normalized by haloperidol administration. Data about the temporal lobes of medicated schizophrenic patients have not been consistent. Except for the reduction in the adenosine triphosphate (ATP) in the basal ganglia and the correlation between the increase in the frontal lobe phosphocreatine (PCr) and negative symptomatology, data related to changes in high-energy phosphates are contradictory. No consensus on the effect of neuroleptics on phosphorus metabolites has been achieved. Methodological problems inherent in 31P-MRS may have contributed to the confusion in understanding available data. Future directions of MRS studies are suggested in the last section of the paper.

Postprocessing method to segregate and quantify the broad components underlying the phosphodiester spectral region of in vivo (31)P brain spectra.

In a typical, in vivo (31)P brain spectrum, the phosphomonoester (PME) and phosphodiester (PDE) spectral region not only contains signals from freely mobile PMEs and PDEs (which are anabolic and catabolic products of membrane phospholipids) but also signals of broader underlying lineshapes from less-mobile molecules. In general, either the PME and PDE resonances are quantified as a combined value of freely mobile metabolites plus less-mobile molecules or the broader underlying signal is reduced/eliminated prior to or post data collection. In this study, a postprocessing method that segregates and quantifies the individual contributions of the freely mobile metabolites and the less-mobile molecules is introduced. To demonstrate the precision and accuracy of the method, simulated data and in vivo (31)P brain spectroscopy data of healthy individuals were quantified. The ability to segregate and quantify these various PME and PDE contributions provides additional spectral information and improves the accuracy of the interpretation of (31)P spectroscopy results. Magn Reson Med 45:390-396, 2001.

Simulated biological effects of microgravity on phospholipid and energy metabolism of chicken embryonic brain cells studied by31P-NMR spectroscopy

Levels of phosphomonoester (PME), phosphodiester (PDE), ATP and pH in brain cells of chicken embryos rotated for 24 h in a clinostat during the period of hatching the 13th day (E13) and 15th day (E15) embryos were investigated by using(31)P-NMR spectroscopy. Significant increases in the values of PME, ATP and pH were identified after E13 rotating for 24 h. With the same treatment, differences were obtained in the phospholipid and energy metabolism of E15, but no significant levels have been reached. The calorimetric assay (malachite green method) was used for measuring the activity of total ATPase. A dramatic decrease was evident in the activity of ATPase in brain cells of rotated E13 and E15. The former is more sensitive than the latter. All the levels mentioned above could restore in 24 h after the rotation stopped, except that the level of ATP was still higher than the control.

Tissue pH in human kidney transplants during hypothermic ischemia

Ex vivo NMR spectroscopy was used to investigate pH in 67 human kidney transplants. 1H and 31P spectra were recorded at 1.5 T during regular hypothermic storage in histidine-tryptophane-α-ketoglutarate (HTK) solution. Estimations of cytosolic pH from chemical shift differences between inorganic phosphate and phosphodiesters and of extracellular pH from the ε1 and δ2 protons of histidine were based upon systematic titration studies. The possibility to predict acute tubular necrosis (ATN) by measuring pH was compared to results obtained with peak area ratios of phosphomonoesters (PME) and Pi and of the γ-phosphorus of nucleoside 5′-triphosphate (γ-NTP) and Pi. Cytosolic pH was 6.86 ± 0.10 in kidneys showing immediate post-transplant function and 6.84 ± 0.10 in those with ATN. Time-dependent studies demonstrated a monoexponential pH decay (velocity constant: 0.14 ± 0.07 h −1). Extracellular pH varied between 7.40 and 7.15. Grafts with immediate function showed higher PME/Pi (2.24 ± 0.57 vs. 1.77 ± 0.50, p < 0.05) and γ-NTP/Pi (0.33 ± 0.16 vs. 0.16 ± 0.08, p < 0.001). Intra- and extracellular pH can be monitored non-invasively during hypothermic transplant storage. The pH gradient between both compartments provides quantitative information about the buffer capacity of the preservation medium. Acidification is not a primary cause of ATN during regular HTK storage. The total nucleotide pool is a determinant of the reversibility of ischemic injury.