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Biomedical subjects

D Labar

Publications and source records attributed to D Labar.

At least 19 recordsLinked to original sources
PubMed2006

Detection of tumour hypoxia: comparison between EF5 adducts and [18F]EF3 uptake on an individual mouse tumour basis.

In the framework of the preclinical validation of the hypoxic tracer [(18)F]EF3, a comparison was performed between uptake of [(18)F]EF3 and EF5 adducts detected by immunofluorescence in MCa-4, FSA, FSAII, Sa-NH and NFSA tumour-bearing mice. Mice were allowed to breath carbogen (5% CO(2), 95% O(2)), 21% oxygen or 10% oxygen. A significant correlation (r (2)=0.57; p<0.01) was found between the [(18)F]EF3 tumour-to-muscle ratio and the fluorescence intensity of EF5.

Animals↗
PubMed2004

Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3.

The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)- N-(3,3,3-trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic cells. Radiosynthesis of [(18)F]EF3 was recently performed by our group. Our aim was to study the pharmacokinetics, biodistribution, metabolism and specificity for hypoxia of [(18)F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour-bearing C3H mice were injected intravenously with [(18)F]EF3 and allowed to breathe air, 10% O(2) or carbogen until sacrifice 5-770 min after injection. Radioactivity was measured ex vivo in various organs, including urine and faeces. Selected organs were additionally processed to measure tracer metabolites with high-performance liquid chromatography. The half-life in blood was 73.9 min. [(18)F]EF3 was eliminated mainly via the kidneys, with 75% of the injected activity found in the urine by 12 h 50 min. The biodistribution was fast and homogeneous except in the brain and the bone, where it was significantly lower, and in the liver and the kidney, where it was significantly higher. In most organs, the exceptions being the gastrointestinal and urinary tract, tissue-to-blood ratios were below or close to unity. In tumours, a relative accumulation of the tracer was observed with time, which, at 220 min after injection, depended on tumour strain and oxygenation conditions, i.e. 10% O(2) significantly increased the tumour-to-muscle ratio whereas carbogen decreased it. [(18)F]EF3 was rapidly metabolised in the kidney and the liver. [(18)F]EF3 is a promising tracer for detection of tumour hypoxia. A phase I study in head and neck cancer patients is in progress at our institution.

Animals↗
PubMed2001

Assessment of [18F]fluoroethylflumazenil metabolites using high-performance liquid chromatography and tandem mass spectrometry.

A simple procedure using HPLC and tandem mass spectrometry has been developed for the determination of fluoroethylflumazenil metabolites. Samples were precipitated with acetonitrile, evaporated to dryness followed by reconstitution with methanol. As mobile phase, 50 mM ammonium formate-methanol (58:42, v/v) was used. The method is valid both for cold and radiolabelled metabolites. Various cold metabolites (hydroxylated and/or dealkylated) were identified in rat and human microsome preparations. Radiolabelled metabolites arise from two or more transformations including hydroxylation. The methodology developed can be applied for further characterisation of metabolites, and for the determination of non metabolised [18F]fluoroethylflumazenil in routine clinical analysis.

Animals↗
PubMed2001

Synthesis of [18F]-labeled EF3 [2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide], a marker for PET detection of hypoxia.

[18F]-2-(2-Nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide ([18F]-EF3) has been prepared, in 65% chemical yield and 5% radiochemical yield, by coupling 2,3,5,6-tetrafluorophenyl 2-(2-nitroimidazol-1-yl) acetate 1 with [18F]-3,3,3-trifluoropropylamine 7. This original radiolabelled key-synthon was obtained in 40% overall chemical yield by oxidative [18F]-fluorodesulfurization of ethyl N-phthalimido-3-aminopropane dithioate 4, followed by deprotection with hydrazine of the resulting [18F]-N-phthalimido-3,3,3-trifluoropropylamine 5. All the process was performed within 90 min, from the [18F]-HF production in the cyclotron to the purification of the final target.

Fluorine Radioisotopes↗
PubMed2001

Biodistribution, binding specificity and metabolism of [18F]fluoroethylflumazenil in rodents.

