Effect of barbiturate coma on glucose utilization in normal brain versus gliomas. Positron emission tomography studies

Glucose utilization by normal and neoplastic cerebral tissue can be measured in humans using positron emission tomography (PET) with fluorine-18-labeled 2-deoxy-D-glucose (FDG). Malignant gliomas are known to exhibit hypermetabolic glucose consumption compared to normal brain. Barbiturate-sensitive cerebral glucose utilization is coupled to neuronal activity, and lesions lacking neuronal activity should be relatively insensitive to barbiturate suppression of glucose utilization. In a study to examine this phenomenon, three patients with cerebral gliomas underwent FDG-PET while awake and during deep barbiturate coma. Cerebral glucose utilization was measured in normal brain, tumor, and a homologous, non-neoplastic control site in the contralateral hemisphere. A glucose utilization ratio for tumor/control tissue was calculated. The mean reduction of glucose utilization during barbiturate coma was: gray matter 67%, white matter 47%, basal ganglia 66%, thalamus 57%, cerebellar cortex 55%, tumor 32%, and the contralateral control site 64%. The mean tumor glucose utilization ratio was 1.48:1 in the awake state and 2.69:1 during barbiturate coma. The changes in gray matter, basal ganglia, thalamus, cerebellar cortex, and tumor/control tissue ratio were significant (p less than 0.05). In one patient, deep tumor invasion not evident on computerized tomography, magnetic resonance imaging, or baseline FDG-PET was apparent during barbiturate-enhanced FDG-PET scanning. The study findings suggest that gliomas resist suppression of glucose utilization by barbiturates; this supports the hypothesis that barbiturates reduce neuronal metabolism by blocking synaptic activity. This differential effect on normal brain and gliomas enhances the capability to assess the extent of neoplastic tissue in brain and may represent the basis for novel therapeutic strategies.     

Regulation of hexokinase in cultured gliomas

Positron emission computed tomographic (PECT) scanning studies have demonstrated that high grade gliomas exhibit increased 2-[18F]fluoro-2-deoxyglucose (18FDG) uptake compared to cerebral white matter and low grade gliomas. Hexokinase catalyzes the phosphorylation of glucose, as well as 18FDG and 2-deoxyglucose (2DG), thereby "trapping" these slowly metabolized analogues intracellularly. We hypothesize that a similar hexokinase-mediated uptake of glucose and glucose analogues occurs in vitro. Hexokinase activity was assayed in homogenates of tissue-cultured lines derived from high (IV) and low (II) grade gliomas and in fibroblasts derived from skin. With glucose as substrate, the maximal activity (Vmax) in the Grade IV lines was 200% of the activity found in the Grade II line, fibroblasts, and astrocytes; however, the Michaelis substrate affinity constant (Km) bore no relationship to tumor grade. With 2DG as substrate, the Vmax of all cell lines decreased, but the Grade IV lines still tended to have greater activity than the others. The Km values for 2DG were 5 times higher than those for glucose. Hexokinase is found in two subcellular compartments: an active form reversibly bound to mitochondria and a less active, cytosolic form. Up to 20% of the total hexokinase was found in the cytosol in all lines tested. High energy phosphate compounds (ATP, ADP, CTP, and others) displaced mitochondria-bound hexokinase, which increased the cytosolic form by 2-fold in the glioma lines, but fibroblast hexokinase distribution was unaffected. Our results suggest that: (a) high grade gliomas have increased hexokinase activity, which may explain the grade-related differences in 18FDG uptake observed by PECT scanning, and (b) human glioma hexokinases may be regulated by reversible subcellular compartmentation.     

No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans.

The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.     

