Biomedical subjects

D L Rothman

Publications and source records attributed to D L Rothman.

At least 91 records · Page 5Linked to original sources

PubMed1996

The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy.

Gabapentin has come into clinical use as adjunctive therapy in the treatment of epilepsy. Designed to mimic gamma-aminobutyric acid (GABA), its mechanism of action remains elusive. In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 13.5-cm3 volume in the occipital cortex. GABA levels were measured in 14 patients enrolled in an open-lbel trial of gabapentin. GABA was elevated in patients taking gabapentin compared with 14 complex partial epilepsy patients, matched for antiepileptic drug treatment. Brain GABA levels appeared to be higher in patients taking high-dose gabapentin (3,300-3,600 mg/day) than in those taking standard doses (1,200-2,400 mg/day). Gabapentin appears to increase human brain GABA levels.

Acetates↗

PubMed1996

Low brain GABA level is associated with poor seizure control.

Low gamma-aminobutyric acid (GABA) concentrations in the cerebrospinal fluid are seen in a variety of epileptic syndromes. Low GABA levels outside of the epileptic focus may facilitate spread of discharges beyond the focus. In vivo measurements of GABA were made by 1H spectroscopy using a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 14-cm3 volume in the occipital lobe. Patients with complex partial seizures had lower GABA levels (1.03 mmol/kg of brain; 95% confidence interval [CI], 0.95-1.12; n = 28; p < 0.02) than did subjects without epilepsy (1.18; 95% CI, 1.13-1.24; n = 19). There was a significant association between low GABA levels and recent seizures (correlation coefficient of 0.548, p < 0.01, df of 32). Conversely, patients with well-controlled seizures had higher brain GABA levels than did patients with recent seizures. Patients with seizures within a day of the measurement had lower GABA levels (0.92 mmol/kg; 95% CI, 0.78-1.06; n = 7) than did patients who were seizure free for 5 years or longer (1.28; 95% CI, 1.09-1.47; n = 4). Poor seizure control is associated with low brain GABA levels.

Adult↗

PubMed1996

Noninvasive assessment of hepatic triglyceride content in humans with 13C nuclear magnetic resonance spectroscopy.

Hepatic lipid content was assessed noninvasively in 15 patients with hepatic steatosis by 13C nuclear magnetic resonance (NMR) spectroscopy, and compared in a double-blind fashion with histological grading and morphometric quantitation of fat in liver biopsies taken within 2 weeks of the study. The lipid content in the liver biopsies was expressed as the volume fraction of total parenchyma occupied by fat. Hepatic triglyceride content was determined by comparing the 13C NMR signal intensity in vivo with the signal intensity obtained from a lipid phantom of known concentrations. There was an approximately 30-fold increase in the 13C NMR signals of the saturated carbons (methyl/methylene [CH2]n) region of hepatic triglycerides from patients with grade 4 steatosis compared with those with grade 0, yielding a good dynamic range for measuring hepatic triglyceride content. The correlation coefficient between the morphometric and 13C NMR techniques was 0.89 (P < .01). These studies demonstrate that 13C NMR spectroscopy can be used to noninvasively assess hepatic triglyceride content in humans. This method may be clinically useful for diagnosis and follow-up of patients with hepatic steatosis.

Adult↗

PubMed1996

Short echo time proton magnetic resonance spectroscopic imaging of macromolecule and metabolite signal intensities in the human brain.

A novel approach is presented for imaging macromolecule and metabolite signals in brain by proton magnetic resonance spectroscopic imaging. The method differentiates between metabolites and macromolecules by T1 weighting using an inversion pulse followed by a variable inversion recovery time before localization and spectroscopic imaging. In healthy subjects, the major macromolecule resonances at 2.05 and 0.9 ppm were mapped at a nominal spatial resolution of 1 x 1 x 1.5 cm3 and were demonstrated to be highly reproducible between subjects. In subacute stroke patients, a highly elevated macromolecule resonance at 1.3 ppm was mapped to infarcted brain regions, suggesting potential applications for studying pathological conditions.

Adult↗

PubMed1996

Dynamic shim updating: a new approach towards optimized whole brain shimming.