Pre-clinical studies were carried out in order to characterize in rodents the biodistribution, the binding specificity and the metabolism of [18F]Fluoroethylflumazenil ([18F]FEF), a potential candidate for in vivo imaging of the benzodiazepine receptors. In vivo competition with flumazenil indicates that [18F]FEF binds specifically to the benzodiazepine receptor in the brain. The accumulation of [18F]FEF was significantly lower than using [3H]Flumazenil. The rather low accumulation in the brain is due to a rapid metabolism of [18F]FEF in hydrophylic metabolites which cannot cross the blood brain barrier, and are rapidly eliminated in the urine. Inhibition of the metabolism by acetaminophen (chemically induced hepatitis) led to a significant increase of the radioactivity found in the circulating blood and in the brain, while these results were not observed using classical inhibitors of the cytochrome CYP450, cimetidine and ketoconazole.

Animals↗
PubMed2001

Vagus nerve stimulation: analysis of device parameters in 154 patients during the long-term XE5 study.

PURPOSE: To determine the effect of changes in device settings and duty cycle (on and off times) on the efficacy of vagus nerve stimulation (VNS) for refractory epilepsy. In the long-term XE5 study of VNS for intractable epilepsy, the median reduction in seizure frequency improved significantly after 1 year of follow-up. A central question is whether device changes improve efficacy. We analyzed the effects of device parameter changes on seizure frequency in 154 subjects who completed the study and who had complete data for analysis. METHODS: Retrospective analysis of device changes during the XE5 long-term study of VNS. During the XE5 long-term follow-up study, the subject's device settings were modified within a Food and Drug Administration (FDA)-approved range of output current, pulse duration, frequency, on time, and off time. Significant changes in device settings occurred after 3 months. We investigated the relationship between percentage reduction in seizures and changes in device parameters between the 3- and 12-month visits. Within-group comparisons were performed for those who continued on standard on/off cycle of 30 s on and 5 min off, and those with the most common off times of 3, 1.8, and < 1.1 min. RESULTS: Output current, pulse duration, frequency, and off time changed significantly between the 3- and 12-month long-term follow-ups. For the group as a whole, changes in device settings were not correlated with an improvement in efficacy. However, a significant improvement in efficacy occurred in a subgroup whose off time was reduced to < or = 1.1 min. In this group, the median reduction in seizures improved from 21% before the change in off time, to 39% after the change in off time (Wilcoxon Signed-Rank, p = 0.011). The responder rate (> 50% reduction in seizures) also significantly improved from 19 to 35% (McNemar's test, p = 0.046). CONCLUSIONS: The data from this retrospective analysis indicate that device changes were not the primary determinant of increased efficacy at 12 months of long-term follow-up. In general, patients who remained on the original settings of 30 s on and 5 min off continued to respond or improve in their response over the 1-year period. However, some patients may benefit from reductions in off time (increases in duty cycle). In a subgroup initially resistant to VNS, a change in off time to < or = 1.1 min off did result in significant improvements in efficacy.

Double-Blind Method↗
PubMed2001

Epileptogenesis: left or right hemisphere dominance? Preliminary findings in a hospital-based population.

The aim of this study was to determine if there is cerebral cortical hemispheral asymmetry in human epileptogenesis. We studied 75 epilepsy patients using electroencephalograms, neuroimaging, ictal semiology and physical examination to determine if epilepsy originates more frequently from the left or the right hemisphere. We considered epilepsy to be definitely-lateralized if one or more of these was abnormal unilaterally and there were no contradictory findings. Twenty-seven of the patients had lateralized epilepsy: 20 from the left hemisphere and seven from the right hemisphere (P< 0.05). These findings from our hospital-based ambulatory patient population suggest that the left hemisphere is more epileptogenic than the right. Further study of lateralization of epileptogenesis in a community population-based sample of incident new-onset cases seems warranted.

Adolescent↗
PubMed2001

Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study.