Renal function and (NA+ + K+)-ATPase in chronic unilateral hydronephrosis in dogs

Recovery of various parameters of kidney function after varying periods of complete unilateral ureteral obstruction was studied in dogs under hydropenic conditions. Changes of PAH and inulin clearance appeared to be parallel. After one week of obstruction, renal clearances of PAH and inulin were decreased to seven per cent of values measured before the obstruction period, after two weeks to four per cent and after three or four weeks to two per cent. Within 10 to 28 days after release of obstruction by cutaneous ureterostomy, PAH and inulin clearance increased to 66 per cent after one week, to 50 per cent after two weeks, to 10 per cent after three weeks with no change after four weeks of obstruction. Na+ content in the hydronephrotic kidney differed from contralateral kidneys only in the inner medulla. The affinity for ouabain (dissociation constant, KD, normal = 3.85 X 10(-9) M; hydronephrotic = 3.05 X 10(-9) M; contralateral = 7.05 X 10(-9) M) was significantly higher only in the outer medulla of contralateral kidneys. Turnover number (normal = 3.6; hydronephrotic = 5.1; contralateral = 3.4 X 10(3) min.-1) in hydronephrotic or contralateral outer medulla was not significantly different from normal. Changes in kinetic constants (association rate constant, k+1, normal = 4.49 X 10(4) M-1 sec.-1; hydronephrotic = 4.13 X 10(4) M-1 sec.-1; contralateral = 5.97 X 10(4) M-1 sec.-1; dissociation rate constant, k-1, normal = 1.03 X 10(-4) sec.-1; hydronephrotic = 1.29 X 10(-4)sec.-1; contralateral = 1.39 X 10(-4) sec.-1) were considered to be too small to be relevant. Similar changes of KD, k+1 and k-1 were observed in the renal cortex. The osmotic concentrating capacity correlated well with (Na+ + K+)-ATPase activity (r = 0.85) and number of 3H-ouabain binding sites (r = 0.89) in renal outer medulla. The results indicate that recovery of osmotic concentrating capacity depends on the length of obstruction, and that a reduction of (Na+ + K+)-ATPase molecules in the thick ascending limb of the loop of Henle is a primary factor in the decrease in the concentrating capacity of chronic unilateral hydronephrotic kidneys.     

Localization and characterization of endothelin receptors in human gliomas: a growth factor?

Localization and characterization of endothelin receptors in surgical specimens of human gliomas (6 benign astrocytomas and 7 glioblastomas multiforme) and in normal human cortices were studied using quantitative receptor autoradiographic methods. Low numbers of [125I]endothelin-1 [( 125I]ET-1) binding sites were detected in the gray matter of the human frontal cortex, with little binding in the white matter. Conversely, relatively high numbers of [125I]ET-1 binding sites were homogeneously present in tissue sections derived from astrocytomas, whereas higher numbers of [125I]ET-1 binding sites were heterogeneously located on groups of cells with a pseudopalisading appearance and pleomorphic astrocytes in glioblastoma multiforme. Necrotic areas within the tissue sections derived from glioblastoma were devoid of binding. Binding of [125I]ET-1 to gliomas and normal gray matter was specific. Unlabeled ET-1 and its natural analogs (ET-2 and ET-3) inhibited the binding of [125I]ET-1 to these lesions in a concentration-dependent manner and with similar high potencies. Possibly related substances, such as ion channel regulators (omega-conotoxin, apamin, and tetrodotoxin), a Ca2+ channel blocker (nicardipine), and growth factors (epidermal growth factor and insulin-like growth factor I), did not affect the binding to tissue sections derived from gliomas or from normal frontal cortices. Scatchard analysis revealed the presence of a single class and high-affinity binding sites for endothelin in normal cortex and in gliomas. There was no significant difference in the binding affinities: dissociation constants (Kd) were 2.1 +/- 0.5 nM in 6 astrocytomas, 2.5 +/- 0.4 nM in 7 glioblastomas, and 1.4 and 1.5 nM in two normal cortices.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic activation of intercortical and corticothalamic pathways during enflurane anesthesia in rats