The static magnetic field within two widely spaced axial slices of the human brain was mapped in five subjects following global shimming. This revealed a first order field shift in the anterior-posterior direction between the cerebellum and cerebrum, which has implications for functional and spectroscopic magnetic resonance imaging. A new method is described called dynamic shim updating (DSU) to compensate for these field differences whereby the shim correction fields are updated in real time during multislice data acquisition to match the current imaging or spectroscopy slice. A hardware unit is presented to demonstrate the method using the first order shim corrections, which can be updated virtually instantaneously between slice acquisitions to give optimal shimming of each slice. The efficiency of the approach is demonstrated using field mapping and high speed MR imaging (echo-planar imaging), which are sensitive to field inhomogeneity.

Brain↗

PubMed1996

The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA).

Brain GABA levels rise and plateau following prolonged administration of the irreversible GABA-transaminase inhibitor vigabatrin (gamma-vinylGABA). Recently it has been shown that increased GABA levels reduces GAD67 protein, one of two major isoforms of glutamic acid decarboxylase (GAD). The effects of GABA elevation on GABA synthesis were assessed in vivo using 1H and 13C-edited NMR spectroscopy. Rates of turnover of cortical glutamate and GABA from intravenously administered [1-13C]glucose were measured in alpha-chloralose anesthetized rats 24 hours after receiving vigabatrin (500 mg/kg, i.p.) and in non-treated controls. GABA concentration was increased 2-fold at 24 hours (from 1.3 +/- 0.4 to 2.7 +/- 0.9 mumol/g) and GABA-T activity was inhibited by 60%. Tricarboxylic acid cycle flux was not affected by vigabatrin treatment compared to non-treated rats (0.47 +/- 0.19 versus 0.52 +/- 0.18 mumol/g, respectively). GABA-C2 fractional enrichment (FE) measured in acid extracts rose more slowly in vigabatrin-treated compared to non-treated rats, reaching > 90% of the glutamate FE after 3 hours. In contrast, GABA FE > or = glutamate FE in non-treated rats. A metabolic model consisting of a single glutamate pool failed to account for the rapid labeling of GABA from glutamate. Metabolic modelling analysis based on two (non-communicating) glutamate pools revealed a approximately 70% decrease in the rate of GABA synthesis following vigabatrin-treatment, from 0.14 (non-treated) to 0.04 mumol/g/min (vigabatrin-treated). These findings, in conjunction with the previously reported differential effects of elevated GABA on the GAD isoforms, suggests that GAD67 may account for a major fraction of cortical GABA synthesis in the alpha-chloralose anesthetized rat brain in vivo.

4-Aminobutyrate Transaminase↗

PubMed1996

Human brain gamma-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy.

Vigabatrin is a novel antiepileptic drug designed to control seizures by raising brain gamma-aminobutyric acid (GABA) concentrations. Seizure control is not improved significantly when the daily dose is increased beyond 50 mg/kg. Serial, in vivo measurements of GABA levels in human occipital lobe were made using 1H NMR spectroscopy before and after the start of vigabatrin treatment. We used a 2.1-T magnetic resonance imagerspectrometer and an 8-cm surface coll to examine serially a 14-cm3 volume in the occipital lobe of 26 patients with complex partial seizures. Brain GABA content increased following the start of vigabatrin treatment up to a daily dose of 60 mg/kg. Additional increases in dose falled to increase brain GABA content further. GABA synthesis may decrease with sustained elevations of human brain GABA levels. Starting vigabatrin treatment reduced seizure frequency by > 50%, from six to seven per month to three. Improved seizure control was not associated with further increases of vigabatrin dose. Increased brain GABA concentration was associated with improved seizure control. Starting vigabatrin treatment improved seizure control twofold when GABA levels increased above 1.8 mmol/kg. Further increases in brain GABA content above 2.5 mmol/kg provided less protection. Measuring occipital lobe GABA concentrations may predict improved seizure control when using antiepileptic drugs designed to increase brain GABA levels.

Adult↗

PubMed1996

1H NMR studies of glucose transport in the human brain.

