Digital color imaging colposcopy: a matter of choice

PURPOSE: The objective of this study was to correlate the findings of sarcoidosis on high resolution CT (HRCT) with indexes of disease activity as measured with 67Ga scan, bronchoalveolar lavage (BAL), and serum angiotensin-converting enzyme (SACE) assay. METHOD: Twenty-nine patients with proven sarcoidosis underwent HRCT scan, 67Ga scan, BAL, and SACE assay within a 1 month period. The extent of parenchymal involvement by nodules, consolidation, ground-glass attenuation, and linear opacities was quantified to the nearest 10% of surface area affected on the CT examination. Whole-lung gallium uptake was quantified and the percentage of BAL-recovered lymphocytes (BAL-%LC) and SACE levels obtained by chart review. CT scores of disease extent were correlated with measured indexes of activity using the Spearman rank correlation coefficient. RESULTS: The mean extent of nodules, consolidation, ground-glass attenuation, and linear opacities on HRCT images was 15.1 +/- 16.6, 1.6 +/- 4.0, 17.5 +/- 25.4, and 7.6 +/- 9.6%, respectively. The extent of nodules and consolidation correlated with the intensity of lung gallium uptake (r = 0.46, p < 0.02), BAL-%LC (r = 0.50, p < 0.01), and SACE levels (r = 0.38, p < 0.05). No significant correlation was found between extent of ground-glass attenuation or linear opacities with any indexes of disease activity. CONCLUSION: On HRCT scan, nodules and consolidation in sarcoidosis reflect disease activity as measured by 67Ga scan, BAL, and SACE assay.     

Gallium scanning in cerebral and cranial disorders

Gallium scanning of cranial and cerebral abnormalities is a complex topic in which neither the mechanism of gallium accumulation or the clinical utility can be clearly defined. In the tests available to the neurologist, neurosurgeon, or practitioner, the gallium brain scan, computed tomographic brain scan, or other noninvasive studies are inconclusive. Its use as a primary localization test for CNS tumors does not appear to be warranted in view of the high sensitivity reported for conventional nuclide brain scanning, as well as computed tomography. In selected cases, the use of a gallium brain scan has been helpful in the differentiation of CNS lesions, as well as the early detection of intracerebral infection. New techniques involving 67Ga may eventually prove useful in the evaluation of CNS disorders, especially in the area of quantitating the amount of abnormal brain tissue removed following craniotomy.     

Benzodiazepine receptors in chronic cerebrovascular disease: comparison with blood flow and metabolism

The brain benzodiazepine (BZD) receptor distribution in patients with chronic cerebrovascular disease was assessed with 123I-iomazenil (IMZ) SPECT, and the findings were compared with the data for the cerebral blood flow (CBF) and cerebral metabolism. METHODS: We examined nine patients with chronic cerebrovascular diseases, six patients with cerebral infarction and three with moyamoya disease. Iodine-123-IMZ SPECT images were obtained for 15 min, 3 hr after the administration of 167 or 222 MBq 123I-IMZ. In seven patients, the CBF and oxygen metabolism were measured by the 50 steady-state method. In two patients, the CBF and glucose metabolism were measured by 99mTc-HMPAO SPECT and 18F-fluoro-2-deoxy-D-glucose-PET, respectively. The brain was initially classified into 18 regions, and abnormalities in the BZD receptor distribution, CBF and cerebral metabolism were visually evaluated. The count ratio of lesion-to-contralateral normal region (L-to-C ratio) was then used for comparison. RESULTS: In the core of the infarct, the 123I-IMZ uptake decreased (L-to-C ratios of the blood flow 0.42 +/- 0.26; metabolism 0.45 +/- 0.24; and 123I-IMZ uptake 0.46 +/- 0.14). In the peri-infarct region, the 123I-IMZ uptake slightly decreased (L-to-C ratios of 0.81, 0.82 and 0.89, respectively). In the region of misery perfusion, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.73, 1.07 and 1.02, respectively). In the remote deafferentiated areas in the ipsilateral cerebrum, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.76 +/- 0.10, 0.75 +/- 0.04 and 0.98 +/- 0.05, respectively). In the remote areas in the contralateral cerebellum, the 123I-IMZ uptake was preserved (L-to-C ratios of 0.84 +/- 0.08, 0.85 +/- 0.04 and 0.94 +/- 0.05, respectively). CONCLUSION: The BZD receptor distribution, as measured by 123I-IMZ SPECT, is not considered to reflect neuronal function, but it may reflect neuronal cell viability. Iodine-123-IMZ SPECT may, therefore, hold promise as a potential probe for neuronal damage.     