The purpose of this study was to examine the effects of enflurane on local cerebral glucose utilization (LCGU), and to provide further insight into the mechanism of the epileptogenic properties of enflurane. Twenty-four male Wistar rats were divided into four groups; three groups with intact cortex received 0.5, 2, or 4% enflurane, and one group with unilateral cortex excised received 4% enflurane. LCGU was measured at each anesthetic concentration using the autoradiographic 2-[14C]deoxyglucose method. LCGU in ten of 33 structures examined during 2% enflurane decreased by 19-33%, and LCGU in 22 structures during 4% enflurane decreased by 19-65%, when compared with that during 0.5% enflurane. While LCGU, in most structures, decreased in a dose-related manner, LCGU in the corpus callosum, thalamic ventrobasal complex, and hippocampal CA3 field during 4% enflurane increased by 31-70%, compared with that during 0.5% and/or 2% enflurane. With unilateral cortical excision during 4% enflurane, the increase in LCGU in the ventrobasal complex was obliterated in the excision side, and the increase in the corpus callosum was attenuated. High LCGU in the hippocampal CA3 field and contralateral ventrobasal complex was not affected with cortical excision. These results indicate that intercortical and corticothalamic pathways are metabolically activated during deep enflurane anesthesia, suggesting that the epileptogenic property of enflurane is related to activation of these pathways.     

The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans

The continuous delivery of glucose to the brain is critically important to the maintenance of normal metabolic function. However, elucidation of the hormonal regulation of in vivo cerebral glucose metabolism in humans has been limited by the lack of direct, noninvasive methods with which to measure brain glucose. In this study, we sought to directly examine the effect of insulin on glucose concentrations and rates of glucose transport/metabolism in human brain using (1)H-magnetic resonance spectroscopy at 4 Tesla. Seven subjects participated in paired hyperglycemic (16.3 +/- 0.3 mmol/l) clamp studies performed with and without insulin. Brain glucose remained constant throughout (5.3 +/- 0.3 micromol/g wet wt when serum insulin = 16 +/- 7 pmol/l vs. 5.5 +/- 0.3 micromol/g wet wt when serum insulin = 668 +/- 81 pmol/l, P = NS). Glucose concentrations in gray matter-rich occipital cortex and white matter-rich periventricular tissue were then simultaneously measured in clamps, where plasma glucose ranged from 4.4 to 24.5 mmol/l and insulin was infused at 0.5 mU. kg(-1). min(-1). The relationship between plasma and brain glucose was linear in both regions. Reversible Michaelis-Menten kinetics fit these data best, and no differences were found in the kinetic constants calculated for each region. These data support the hypothesis that the majority of cerebral glucose uptake/metabolism is an insulin-independent process in humans.     

Spreading depression following experimental head injury in the rat

The direct current (DC) potential and electroencephalographic (EEG) changes were continuously monitored following fluid percussion head injury (brain contusion) in 10 conscious rats. Local cerebral glucose utilization (LCGU) was measured by the autoradiographic [14C]deoxyglucose method. Measurement of LCGU was started at the lowest point of the first or second DC potential negative shift when it occurred, and 2 hours after contusion if no DC potential changes were observed. The DC potential did not change in four rats (Group A), whereas DC potential negative shifts together with marked suppression of EEG activity occurred at 54 +/- 6.9 minutes after injury in six rats (Group B). In Group A, LCGU was decreased nonsignificantly in both the right and left cortices. In Group B, however, LCGU in the lesioned cortex rose to 160-190% of the level observed in the contralateral cortex (p less than 0.05). The autoradiographic pattern in Group B was identical to that seen in spreading depression. These findings can contribute to the effort to better understand the pathophysiology of head injury.     