Hypothyroidism is often associated with defective memory, psychomotor slowing, and depression. However, the relationship between thyroid status and cognitive or psychiatric disturbances remains unclear. Using psychometric scales, 10 patients who had undergone total thyroidectomy for thyroid carcinoma were evaluated for depression, anxiety, and psychomotor slowing; they were examined both when euthyroid and hypothyroid after thyroid hormone withdrawal. Positron emission tomography was used, with oxygen-15-labeled water and fluorine-18F-labeled 2-deoxy-2fluoro-D-glucose as the tracers, to correlate the regional cerebral blood flow and cerebral glucose metabolism with the mental state in patients. Two different image analysis techniques (regions of interest and statistical parametric maps) were applied. In hypothyroidism, there was a generalized decrease in regional cerebral blood flow (23.4%, P < 0.001) and in cerebral glucose metabolism (12.1%, P < 0.001) and there were no specific local defects. Patients were also significantly more depressed (P < 0.001), anxious (P < 0.001) and psychomotor slowed (P < 0.005) in hypo than in euthyroid status. These results indicate that the brain activity was globally reduced in severe hypothyroidism of short duration without the regional modifications usually observed in primary depression.

Adult↗
PubMed2000

Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging.

The regional cerebral blood flow (rCBF) and metabolic rate for glucose (rCMRGlc) are associated with functional activity of the neural cells. The present work reports a comparison study between rCBF and rCMRGlc in a normal population as a function of age. 10 young (25.9+/-5.6 years) and 10 old (65.4+/-6.1 years) volunteers were similarly studied at rest. In each subject, rCBF and rCMRGlc were measured in sequence, during the same session. Both rCBF and rCMRGlc values were found to decrease from young (mean rCBF=43.7 ml/100 g per min; mean rCMRGlc=40.6 micromol/100 g per min) to old age (mean rCBF=37.3 ml/100 g per min; mean rCMRGlc=35.2 micromol/100 g per min), resulting in a drop over 40 years of 14.8% (0.37%/year) and 13.3% (0.34%/year), respectively. On a regional basis, the frontal and the visual cortices were observed to have, respectively, the highest and the lowest reduction in rCBF, while, for rCMRGlc, these extremes were observed in striatum and cerebellum. Despite these differences, the ratio of rCBF to rCMRGlc was found to have a similar behavior in all brain regions for young and old subjects as shown by a correlation coefficient of 88%. This comparative study indicates a decline in rCBF and rCMRGlc values and a coupling between CBF and CMRGlc as a function of age.

Adult↗
PubMed2000

Vagus nerve stimulation therapy for epilepsy in older adults.

The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

Electric Stimulation↗
PubMed2000

[11C]flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification.

In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [11C]flumazenil ([11C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [11C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density Bmax and equilibrium dissociation constant Kd obtained with the direct metabolite correction with those values obtained with the indirect correction. For Bmax, the correlation coefficient r2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For Kd, r2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [11C]FMZ injection and a linear compartmental model are used. The resulting [11C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r2=1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [11C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although validation with real data is necessary, simulation results suggest that our analysis method may also be applied to single-injection protocols.

Adult↗
PubMed2000

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures.

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.

Electric Stimulation Therapy↗
PubMed2000

Vagus nerve stimulation treatment for Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a severe age-specific epilepsy syndrome that presents with medication-resistant seizures in childhood. Antiepileptic drugs are the mainstay of treatment. Nonpharmacologic treatments include corpus callosum section and the ketogenic diet. However, no single treatment is safe and effective. We treated 13 patients with Lennox-Gastaut syndrome between the ages of 4 and 44 years (mean, 16.7 years) with vagus nerve stimulation. During the first 6 months of treatment, vagus nerve stimulation produced a median seizure rate reduction of 52% (range, 0% to 93%; P = .04). At 6 months of follow-up, three patients had a greater than 90% reduction in seizures, two had a greater than 75% reduction, one had a greater than 50% reduction, and six had at least a 25% reduction. One patient did not improve. No patient worsened after initial improvement. Side effects, including hoarseness, coughing, and pain in the throat, were transient and tolerable. No patient discontinued vagus nerve stimulation. Our results suggest that vagus nerve stimulation could be an effective and safe adjunct therapy for the treatment of Lennox-Gastaut syndrome.