Transferrin receptor-dependent and -independent iron transport in gallium-resistant human lymphoid leukemic cells

Recent studies showed that gallium and iron uptake are decreased in gallium-resistant (R) CCRF-CEM cells; however, the mechanisms involved were not fully elucidated. In the present study, we compared the cellular uptake of 59Fe-transferrin (Tf) and 59Fe-pyridoxal isonicotinoyl hydrazone (PIH) to determine whether the decrease in iron uptake by R cells is caused by changes in Tf receptor (TfR)-dependent or TfR-independent iron uptake. We found that both 59Fe-Tf and 59Fe-PIH uptake were decreased in R cells. The uptake of 59Fe-Tf but not 59Fe-PIH could be blocked by an anti-TfR monoclonal antibody. After 59Fe-Tf uptake, R cells released greater amounts of 59Fe than gallium-sensitive (S) cells. However, after 59Fe-PIH uptake 59Fe release from S and R cells was similar. 125I-Tf exocytosis was greater in R cells. At confluency, S and R cells expressed equivalent amounts of TfR; however, at 24 and 48 hours in culture, TfR expression was lower in R cells. Our study suggests that the decrease in Tf-Fe uptake by R cells is caused by a combination of enhanced iron efflux from cells and decreased TfR-mediated iron transport into cells. Furthermore, because TfR-dependent and -independent iron uptake is decreased in R cells, both uptake systems may be controlled at some level by similar regulatory signal(s).     

Effects of agents that inhibit cellular iron incorporation on bladder cancer cell proliferation

Agents that interfere with cellular iron (Fe) incorporation inhibit tumor cell proliferation, including metals that bind to transferrin (Tf) such as gallium (Ga) or indium (In) and Fe chelators such as desferrioxamine (DFO). Ga nitrate is effective in the treatment of metastatic bladder cancer and these patients exhibit evidence for interference with Fe metabolism. We show here that bladder cancer cell proliferation in vitro is dependent on Tf-Fe. Concentrations of DFO that can be readily achieved in vivo inhibit cellular proliferation even in the presence of physiologic concentrations of Tf-Fe. Inhibition of proliferation by Tf-Ga is associated with decreased cellular Fe incorporation. However, when a physiologic concentration of Tf-Fe is added to an equimolar concentration of Tf-Ga, significant Fe incorporation is evident despite inhibition of proliferation. Thus, besides interference with Fe incorporation, Ga may also interfere with intracellular Fe distribution and/or directly inhibit an Fe- (or non-Fe-) requiring process necessary for cellular proliferation. DFO followed sequentially by Tf-Ga results in marked potentiation of inhibition of proliferation. The effects of this combination appear to be related to both interference with Fe metabolism and increased Ga uptake. This sequential combination may be useful in the treatment of bladder cancer.     

Inhibition of uptake of transferrin-bound iron by human hepatoma cells by nontransferrin-bound iron

The liver acquires iron from transferrin by transferrin receptor-mediated (TR) and transferrin receptor-independent pathways (NTR) and from nontransferrin-bound iron (NTB-Fe). Iron uptake by the NTR processes involves an iron-carrier mediated step. Experiments, using human hepatoma cells (HuH7) transfected with TR antisense (sense for control) RNA expression vectors to suppress TR expression, were performed to examine the effect of unlabeled NTB-Fe as iron citrate on the uptake of 59Fe-125I-transferrin. This was to determine if the uptake of transferrin-bound iron (Tf-Fe) and NTB-Fe uptake is mediated by a common iron-carrier. Iron citrate inhibited the uptake of 59Fe-transferrin (2.5 micromol/L Fe) in a concentration-dependent manner with a maximum effect when the citrate-iron:Tf-Fe molar ratio was 10:1. Transferrin uptake was not affected. At a lower Tf-Fe concentration of (0.125 micromol/L) when uptake of iron is TR-mediated, a 10-fold molar excess of iron citrate had no effect on Tf-Fe uptake by HuH7 TR antisense and sense cells. However, at a higher Tf-Fe concentration (2.5 micromol/L), when uptake occurs mainly by the NTR-mediated process, there was a 40% reduction in the membrane-bound and intracellular uptake of iron. Iron citrate did not affect the maximum rate (Vmax) of Tf-Fe uptake but the Michaelis-Menten constant (Km) for Tf-Fe uptake by the NTR-mediated process was increased, indicating there was competitive inhibition of Tf-Fe uptake by iron citrate. These results suggest that the uptake of NTB-Fe and Tf-Fe by the NTR- mediated process occurs by the same cellular pathway, using a common iron-carrier.     