Modulation of cerebrospinal metabolic responses to peripheral stimulation by enflurane anesthesia in rats

Enflurane-induced modulation of cerebrospinal metabolic responses to peripheral nerve stimulation was examined in 30 rats. Local glucose utilization in the brain and lumbar spinal cord was measured using the autoradiographic 2-[C]deoxyglucose method at three anesthetic concentrations (0,5, 2, and 4%) either with or without electrical stimulation (5 mA, 0.5 ms, 10 Hz) of the unilateral sciatic nerve. Stimulation produced a 71 to 111% increase in glucose utilization in the ipsilateral dorsal horn of the spinal cord at all anesthetic concentrations examined. Stimulation also produced a 32 to 48% increase in glucose utilization in the hindlimb projectionarea of the contralateral somatosensory cortex at the two lowest concentrations (0.5 and 2%), while at 4% no stimulus-induced increase in glucose utilization was observed. The results show that there is a threshold at which enflurane suppresses the metabolic responses to peripheral stimulation in the somatosensory cortex but not in the spinal cord. If electrical stimulation of a peripheral nerve is regarded as analogous to surgical stimulation, considerable increase in the spinal cord metabolism may occur during surgery even in a deeply anesthetized subject.     

Analysis of regional blood flow, blood volume, oxygen and glucose metabolism in heterogeneous parts of untreated high grade gliomas using positron emission tomography (PET)

A high resolution positron emission tomography (PET), HEADTOME III, has enabled us to visualize heterogeneous parts, i.e. viable, necrotic, and edematous portions in malignant gliomas, and to quantify regional hemocirculation and metabolism of the tumors using 15O and 18F-fluorodeoxyglucose tracers. Hemocirculatory and metabolic indices of regional cerebral blood flow (rCBF), blood volume (rCBV), oxygen extraction fraction (rOEF), oxygen consumption (rCMRO2) and glucose consumption (rCMRGl) were studied in eight patients with untreated malignant gliomas. Regions of interest (ROIs) in PET images were focused on lesions corresponding to contrast enhancing areas, central low density areas of the tumors, and peritumoral low density areas in CT scans. In the viable portion of the gliomas, rCBV (5.20 +/- 1.18ml/100ml, mean +/- SD, n = 8) was significantly higher than that of the contralateral gray matter (p less than 0.05), which is suggestive of high vascularity; rOEF (0.36 +/- 0.16) and rCMRO2 (1.66 +/- 0.45ml/100ml/min) values markedly decreased (p less than 0.05, p less than 0.01). On the other hand, rCBF (36.3 +/- 13.0ml/100ml/min) and rCMRGl (5.94 +/- 1.15mg/100ml/min) were similar to that of the contralateral gray matter. A relative dissociation between oxygen and glucose metabolism indicates anaerobic glycolysis in the energy metabolism of malignant gliomas. In the central low density area, rCBF, rCBV, rOEF, rCMRO2, rCMRGl values decreased significantly from the viable portion and the contralateral gray matter. rOEF was markedly reduced in the central low density area as compared with that of the peritumoral low density area. The rOEF reduction indicates that oxygen metabolism of gliomas is the first to fail, accompanied by autoregulatory impairment of vessels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positron-emission tomography imaging of early events after transplantation of islets of Langerhans

The aim of our study was to assess cell trafficking and early events after intraportal islet transplantation. Sprague-Dawley rat islets were incubated for various times, with various concentrations of 2-[F]fluoro-2deoxy-D-glucose (FDG), and in presence of various glucose concentrations. FDG-labeled syngeneic islets or FDG alone were injected in rats. Radioactivity was measured in the liver and in various organs by positron-emission tomography for 6 hours. FDG uptake increased with incubation time or FDG concentration and decreased in presence of glucose. In vivo, all islets implanted in the liver, with an uptake 4.4 times higher than controls (44.2% vs. 10.1%, P=0.02). Radioactivity in the liver decreased at the same rate after injection of labeled-islets and FDG alone. Ex vivo labeling of islets and imaging of posttransplant early events were feasible. Islets engrafted exclusively in the liver. No islet loss could be demonstrated 6 hours after transplantation.     

