Biomedical subjects

Douglas L Rothman

Publications and source records attributed to Douglas L Rothman.

60 records · Page 4Linked to original sources

PubMed2002

Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors.

OBJECTIVE: Studies have demonstrated low concentrations of gamma-aminobutyric acid (GABA) in the plasma and CSF of individuals with major depression, and low GABA concentrations have also been found in the occipital cortex of depressed subjects. The goal of this study was to determine whether these occipital cortex GABA concentrations are altered after administration of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. METHOD: By means of proton magnetic resonance spectroscopy, occipital cortex GABA concentrations were measured in 11 medication-free depressed patients before initiation of treatment with SSRI medications and after an average of 2 months of treatment. RESULTS: A significant increase in occipital cortex GABA concentrations was seen after SSRI treatment. CONCLUSIONS: SSRI treatment of major depression is associated with increased occipital cortex GABA concentrations. This appears to result in a normalization of low pretreatment GABA concentrations, an effect that may contribute to a common mechanism of antidepressant action.

Adult↗

PubMed2002

Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity.

The metabolism and composition of skeletal muscle tissue is of special interest because it is a primary site of insulin action and plays a key role in the pathogenesis of insulin resistance. Intramyocellular (IMCL) triglyceride stores are an accessible form of energy that may decrease skeletal muscle glucose utilization, thereby contributing to impaired glucose metabolism. Because of the invasive nature of muscle biopsies, there is limited, if any, information about intramuscular lipid stores in children. The development of (1)H nuclear magnetic resonance (NMR) spectroscopy provides a unique noninvasive alternative method that differentiates intracellular fat from intercellular fat in muscle tissue. The present study was performed to determine whether IMCL and extramyocellular (EMCL) lipid contents are increased early in the development of juvenile obesity and to explore the relationships between IMCL and EMCL to in vivo insulin sensitivity, independently of total body fat and central adiposity in obese and nonobese adolescents. Eight nonobese (BMI 21 kg/m(2), age 11-16 years) and 14 obese (BMI 35 +/- 1.5 kg/m(2), age 11-15 years) adolescents underwent 1) (1)H-NMR spectroscopy to noninvasively quantify IMCL and EMCL triglyceride content of the soleus muscle, 2) a 2-h euglycemic-hyperinsulinemic clamp (40 mU.m(-2).min(-1)) to assess insulin sensitivity, 3) a dual-energy X-ray absorptiometry scan to measure total percent body fat, and 4) magnetic resonance imaging to measure abdominal fat distribution. Both the IMCL and EMCL content of the soleus muscle were significantly greater in the obese adolescents than in the lean control subjects. A strong inverse correlation was found between IMCL and insulin sensitivity, which persisted and became even stronger after controlling for percent total body fat and abdominal subcutaneous fat mass (partial correlation r = -0.73, P < 0.01) but not when adjusting for visceral fat (r = - 0.54, P < 0.08). In obese adolescents, increase in total body fat and central adiposity were accompanied by higher IMCL and EMCL lipid stores. The striking relationships between both IMCL and EMCL with insulin sensitivity in childhood suggest that these findings are not a consequence of aging but occur early in the natural course of obesity.

Absorptiometry, Photon↗

PubMedDate not supplied

Cerebral pyruvate carboxylase flux is unaltered during bicuculline-seizures.

Glutamine synthesis in the astroglia reflects the sum of neurotransmitter cycling (glutamate and gamma-aminobutyric acid [GABA]) and de novo synthesis (anaplerosis), the latter catalyzed by pyruvate carboxylase. Previous studies have shown that the glutamate plus GABA cycling flux is correlated strongly with neuronal activity; however, the relationship between pyruvate carboxylase flux and neuronal activity is not known. In this study, pyruvate carboxylase flux was assessed during intravenous infusion of [2-(13)C]glucose using localized (1)H-[(13)C] NMR spectroscopy at 7 Tesla in vivo in halothane-anesthetized and ventilated adult Wistar rats during 85 min of bicuculline-induced seizures (1 mg/kg, intravenously) and in nontreated controls. During seizures, concentrations of lactate, alanine, glutamine, GABA, and succinate increased whereas glutamate and aspartate decreased such that the decrease in glutamate plus aspartate equaled the increase in glutamine plus GABA. Pyruvate carboxylase flux was assessed by the sum of [2-(13)C] and [3-(13)C] of glutamine and glutamate (Glx(2+3)) labeling during [2-(13)C]glucose infusion. During seizures the initial rate of Glx(2+3) synthesis (0.069 +/- 0.013 micromol/g/min) was not significantly different (P = 0.68) from that of the controls (0.059 +/- 0.010 micromol/g/min), indicating that anaplerotic flow through pyruvate carboxylase was unaltered. Intense neuronal activation of seizures did not seem to increase anaplerosis through pyruvate carboxylase, despite the substantial increase in neuronal activity and glutamate/glutamine cycling shown in a previous study (Patel et al., 2004b).