Down-regulation of brain muscarinic cholinergic receptor promoted by diacylglycerols and phorbol ester

Sustained agonist stimulation induces an asymmetric down-regulation of brain muscarinic acetylcholine receptor (mAChR): 43 +/- 2% in the right and 26 +/- 2% in the left cerebral hemisphere, respectively (Ref. 1). In order to determine the possible involvement of endogenous diacylglycerols produced under muscarinic stimulation in the down-regulation phenomenon, here we have studied the effects of synthetic diacylglycerols and a phorbol ester on cells dissociated from rat cerebral cortex. Oleylacetylglycerol decreased the amount of cell-surface mAChR by 37 +/- 2% and 25 +/- 2% in right and left cerebral cortex, respectively. Long-term treatment with phorbol dibutyrate also produced internalization of the mAChR (25 +/- 1.5% and 33 +/- 2% in right and left cortical cells, respectively). These changes occurred without modification of the Kdapp for the selective antagonist pirenzepine. The action of calcium ions was also studied using incubation of cells with the ionophore A23187. No changes were observed in the amount of mAChR detected at the plasma membrane with the ionophore alone, but when used in combination with phorbol dibutyrate and the agonist carbamylcholine a sinergistic decrease in mAChR was apparent. It is concluded that long-term exposure to exogenously added diacyglycerols and phorbol ester significantly reduces the amount of mAChR detected at the plasma membrane and abolishes the asymmetry of the down-regulation phenomenon observed under specific muscarinic stimulation, suggesting that diacylglycerols may be one of the factors responsible for such asymmetry.     

Uptake of 67Ga in the lactating breast and its persistence in milk: case report

The concentration of 67Ga in the milk of a postpartum woman was measured at intervals up to 8 days after the injection of 3 mCi of 67Ga-citrate. The 67Ga concentration was about 0.15 muCi/ml at 3 days after injection and fell to 0.035 muCi/ml by 8 days. Since the biologic clearance of gallium was slow (T1/2 approximately 9 days), the major determinant of the clearance of radioactivity was the physical decay of the gallium. An estimate of the radiation dose to a nursing infant suggests that nursing be interrupted for about 2 weeks after the mother has had a 67Ga study.     

Heavy metal removal by microalgae

The liver is one of the principal sites of iron overload in diseases such as hemochromatosis and beta thalassemia. Hence, much effort has been invested in examining the mechanisms of Fe uptake by hepatocytes. In the present study we have examined the effect of small molecular weight (M(r)) Fe complexes on Fe uptake from iron 59-labeled transferrin (Tf) and 59Fe-labeled citrate by primary cultures of hepatocytes. This was important to assess because Fe-citrate and saturated diferric Tf coexist in the serum of patients with untreated Fe overload. Preincubation of hepatocytes with the low-M(r) Fe complex ferric ammonium citrate (FAC; 25 microg/mL; (Fe) = 4.4 microg/mL) followed by incubation with 59Fe-Tf or 59Fe-citrate ((Fe) = 0.25 to 25 micromol/L) resulted in the marked stimulation of 59Fe uptake. For example, at a physiologically relevant Tf-Fe concentration of 25 micromol/L, there was an 8-fold increase in 59Fe uptake by cells incubated with FAC compared to control cells. In contrast, at Tf-Fe concentrations of 0.25 to 2.5 micromol/L, 59Fe uptake in FAC-treated cells was only 1-fold to 3-fold greater than that in the corresponding controls. These data suggest that the FAC-activated Fe uptake process predominates at physiologically relevant Tf concentrations above the saturation of the Tf receptor (TfR). This is the first study to demonstrate that preincubation of hepatocytes with Iow-M(r)Fe complexes can markedly increase Fe uptake from diferric Tf. In conclusion, these results may help to explain the loading of hepatocytes with Fe that occurs in Fe-overload disease despite marked down-regulation of the TfR.     