DNA synthesis, blood flow, and glucose utilization in experimental rat brain tumors

The relationships between distribution of deoxyribonucleic acid (DNA)-synthesizing cells (S-phase cells) and blood flow and glucose utilization were investigated in rat brain tumors using an autoradiographic technique and immunoperoxidase staining for bromodeoxyuridine (BUdR). Two strains of rat brain tumor were used: strain A and B, both induced by the Rous sarcoma virus. Strain A was biologically more malignant than strain B. The blood flow was unevenly distributed in the tumor, compared with the contralateral cortex, the average blood flow in the tumor was about 50% in strain A and 60% in strain B. The distribution of blood flow did not correlate with the distribution of S-phase cells or with the distribution of vessels in the tumor in either strain A or B. The average glucose utilization in strain A was about 250% and in strain B about 170% of that of the contralateral cortex. The high glucose utilization area correlated well with the distribution of BUdR-positive nuclei in strain B. These findings suggest that the biological malignancy of a tumor correlates with glucose utilization rather than with blood flow, and that malignant brain tumors show a marked increase in glucose utilization for nucleic acid synthesis.     

Examination of the metabolism of oedematous brain tissue

Summary We induced oedema in rabbit brains by applying cold to a defined area of the intact dura for a constant time. 24 hours later the animals were killed, and a piece of brain cortex adjacent to the region of cold application and an exactly similar piece from the other hemisphere were removed. In both pieces we determined the water content, the water uptake of the sliced brain in vitro, and the glucose metabolism of the brain slices. Respiration, carbon dioxide production in the presence of bicarbonate, consumption of glucose, and production of lactate and pyruvate were measured. The incubations were made in physiological saline with different concentrations of glucose (2.5 ml, 5 mM, and 10 mM).The mean difference of the water contents in vivo was 1.9%. The water uptake in vitro did not depend on the glucose concentration.The oedematous tissue had a slightly stimulated respiration, and its aerobic glycolysis was markedly increased.The respiration was independent of the glucose concentration. The lactate: pyruvate quotient was somewhat higher on the oedematous side, and it became greater on both sides with increasing glucose concentration.The glycolysis increased considerably between 2.5 mM and 5 mM glucose, especially in the oedematous brain. Between 5 mM and 10 mM glucose the aerobic glycolysis was accelerated only slightly by increasing glucose concentration.We think that the increased glycolysis is an expression of a preceding energy deficit. By a simple enhancement of the glucose concentration to more than 100 mg/100 ml the metabolism is not stimulated further, and the water content is not diminished.Supported by the Deutsche Forschungsgemeinschaft: H. 573/3.Part of the Dissertation, Med. Fakultät Homburg (Saar), 1972.     

Effect of traumatic brain injury and nitrone radical scavengers on relative changes in regional cerebral blood flow and glucose uptake in rats

Changes in regional cerebral blood flow (rCBF) and glucose metabolism are commonly associated with traumatic brain injury (TBI). Reactive oxygen species (ROS) have been implicated as key contributors to the secondary injury process after TBI. Here, pretreatment with the nitrone radical scavengers (alpha-phenyl-N-tert-butyl nitrone (PBN) or its sulfonated analogue sodium 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) were used as tools to study the effects of ROS on rCBF and glucose metabolism after moderate (2.4-2.6 atm) lateral fluid percussion injury (FPI) in rats. S-PBN has a half-life in plasma of 9 min and does not penetrate the blood-brain barrier (BBB). In contrast, PBN has a half-life of 3 h and readily penetrates the BBB. Regional cerebral blood flow (rCBF) and glucose metabolism was estimated by using (99m)Tc-HMPAO and [(18)F]Fluoro-2-deoxyglucose (FDG) autoradiography, respectively, at 42 min (n = 37) and 12 h (n = 34) after the injury. Regions of interest were the parietal cortex and hippocampus bilaterally. As expected, FPI produced an early (42-min) hypoperfusion in ipsilateral cortex and an increase in glucose metabolism in both cortex and hippocampus, giving way to a state of hypoperfusion and decreased glucose metabolism at 12 h postinjury. On the contralateral side, a hypoperfusion in the cortex and hippocampus was seen at 12 h only, but no significant changes in glucose metabolism. Both S-PBN and PBN attenuated the trauma-induced changes in rCBF and glucose metabolism. Thus, the early improvement in rCBF and glucose metabolism correlates with and may partly mediate the improved functional and morphological outcome after TBI in nitrone-treated rats.     

Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance: a dose-response assessment using positron emission tomography

It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography (PET) imaging of 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) during insulin infusions at three rates (0, 40, and 120 mU/m2 per min) in lean glucose-tolerant, obese glucose-tolerant, and obese type 2 diabetic subjects. Parallel studies of arteriovenous fractional extraction across the leg of [18F]FDG and [2-3H] glucose were performed to measure the "lumped constant" (LC) (i.e., the analog effect) for [18F]FDG to determine whether this value is affected by insulin dose or insulin resistance. The value of the LC was similar across insulin doses and groups. Leg glucose uptake (LGU) also provided a measure of skeletal muscle glucose metabolism independent of PET. [18F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r = 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r = 0.67, P < 0.001) and glucose phosphorylation (r = 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.     

Prediction of survival in glioma patients by means of positron emission tomography

The aim of this study was to determine whether positron emission tomography (PET) with fluorine-18 (18F)-2-deoxyglucose (FDG) can be used as a prognostic test in patients with high-grade cerebral gliomas, regardless of the treatment given. Forty-five patients with astrocytoma Grade III or IV were included in this analysis. The mean survival time of patients with tumors exhibiting high glucose utilization as determined by PET-FDG was 5 months, whereas patients with gliomas showing lower glucose utilization had a mean survival period of 19 months. It is postulated that PET-FDG scans reflect the biological behavior of high-grade astrocytomas and may be used to predict the survival time of patients harboring such neoplasms.     

The effect of hyperbaric oxygen on glucose utilization in a freeze-traumatized rat brain

Local cerebral glucose utilization was measured with the autoradiographic 2-deoxyglucose technique in rats injured by a focal parietal cortical freeze lesion then treated with hyperbaric oxygen (HBO). The cold lesion depressed glucose utilization in the contralateral as well as in the ipsilateral hemisphere. The largest decreases were observed in ipsilateral cortical areas. Treatment of lesioned animals with HBO at 2 atm for 90 minutes on each of 4 consecutive days tended to increase the overall cerebral glucose utilization measured 5 days after injury when compared to animals exposed to normobaric air. This improvement reached statistical significance in five of the 21 structures studied: the auditory cortex, medial geniculate body, superior olivary nucleus, and lateral geniculate body ipsilateral to the lesion, and the mammillary body. The data indicate that changes in lesioned rats exposed to HBO are not restricted to the period of time that the animals are in the hyperbaric chamber but are persistent.     

Diminution of metabolism/blood flow uncoupling following traumatic brain injury in rats in response to high-dose human albumin treatment