Adolescent↗
PubMed1999

Changes in occipital cortex activity in early blind humans using a sensory substitution device.

The purpose of this study was to investigate the neural networks involved when using an ultrasonic echolocation device, which is a substitution prosthesis for blindness through audition. Using positron emission tomography with fluorodeoxyglucose, regional brain glucose metabolism was measured in the occipital cortex of early blind subjects and blindfolded controls who were trained to use this prosthesis. All subjects were studied under two different activation conditions: (i) during an auditory control task, (ii) using the ultrasonic echolocation device in a spatial distance and direction evaluation task. Results showed that the abnormally high metabolism already observed in early blind occipital cortex at rest [C. Veraart, A.G. De Volder, M.C. Wanet-Defalque, A. Bol, C. Michel, A.M. Goffinet, Glucose utilization in human visual cortex is, respectively elevated and decreased in early versus late blindness, Brain Res. 510 (1990) 115-121.] was also present during the control task and showed a trend to further increase during the use of the ultrasonic echolocation device. This specific difference in occipital cortex activity between the two tasks was not observed in control subjects. The metabolic recruitment of the occipital cortex in early blind subjects using a substitution prosthesis could reflect a concurrent stimulation of functional cross-modal sensory connections. Given the unfamiliarity of the task, it could be interpreted as a prolonged plasticity in the occipital cortex early deprived of visual afferences.

Acoustic Stimulation↗
PubMed1999

Vagus nerve stimulation for medication-resistant generalized epilepsy. E04 VNS Study Group.

We treated 24 generalized epilepsy patients with vagus nerve stimulation (VNS), comparing seizure rates during a 1-month baseline with 3 months of VNS. Median seizure rate reduction was -46%. Sixteen of the 24 patients had better than a -30% reduction and 11 of the 24 patients had better than a -50% reduction in seizure rate. A mild cough during stimulation occurred in six patients. Patients with higher baseline seizure rates and later ages at epilepsy onset had the best responses to VNS. Our findings suggest VNS is an effective treatment for medication-resistant generalized epilepsy even in patients as young as 4 years.

Adolescent↗
PubMed1999

Emotional status after right vs. left temporal lobectomy.

Nineteen temporal lobectomy patients with epilepsy were evaluated (11 right and 8 left) with a brief questionnaire that addressed: (1) General Happiness; (2) Depression; (3) Anxiety; (4) Impulse Control; and (5) Socialization. The patients with left temporal lobectomy reported increases in depression and decreases in socialization compared with the right temporal lobectomy patients after surgery. Furthermore although the right temporal lobectomy patients reported increases in general happiness, no changes in general happiness were reported by the left temporal lobectomy patients. The present study supported the idea that an increased negative affect is associated with left rather than right temporal lobectomy. This is consistent with a model of negative emotional valence when the right hemisphere dominates awareness.

Adult↗
PubMed1999

Affective verbal memory in patients with temporal lobe epilepsy.

Eighteen epileptic patients with unilateral temporal lobe epilepsy (9 left, 9 right) were evaluated with a verbal memory task involving recall of 2 stories, 1 with affective content and 1 that was neutral. A trend for better performance by the group with intact left hemispheres was found for a quantitative score of number of story units recalled. For a qualitative score of number of symbolic distortions, a main effect of affective load was found, such that more distortions were made for the story with affective than neutral content. This effect remained significant when the left temporal lobe epilepsy patients were analyzed separately and was not found for the right temporal lobe epilepsy patients alone. Additional analyses for the subset of 5 patients with left and 6 patients with right temporal lobectomies involving removal of the hippocampus and amygdala were in the same direction as the analyses for all 18 participants. These findings are consistent with other reports of material-specific memory deficits, such that verbal memory deficits are associated with left temporal lobe epilepsy. The differences between performance on the affective and neutral stories for the left and right temporal lobe epilepsy patients are discussed and related to the role of the amygdala in affective processing.

Adult↗