Gallium-67 (Ga-67) scintigraphy in tuberculosis and Mycobacterium avium-M. intracellulare infections in patients with HIV infections

BACKGROUND: Diagnosis of mycobacterioses in HIV infected patients is sometimes difficult because of atypical findings. The aim of this study was to assess the utility of gallium scintigraphy in diagnosis of AIDS related mycobacterioses in patients with fever of unknown origin. PATIENTS AND METHODS: We retrospectively reviewed the scans of 220 HIV(+) patients with fever (176 males [80%] and 44 females) who were evaluated with conventional diagnostic procedures at least of a week before. RESULTS: Gallium scintigraphy was positive in 114 patients (51%) and negative in 106 (49%). Mycobacteria were isolated in 83 patients (38%), 75 of these patients (90%) had a positive scintigraphy (sensitivity 90%; specificity 71%). Positive predictive value was 66% and negative predictive value was 92%. Mycobacterium avium-M. intracellulare (MAI) and M. tuberculosis were diagnosed in 22 (29%) and 53 (71%) HIV(+) patients, respectively. Seventy one (94%) of 75 patients with mycobacterioses had gallium uptake in at least two localizations. CONCLUSIONS: 67Ga scintigraphy is very useful in HIV(+) patients with fever of unknown origin. A negative gallium scintigraphy makes unlikely the diagnosis of mycobacterioses.     

Gallium citrate Ga 67 scanning: clinical usefulness in lymphoma patients

Gallium citrate Ga 67 (67Ga) scans were performed in 50 consecutive lymphoma patients who underwent routine staging. The overall accuracy of 67Ga scans was greater than 80% for all nodal sites except the spleen (68%). Sensitivity was greater than 88% in the neck and mediastinum, 67% in the abdomen-pelvis, and 33% for the spleen. Specificity was greater than 85% for all nodal sites except for the mediastinum (67%). The accuracy of pedal lymphangiograms was 75%, sensitivity 87%, and specificity 68%. Gallium 67 scans complemented the lymphogram in the abdomen-pelvis but, due to limited sensitivity and high number of equivocal studies (16%), did not replace it. Infraclavicular, pectoral, and mediastinal lesions were detected by 67Ga scans when missed by other means. In 20% to 25% of patients, 67Ga scans provided information not afforded by other diagnostic studies and are therefore considered an important staging procedure for lymphoma patients.     

Reverse dorsal digital and metacarpal flaps: a review of 27 cases

It was reported previously that normal soft tissues accumulate 67Ga by a transferrin-dependent route, but uptake by tumors can be transferrin independent. It was also reported that, although overexpression of the transferrin receptor can promote Ga avidity, the transferrin-independent uptake of 67Ga is significant and can be augmented to exceed transferrin-mediated levels by increasing extracellular calcium. In assessing the effect of calcium channel blockers on uptake of 67Ga, it was observed that, after exposure to light (either visible or ultraviolet [UV]), nifedipine strongly potentiates the cellular uptake of 67Ga by a transferrin-independent process. METHODS: The effect of nifedipine on 67Ga uptake as a function of time, concentration, duration and type of preexposure to light was determined in two cultured Chinese hamster ovary cell lines. One cell line lacks the transferrin receptor. In the other, the human transferrin receptor has been restored by transfection and is overexpressed constitutively. RESULTS: Although there are some differences in pattern of stimulation of uptake, nifedipine subjected to either UV or fluorescent light strongly promotes the uptake of 67Ga in the cultured cells in a time-dependent and concentration-dependent manner. Maximal uptake of 67Ga occurs when the cells are incubated for 30 min with 25 micromol/L nifedipine preexposed to either 4h of fluorescent or 1h of UV light. Under these conditions, uptake of 67Ga is 1000-fold greater than basal levels and 50-fold greater than can be achieved by the transferrin-dependent route. Light-shielded nifedipine has no effect on 67Ga uptake. CONCLUSION: The effect of photodegraded nifedipine on the uptake of 67Ga is independent of expression of the transferrin receptor. The potential for photodegraded nifedipine to improve oncologic imaging with 67Ga warrants further investigation.     