OBJECT: The authors have recently demonstrated that high-dose human albumin is markedly neuroprotective in experimental traumatic brain injury (TBI) and cerebral ischemia. The pathophysiology of TBI involves acute uncoupling of cerebral glucose utilization and blood flow. The intent of this study was to establish whether the use of human albumin therapy in a model of acute TBI would influence this phenomenon. METHODS: Anesthetized, physiologically regulated rats received moderate (1.5-2 atm) fluid-percussion injury to the parietal lobe. Fifteen minutes after trauma or sham injury, rats in one group received human albumin (2.5 g/kg) administered intravenously and those in another group received 0.9% saline vehicle. At 60 minutes and 24 hours posttrauma, autoradiographic studies of local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) were conducted, and the LCMRglu/LCBF ratio was determined. Sham-injured rats had normal levels of LCBF and LCMRglu, and no differences between vehicle- and albumin-treated rats were evident. Sixty minutes after TBI, LCBF was moderately reduced bilaterally in vehicle-treated rats, whereas in albumin-treated animals, the LCBF contralateral to the side of injury was generally normal. Despite acutely depressed LCBF, LCMRglu in vehicle-treated rats at 60 minutes was paradoxically normal bilaterally, and foci of elevated LCMRglu were noted in the ipsilateral hippocampus and thalamus. By contrast, in albumin-treated rats studied 60 minutes post-TBI, reduced LCMRglu values were measured in the ipsilateral caudoputamen and parietal cortex, whereas LCMRglu in other ipsilateral and contralateral sites did not differ from that measured in sham-injured animals. The metabolism/blood flow ratio was normal in sham-injured rats, but became markedly elevated in vehicle-treated rats 60 minutes post-TBI (on average, by threefold ipsilaterally and 2.1-fold contralaterally). By contrast, the mean metabolism/blood flow ratio in albumin-treated animals was elevated by only 1.6-fold ipsilaterally and was normal contralaterally. Twenty-four hours after TBI, LCBF contralateral to the side of injury had generally returned to normal levels in the albumin-treated group. CONCLUSIONS: These results demonstrate that human albumin therapy benefits the posttraumatic brain by diminishing the pronounced metabolism > blood flow dissociation that would otherwise occur within the 1st hour after injury. Viewed together with our previous evidence of histological neuroprotection, these findings indicate that human albumin therapy may represent a desirable treatment modality for acute TBI.     

Theoretical Studies on Self-Regulating Insulin Delivery System

A theoretical analysis of a self-regulating insulin delivery (SRID) system was made using published in vitro results. The SRID system consists of an encapsulated glycosylated insulin bound to concanavalin A (conA) that exchanges insulin with glucose through a reversible chemical reaction between glucose and conA-insulin (C-I). The mathematical analysis of the in vitro results gave the values of the forward and reverse reaction rate constants. Using these calculated reaction rate constants, the insulin release rate was predicted from a SRID cylindrical pouch in response to a change in glucose concentration. The insulin release rate was found to be strongly affected by the diffusivity coefficients of insulin and glucose within the pouch, the radius of the pouch, membrane permeability, C-I concentration, and the kinetic rate constants. This mathematical analysis provides useful guidelines for the rational design of the SRID system.     

Association between fluorine-18-labeled fluorodeoxyglucose uptake and 1p and 19q loss of heterozygosity in World Health Organization Grade II gliomas

OBJECT: Oligodendroglial tumors harboring combined 1p and 19q loss (1p/19q LOH) are characterized by a favorable prognosis and response to chemotherapy and radiotherapy, but detection of 1p/19q LOH relies on postoperative procedures. The authors investigated the potential of fluorine-18-labeled fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) to predict 1p/19q LOH preoperatively in tumors whose appearance on initial magnetic resonance images was consistent with that of low-grade glioma. METHODS: The study population comprised 25 patients who had undergone preoperative FDG-PET followed by tumor resection. Neuronavigation ensured a precise match of FDG uptake with the site of biopsy. All tumor specimens were graded according to the World Health Organization (WHO) classification system. Microsatellite analysis was used to identify 1p/19q LOH. In this series, 16 of 25 gliomas corresponded to WHO Grade II. In eight of these 16, 1p/19q LOH was detected. Raised glucose utilization within the tumor was seen in the six of eight WHO Grade II gliomas with 1p/19q LOH and in none of the WHO Grade II gliomas without this genetic alteration (p = 0.003). CONCLUSIONS: These findings demonstrate the potential of FDG-PET to predict 1p/19q LOH in WHO Grade II gliomas.