The difference between 1H nuclear magnetic resonance (NMR) spectra obtained from the human brain during euglycemia and during hyperglycemia is depicted as well-resolved glucose peaks. The time course of these brain glucose changes during a rapid increase in plasma glucose was measured in four healthy subjects, aged 18-22 years, in five studies. Results demonstrated a significant lag in the rise of glucose with respect to plasma glucose. The fit of the integrated symmetric Michaelis-Menten model to the time course of relative glucose signals yielded an estimated plasma glucose concentration for half maximal transport, Kt, of 4.8 +/- 2.4 mM (mean +/- SD), a maximal transport rate, Tmax, of 0.80 +/- 0.45 micromol g-1 min-1, and a cerebral metabolic glucose consumption rate (CMR)glc of 0.32 +/- 0.16 micromol g-1 min-1. Assuming cerebral glucose concentration to be 1.0 micromol/g at euglycemia as measured by 13CMR, the fit of the same model to the time course of brain glucose concentrations resulted in Kt = 3.9 +/- 0.82 mM, Tmax = 1.16 +/- 0.29 micromol g-1 min-1, and CMRglc = 0.35 +/- 0.10 micromol g-1 min-1. In both cases, the resulting time course equaled that predicted from the determination of the steady-state glucose concentration by 13C NMR spectroscopy within the experimental scatter. The agreement between the two methods of determining transport kinetics suggests that glucose is distributed throughout the entire aqueous phase of the human brain, implying substantial intracellular concentration.

Adolescent↗

PubMed1996

Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period.

Relative contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production during the first 12 h of a fast were studied in 13 healthy volunteers by noninvasively measuring hepatic glycogen content using 13C nuclear magnetic resonance spectroscopy. Rates of net hepatic glycogenolysis were calculated by multiplying the change in liver glycogen content with liver volume determined by magnetic resonance imaging. Rates of gluconeogenesis were calculated as the difference between rates of glucose production determined with an infusion of [6,6-2H]-glucose and net hepatic glycogenolysis. At 6 P.M. a liquid mixed meal (1,000 kcal; 60% as glucose) was given, to which [2-2H]glucose was added to trace glucose absorption. Hepatic glycogen content was measured between 11 P.M. and 1 A.M. and between 3 and 6 A.M. At 11 P.M. the concentration was 470 mM and it decreased linearly during the night. The mean liver volume was 1.47 +/- 0.06 liters. Net hepatic glycogenolysis (5.8 +/- 0.8 mumol.kg body wt-1.min-1) accounted for, on average, 45 +/- 6% and gluconeogenesis for 55 +/- 6% of the rate of whole body glucose production (12.6 +/- 0.6 mumol.kg body wt-1.min-1). In conclusion, this study shows that, even early in the phase of the postabsorptive period when liver glycogen stores are maximal, gluconeogenesis contributes approximately 50% to hepatic glucose production.

Adult↗

PubMed1996

Human brain GABA levels rise after initiation of vigabatrin therapy but fail to rise further with increasing dose.

Using 1H spectroscopy, we measured occipital lobe GABA levels serially in 18 patients enrolled in an ongoing open label trial of vigabatrin. Brain GABA levels were elevated twofold in patients taking vigabatrin (3 to 4 g/d) compared with nonepileptic subjects. Serial measurements suggested that brain GABA rose in proportion to vigabatrin dose up to 3 g/d. Doubling the dose from 3 to 6 g/d failed to increase brain GABA further. Serial measurements on three patients taking 6 g/d showed a gradual decrease in brain GABA in two patients over 1 to 2 years of treatment. These observations suggest that GABA synthesis may decrease at high GABA levels.

Adult↗

PubMed1996

Human brain GABA levels rise rapidly after initiation of vigabatrin therapy.

OBJECTIVE: The purpose of this study was to measure changes in brain GABA after a single oral dose (50 mg/kg) of vigabatrin in patients with intractable epilepsy. BACKGROUND: Vigabatrin is a safe and effective antiepileptic medication designed to increase brain GABA by irreversibly inhibiting GABA-transaminase. Serial measurements showed that brain GABA levels increased from 1.0 (SEM, 0.07) to 2.4 mmol/kg (SEM, 0.09) in patients who were regularly taking vigabatrin (50 mg/kg/day divided into two doses). METHODS: In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T NMR spectrometer and an 8-cm surface coil to measure a 13.5 cm3 volume in the occipital cortex. RESULTS: Brain GABA increased by more than 40% within 2 hours of administration of a single 50 mg/kg oral dose of vigabatrin from 0.95 (SEM, 0.07; n = 7) to 1.34 mmol/kg (SEM, 0.13). By the next day, brain GABA increased further to 1.44 mmol/kg (SEM, 0.08). Levels declined gradually to 1.16 mmol/kg (SEM, 0.14) by day 5 and 1.03 mmol/kg (SEM, 0.10) at day 8. The patients reported no side effects and were calm but not drowsy. CONCLUSIONS: A single oral dose of vigabatrin rapidly increased brain GABA without side effects. Once-a-day dosing should be as effective as divided doses.