Brain slice protein degradation and development

Protein degradation rates were measured in brain slices prepared from rats of various ages. This was done by adding the protein synthesis rate, determined by incorporation of a labeled precursor, and the net protein degradation rate, determined by measuring the changes with time of total free amino acids. These rates are about 30% higher than those previously calculated from data on protein synthesis rates and protein accumulation rates in vivo. The protein degradation rates in brain slices diminish with age; i.e., 2-day cerebellum greater than 2-day cerebral hemisphere greater than 12-day cerebral hemisphere greater than young adult cerebral hemisphere. Protein degradation rates in slices from young brain are initially slightly higher than protein synthesis rates, resulting in a small net degradation with time. Unlike slices from adult brain, the protein degradation rates in slices from young brain decline only modestly with time for as much as 100 min of incubation. The characteristics of protein degradation in brain slices from young animals are roughly similar to some of the data calculated for protein degradation in vivo, suggesting that this system may prove useful for studying factors which control or affect brain protein degradation.     

Scintigraphy with gallium-67 citrate in patients with AIDS: pathologic extrapulmonary uptake

67Gallium citrate can accumulate in different inflammatory and neoplastic lesions. The mechanisms of 67Gallium uptake in abnormal tissue are still partially unknown and the tracer is considered a nonspecific indicator of disease. In AIDS patients, 67Gallium citrate is used in the diagnosis and characterization of opportunistic pulmonary infections and especially of Pneumocystis carinii pneumonia. From June 1989 through December 1992 in our Department 140 67Gallium scans were performed on 103 AIDS patients, referred for evaluation of pulmonary symptoms. All studies were carried out 72 hours after i.v. administration of 185 MBq 67Gallium citrate, with anterior and posterior views of head, chest and abdomen. The images were evaluated with conventional diagnostic criteria and site, number and intensity of abnormal foci of extrapulmonary uptake were recorded. Abnormal extrapulmonary uptake was found in 17 patients (12%): gastric (3, two of which also exhibited abnormal intestinal uptake), esophageal (1) hepatic (1), intestinal (2) renal (4), nodal (3), ocular (1), cutaneous (1), sinusal (1) localizations. In all cases clinical, endoscopic, bioptic or microbiological demonstration of the possible cause of 67Gallium uptake was obtained. An intriguing finding in our series was the lower incidence of gastric uptake (two patients with miliary tuberculosis and one patient with gastric candidiasis) than in the literature. This finding could be explained by clinical and epidemiologic differences between different patient populations. However, the scan interval after tracer administration should be also taken into account, since in our study scans were always performed at 72 hours, while in other series the interval ranged 24-48 hours. The relatively high incidence of abnormal extrapulmonary uptake confirms the opportunity of whole body exploration after 67Gallium administration in the patients with such multisystemic disease as AIDS, even when the patients are referred mainly for respiratory problems.     

Treatment of hypothyroidism

A series of 77 gallium-67 citrate (67Ga citrate) scans of the abdomen revealed lymphoma in 12 cases (nine of non-Hodgkin's lymphoma, three of Hodgkin's disease). Scanning was undertaken (i) to confirm the suspicion of lymphoma, or (ii) as part of a staging procedure when the diagnosis of lymphoma had been established, or (iii) as a follow-up investigation after treatment of lymphoma. The diagnosis of lymphoma in the upper part of the abdomen is difficult with conventional techniques such as lymphography, and it is in this area that 67Ga citrate scanning is shown to be of value.     

Liquid-liquid extraction of gallium by tri-n-butyl phosphate

The recovery of gallium from discarded germanium plant solutions by solvent extraction with tri-n-butyl phosphate (TBP) has been investigated. Because of the high content of iron, selective extraction of gallium with undiluted TBP is not possible, but suitable conditions are obtained by diluting the TBP with an aliphatic hydrocarbon and extracting at an acidity of 4 M. It is advantageous to reduce the Fe^III in the initial solution to the bivalent state; scrubbing of the loaded organic phase with HCl also increases the final Ga/Fe ratio.Gallium can be recovered from the strip solution by hydrolysis, and it is again beneficial to add a reducing agent.A gallium yield of 99.5% has been obtained in a final dry product containing 50.9% Ga and 1% Fe.     

Localization of gallium-67 citrate in salivary glands following radiation therapy

Gallium-67 citrate was found to localize in the salivary glands of eight patients after therapeutic doses of radiation to a treatment field including the glands. In two patients, autopsy evidence to the effect that no primary disease was present to explain such uptake was obtained. In another two patients the abnormal uptake was not observed on follow-up. The recognition that radiation sialadenitis is a potential cause of false-positive gallium scintiscans is important in their interpretation.     