Amino Acids↗

PubMedDate not supplied

In vivo 1H-[13C]-NMR spectroscopy of cerebral metabolism.

13C NMR spectroscopy in combination with the infusion of (13)C-labeled precursors is currently the only technique that is capable of quantitatively studying energy metabolism, neurotransmission and other metabolic pathways non-invasively in vivo. (1)H-[(13)C]-NMR spectroscopy is a high-sensitivity alternative to direct (13)C NMR spectroscopy. The development of improved NMR methods for water suppression, spatial localization, broadband decoupling, shimming and signal quantification, together with the availability of high magnetic field strengths, has made (1)H-[(13)C]-NMR spectroscopy the method of choice for the detection of metabolism at a high spatial and/or temporal resolution. (1)H-[(13)C]-NMR spectroscopy can now be used to discriminate glutamatergic (excitatory) and GABAergic (inhibitory) neuronal activity. The improved sensitivity allows the detection of metabolism in different tissues (e.g. gray and white matter) and potentially even in smaller structures, like cortical layers. Finally, (1)H-[(13)C]-NMR spectroscopy allows the detection of energy metabolism and neurotransmission during functional activation, thereby further strengthening our understanding of the neurochemical basis of brain function.

Algorithms↗

PubMedDate not supplied

Magnetic resonance spectroscopic imaging of tumor metabolic markers for cancer diagnosis, metabolic phenotyping, and characterization of tumor microenvironment.

Cancer cells display heterogeneous genetic characteristics, depending on the tumor dynamic microenvironment. Abnormal tumor vasculature and poor tissue oxygenation generate a fraction of hypoxic tumor cells that have selective advantages in metastasis and invasion and often resist chemo- and radiation therapies. The genetic alterations acquired by tumors modify their biochemical pathways, which results in abnormal tumor metabolism. An elevation in glycolysis known as the "Warburg effect" and changes in lipid synthesis and oxidation occur. Magnetic resonance spectroscopy (MRS) has been used to study tumor metabolism in preclinical animal models and in clinical research on human breast, brain, and prostate cancers. This technique can identify specific genetic and metabolic changes that occur in malignant tumors. Therefore, the metabolic markers, detectable by MRS, not only provide information on biochemical changes but also define different metabolic tumor phenotypes. When combined with the contrast-enhanced Magnetic Resonance Imaging (MRI), which has a high sensitivity for cancer diagnosis, in vivo magnetic resonance spectroscopic imaging (MRSI) improves the diagnostic specificity of malignant human cancers and is becoming an important clinical tool for cancer management and care. This article reviews the MRSI techniques as molecular imaging methods to detect and quantify metabolic changes in various tumor tissue types, especially in extracranial tumor tissues that contain high concentrations of fat. MRI/MRSI methods have been used to characterize tumor microenvironments in terms of blood volume and vessel permeability. Measurements of tissue oxygenation and glycolytic rates by MRS also are described to illustrate the capability of the MR technology in probing molecular information non-invasively in tumor tissues and its important potential for studying molecular mechanisms of human cancers in physiological conditions.

Adult↗

PubMedDate not supplied

Reference values for long echo time MR spectroscopy in healthy adults.

BACKGROUND AND PURPOSE: There is a lack of information with regard to normal metabolic ratios acquired with MR spectroscopy utilizing a long echo time technique. Our purpose was to measure metabolic ratios in healthy adults to determine whether the metabolites varied across brain regions and by sex. METHODS: Single voxel proton spectra were acquired with an echo time of 135 milliseconds in 10 brain regions of 72 healthy subjects ranging in age from 20 to 44 years. Six gray matter sites in the cerebrum included four cortical areas in the frontal, parietal, temporal, and occipital lobes, and two deep nuclear sites in the basal ganglia and the thalamus. Two subcortical white matter regions were in the parietal and the frontal lobes. Two posterior fossa sites included the pons and the cerebellum. All 10 brain regions were not studied in each subject. For each spectrum, the metabolites n-acetylaspartate (NAA), creatine (Cr), and choline (Ch) were identified and ratios of NAA/Cr and Ch/Cr calculated for each brain region. A multifactorial analysis of variance was performed with the two metabolic ratios as dependent variables and with brain region and sex as independent variables. Post hoc statistical analysis consisted of the Scheffé F statistic for significant difference between pairs of brain regions for both metabolic ratios. RESULTS: There was significant regional variation for both the NAA/Cr ratio (P < .0001) and the Ch/Cr ratio (P < .0001). The NAA/Cr ratio was consistent within cortical gray and white matter but differed between cortical gray (smaller ratio) and white matter (larger ratio). The Ch/Cr ratio was variable in the gray matter, differed between some but not all gray and white matter regions, but was consistent within subcortical white matter regions. There was no difference between men and women for either metabolic ratio. CONCLUSION: There was variation of the NAA/Cr ratio and the Ch/Cr ratio across brain regions, but no sex differences were found. These findings provide the requisite normative values to use single voxel, long-echo-time MR spectroscopy in adult patients with neurologic disorders.

Adult↗