Administration, Oral↗

PubMed1996

Nuclear magnetic resonance studies of muscle and applications to exercise and diabetes.

Natural-abundance 13C nuclear magnetic resonance (NMR) spectroscopy is a noninvasive technique that enables in vivo assessments of muscle and/or liver glycogen concentrations. When directly compared with the traditional needle biopsy technique, NMR was found to be more precise. Over the last several years, we have developed and used 13C-NMR to obtain information about human glycogen metabolism both under conditions of altered blood glucose and/or insulin and with exercise. Because NMR is noninvasive, we have been able to obtain more data points over a specified time course, thereby dramatically improving the time resolution. This improved time resolution has enabled us to document subtleties of the resynthesis of muscle glycogen after severe exercise that have not been observed previously. An added advantage of NMR is that we are able to obtain information simultaneously about other nuclei, such as 31P. With interleaved 13C- and 31P-NMR techniques, we have been able to follow simultaneous changes in muscle glucose-6-phosphate and muscle glycogen. In this article, we review some of the work that has been reported by our laboratory and discuss the relevance of our findings for the management of diabetes.

Animals↗

PubMed1996

Pediatric orofacial injuries.

Perioral injuries may have significant medical, dental and psychological consequences in children. Soft-tissue injuries are common-place, with the most common types being contusions, abrasions, lacerations and electrical and chemical burns. Each type requires specific care and follow through. Immediate intervention and treatment are important, and rapid neurologic assessment of a child before treatment helps the long-term prognosis. Children must also be screened for abuse and neglect. The common goal of treatment is to prevent infection, provide function and minimize scarring. Perioral injuries are preventable.

Burns, Chemical↗

PubMed1995

In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis.

The activity of glycogen synthase (GSase; EC 2.4.1.11) is regulated by covalent phosphorylation. Because of this regulation, GSase has generally been considered to control the rate of glycogen synthesis. This hypothesis is examined in light of recent in vivo NMR experiments on rat and human muscle and is found to be quantitatively inconsistent with the data under conditions of glycogen synthesis. Our first experiments showed that muscle glycogen synthesis was slower in non-insulin-dependent diabetics compared to normals and that their defect was in the glucose transporter/hexokinase (GT/HK) part of the pathway. From these and other in vivo NMR results a quantitative model is proposed in which the GT/HK steps control the rate of glycogen synthesis in normal humans and rat muscle. The flux through GSase is regulated to match the proximal steps by "feed forward" to glucose 6-phosphate, which is a positive allosteric effector of all forms of GSase. Recent in vivo NMR experiments specifically designed to test the model are analyzed by metabolic control theory and it is shown quantitatively that the GT/HK step controls the rate of glycogen synthesis. Preliminary evidence favors the transporter step. Several conclusions are significant: (i) glucose transport/hexokinase controls the glycogen synthesis flux; (ii) the role of covalent phosphorylation of GSase is to adapt the activity of the enzyme to the flux and to control the metabolite levels not the flux; (iii) the quantitative data needed for inferring and testing the present model of flux control depended upon advances of in vivo NMR methods that accurately measured the concentration of glucose 6-phosphate and the rate of glycogen synthesis.

Allosteric Regulation↗

PubMed1995

Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus.