Passive care and active rehabilitation in a patient with failed back surgery syndrome

Blood-borne cytokines enter the brain by transport across the blood-brain barrier (BBB) or by leakage through extracellular pathways at sites, such as circumventricular organs (CVOs), without a BBB. We used radioactively labeled albumin (T-Alb) to differentiate the relative contribution of transport and extracellular pathways to the passage of interleukin-1 alpha ([125I]IL-1 alpha) across the BBB. The major mechanism of entry for [125I]IL-1 alpha after intravenous (i.v.) injection was a saturable transport system with extracellular pathways accounting for only a small fraction of entry into brain. CVOs concentrated blood-borne [125I]IL-1 alpha in a saturable manner to a much greater extent than did the cerebral cortex and cerebellum, but accounted for less that 5% of total brain uptake. After intracerebroventricular (i.c.v.) injection, [125I]IL-1 alpha and T-Alb were concentrated in the CVOs, especially the median eminence, although CVOs contained less that 1% of the substances injected. Distribution after i.c.v. injection was largely due to diffusion and leakage through extracellular pathways. We conclude that after i.c.v. injection, leakage across extracellular pathways accounts for the small but concentrated amount of [125I]IL-1 alpha found in CVOs. After i.v. injection, transport across the BBB accounts for the majority of [125I]IL-1 alpha in brain.     

Use of radioactive isotopes in the diagnosis of pulmonary tumors. Analysis of the results of 18 anatomically verified cases

18 cases of anatomically verified lung cancer were studied scintigraphically with microspheres of human albumin labelled with 99Tc, mercury bichloride (197Hg) and citrate of gallium (67Ga), to assess the diagnostic value of this technique. Using albumin microspheres, changes in the scintigraphic picture were obtained in 100% of cases, but inferior results were obtained with the two other tracers (gallium 75% and mercury bichloride 58.8%). The poor specificity of scintigraphy with albumin, which was changed in numerous non-neoplastic pathologies, removes all significance from this apparently brilliant result. From an overall assessment of all three scintigraphies, no increase in positivity percentages is obtained; the agreement of all three with respect to the neoplastic nature of the condition is however very good. Although possible conclusions are less favourable than those reported by other workers, the investigation with radioisotopes plays an important r?le in the diagnosis of lung tumours, in view also of its harmlessness and tolerability, although it is not enough on its own for diagnosis. Large series and constant anatomical and histological monitoring are needed before any definitive assessment can be attempted of the diagnostic value of this method.     

Compartmentation of [14C]glutamate and [14C]glutamine oxidative metabolism in the rat hippocampus as determined by microdialysis

Metabolic compartmentation of amino acid metabolism in brain is exemplified by the differential synthesis of glutamate and glutamine from the identical precursor and by the localization of the enzyme glutamine synthetase in glial cells. In the current study, we determined if the oxidative metabolism of glutamate and glutamine was also compartmentalized. The relative oxidation rates of glutamate and glutamine in the hippocampus of free-moving rats was determined by using microdialysis both to infuse the radioactive substrate and to collect 14CO2 generated during their oxidation. At the end of the oxidation experiment, the radioactive substrate was replaced by artificial CSF, 2 min-fractions were collected, and the specific activities of glutamate and glutamine were determined. Extrapolation of the specific activity back to the time that artificial CSF replaced 14C-amino acids in the microdialysis probe yielded an approximation of the interstitial specific activity during the oxidation. The extrapolated interstitial specific activities for [14C]glutamate and [14C]glutamine were 59 +/- 18 and 2.1 +/- 0.5 dpm/pmol, respectively. The initial infused specific activities for [U-14C]glutamate and [U-14C]glutamine were 408 +/- 8 and 387 +/- 1 dpm/pmol, respectively. The dilution of glutamine was greater than that of glutamate, consistent with the difference in concentrations of these amino acids in the interstitial space. Based on the extrapolated interstitial specific activities, the rate of glutamine oxidation exceeds that of glutamate oxidation by a factor of 5.3. These data indicate compartmentation of either uptake and/or oxidative metabolism of these two amino acids. The presence of [14C]glutamine in the interstitial space when [14C]glutamate was perfused into the brain provided further evidence for the glutamate/glutamine cycle in brain.