Recent studies have demonstrated that reduced insulin-stimulated muscle glycogen synthesis is the major cause of insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM). This reduced rate has been assigned to a defect in either glucose transport or hexokinase activity. However it is unknown whether this is a primary or acquired defect in the pathogenesis of NIDDM. To examine this question, we measured the rate of muscle glycogen synthesis and the muscle glucose 6-phosphate (G6P) concentration using 13C and 31P NMR spectroscopy as well as oxidative and nonoxidative glucose metabolism in six lean, normoglycemic offspring of parents with NIDDM and seven age/weight-matched control subjects under hyperglycemic (approximately 11 mM)-hyperinsulinemic (approximately 480 pM) clamp conditions. The offspring of parents with NIDDM had a 50% reduction in total glucose metabolism, primarily due to a decrease in the nonoxidative component. The rate of muscle glycogen synthesis was reduced by 70% (P < 0.005) and muscle G6P concentration was reduced by 40% (P < 0.003), which suggests impaired muscle glucose transport/hexokinase activity. These changes were similar to those previously observed in subjects with fully developed NIDDM. When the control subjects were studied at similar insulin levels (approximately 440 pM) but euglycemic plasma glucose concentration (approximately 5 mM), both the rate of glycogen synthesis and the G6P concentration were reduced to values similar to the offspring of parents with NIDDM. We conclude that insulin-resistant offspring of parents with NIDDM have reduced nonoxidative glucose metabolism and muscle glycogen synthesis secondary to a defect in muscle glucose transport/hexokinase activity prior to the onset of overt hyperglycemia. The presence of this defect in these subjects suggests that it may be the primary factor in the pathogenesis of NIDDM.

Adenosine Diphosphate↗

PubMed1995

Image reconstruction of sequentially sampled echo-planar data.

For echo-planar imaging (EPI), failure to time-reverse alternate echoes results in aliasing in the image. We encountered image artifacts in EPI acquired on a system with sequential sampling. After examining the source of these image artifacts, we concluded that the artifacts were a result of the type of sampling method used in data acquisition and the way the time-reversal of alternate echoes was carried out prior to Fourier transformation. Two methods are demonstrated to obtain artifact-free EPI with sequential data sampling.

Echo-Planar Imaging↗

PubMed1995

Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR.

13C isotopic tracer data previously obtained by 13C nuclear magnetic resonance in the human brain in vivo were analyzed using a mathematical model to determine metabolic rates in a region of the human neocortex. The tricarboxylic acid (TCA) cycle rate was 0.73 +/- 0.19 mumol min-1 g-1 (mean +/- SD; n = 4). The standard deviation reflects primarily intersubject variation, since individual uncertainties were low. The rate of alpha-ketoglutarate/glutamate exchange was 57 +/- 26 mumol min-1 g-1 (n = 3), which is much greater than the TCA cycle rate; the high rate indicates that alpha-ketoglutarate and glutamate are in rapid exchange and can be treated as a single combined kinetic pool. The rate of synthesis of glutamine from glutamate was 0.47 mumol min-1 g-1 (n = 4), with 95% confidence limits of 0.139 and 3.094 mumol min-1 g-1; individual uncertainties were biased heavily toward high synthesis rates. From the TCA cycle rate the brain oxygen consumption was estimated to be 2.14 +/- 0.48 mumol min-1 g-1 (5.07 +/- 1.14 ml 100 g-1 min-1; n = 4), and the rate of brain glucose consumption was calculated to be 0.37 +/- 0.08 mumol min-1 g-1 (n = 4). The sensitivity of the model to the assumptions made was evaluated, and the calculated values were found to be unchanged as long as the assumptions remained near reported physiological values.

Brain↗

PubMed1995

Initial observations on effect of vigabatrin on in vivo 1H spectroscopic measurements of gamma-aminobutyric acid, glutamate, and glutamine in human brain.

Recent developments involving 1H nuclear magnetic resonance (NMR) spectroscopic editing techniques have allowed noninvasive measurements of gamma-aminobutyric acid (GABA) in human cerebrum. The additional information gained from GABA and macromolecule measurements permitted more precise glutamate (Glu) and glutamine (Gln) measurements. Occipital lobe GABA in 10 nonepileptic, healthy subjects was 1.0 mumol/g brain [95% confidence interval (CI) 0.9-1.1]. Vigabatrin (VGB) is a safe and effective antiepileptic drug (AED) that irreversibly inhibits neuronal and glial GABA-transaminase. GABA levels were increased in all patients treated with VGB. With a standard dose of 3-6 g/day, GABA levels were 2.6 mumol/g (95% CI 2.3-2.8). Mean occipital GABA level measured in epileptic patients not receiving VGB was 0.9 mumol/g (95% CI 0.7-1.1). Gln was increased by 1.9 mumol/g and Glu was decreased by 0.8 mumol/g in patients receiving VGB as compared with patients receiving standard medications alone.

Adult↗