Endovascular method for transplantation of insulin-producing cells to the pancreas parenchyma in swine.

Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events.

Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.

Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs.

Microwaving in F-18 chemistry: quirks and tweaks.

Since the late 1980s, microwave dielectric heating has been used to speed up chemical transformations, also in radiolabeling tracers for positron emission tomography. In addition to shorter reaction times, higher yields, cleaner product mixtures and improved reproducibility have also been obtained for reactions involving polar components that require heating at elevated temperatures. The conditions used in microwave chemistry can differ considerably from those in conventional heating. Understanding the factors that influence the interaction of the electromagnetic field with the sample is critical for the successful implementation of microwave heating. These parameters are discussed here and exemplified with radiolabelings with fluorine-18.

Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients.

Using R-beta-[1-(11)C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7-1.7 micromol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA(1c) = 8.1 +/- 1.7%). An infusion of unlabeled R-beta-hydroxybutyrate was started 1 h before the bolus injection of R-beta-[1-(11)C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 +/- 0.3 micromol/ml for nondiabetic subjects and 1.3 +/- 0.3 micromol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-beta-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.

Pain-related cerebral activation is altered by a distracting cognitive task.

It has previously been suggested that the activity in sensory regions of the brain can be modulated by attentional mechanisms during parallel cognitive processing. To investigate whether such attention-related modulations are present in the processing of pain, the regional cerebral blood flow was measured using [(15)O]butanol and positron emission tomography in conditions involving both pain and parallel cognitive demands. The painful stimulus consisted of the standard cold pressor test and the cognitive task was a computerised perceptual maze test. The activations during the maze test reproduced findings in previous studies of the same cognitive task. The cold pressor test evoked significant activity in the contralateral S1, and bilaterally in the somatosensory association areas (including S2), the ACC and the mid-insula. The activity in the somatosensory association areas and periaqueductal gray/midbrain were significantly modified, i.e. relatively decreased, when the subjects also were performing the maze task. The altered activity was accompanied with significantly lower ratings of pain during the cognitive task. In contrast, lateral orbitofrontal regions showed a relative increase of activity during pain combined with the maze task as compared to only pain, which suggests the possibility of the involvement of frontal cortex in modulation of regions processing pain.

A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy.

The objective of this study was to investigate the central processing of dynamic mechanical allodynia in patients with mononeuropathy. Regional cerebral blood flow, as an indicator of neuronal activity, was measured with positron emission tomography. Paired comparisons were made between three different states; rest, allodynia during brushing the painful skin area, and brushing of the homologous contralateral area. Bilateral activations were observed in the primary somatosensory cortex (S1) and the secondary somatosensory cortex (S2) during allodynia compared to rest. The S1 activation contralateral to the site of the stimulus was more expressed during allodynia than during innocuous touch. Significant activations of the contralateral posterior parietal cortex, the periaqueductal gray (PAG), the thalamus bilaterally and motor areas were also observed in the allodynic state compared to both non-allodynic states. In the anterior cingulate cortex (ACC) there was only a suggested activation when the allodynic state was compared with the non-allodynic states. In order to account for the individual variability in the intensity of allodynia and ongoing spontaneous pain, rCBF was regressed on the individually reported pain intensity, and significant covariations were observed in the ACC and the right anterior insula. Significantly decreased regional blood flow was observed bilaterally in the medial and lateral temporal lobe as well as in the occipital and posterior cingulate cortices when the allodynic state was compared to the non-painful conditions. This finding is consistent with previous studies suggesting attentional modulation and a central coping strategy for known and expected painful stimuli. Involvement of the medial pain system has previously been reported in patients with mononeuropathy during ongoing spontaneous pain. This study reveals a bilateral activation of the lateral pain system as well as involvement of the medial pain system during dynamic mechanical allodynia in patients with mononeuropathy.

In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants.

The biodistribution of 11C-labeled 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, an inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase, has been evaluated in vivo in rats using positron emission tomography (PET). Time-activity data obtained after i.v. administration in one rat revealed that the radiotracer rapidly cleared from plasma with subsequent uptake in major organs of the body (brain, heart, liver, gastrointestinal tract and bladder). Uptake in proliferating tissue in rats with human neuroblastoma xenografts indicate that [O-11C-methyl]PD153035 shows promise as a new agent for in vivo imaging of tumors with PET.

Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study.

We used positron emission tomography (PET) to monitor the regional cerebral blood flow (rCBF) as an index of brain activity in regions proposed to participate in affective-motivational and cognitive-evaluative dimensions of pain during anticipation of a noxious stimulation. Specifically we were interested in the anterior cingulate cortex (ACC), the ventromedial prefrontal cortex (VMPFC) and the periaqueductal grey (PAG). Anticipating an unpredictable and unlearned pain stimulus activated the right ACC, the VMPFC and the PAG while anticipating a learned pain-stimulus resulted in a decreased activity in the ACC and the VMPFC. These patterns are compatible with two facets of affect-laden cognitive coping: alertness and attention-distraction. The right-preponderant expression of the changes in the ACC supports the hypothesis of a preferential role of the non-dominant hemisphere in negative emotional processing. The data demonstrate an anticipatory coping mechanism and illustrate a neurophysiological process underlying the modulation of attention to pain.

The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose.

The effect of hyperglycaemia on regional cerebral glucose utilization was studied in five healthy males fasted over-night using positron emission tomography. Selectively labelled glucose, [1-11C]-D-glucose, was used as a tracer. After correction for the small loss of [11C]CO2 from the tissue, this tracer measures the rate of glucose oxidation rather than the total rate of glucose metabolism. Each subject was investigated twice: during normoglycaemia (plasma glucose 5.3 +/- 0.3 mumol mL-1) and at the end of a 2-h period of hyperglycaemia (plasma glucose 13.8 +/- 0.7 mumol mL-1). Assuming unchanged rate constant for loss of labelled CO2 at normo- and hyperglycaemia the oxidative metabolic rate of glucose was found to be slightly larger at combined hyperglycaemia and hypersulinemia (0.30 +/- 0.01 mmol mL-1 min-1) than at normal glucose and insulin levels (0.25 +/- 0.01 mmol mL-1 min-1). This suggests that the process of glucose phosphorylation might not be fully saturated in the human brain or, alternatively, that the glycogen deposition increases during short-term hyperglycaemia. The relative increase of oxidative metabolic rate was considerably larger (approximately 50%) in white matter than in the brain as a whole (20%). The brain glucose content was found to increase non-linearly with increasing plasma glucose. Together with data from previous studies these results suggest that the free glucose in the human brain is close to zero when the plasma glucose is below 2 mumol mL-1.

The illiterate brain. Learning to read and write during childhood influences the functional organization of the adult brain.

Learning a specific skill during childhood may partly determine the functional organization of the adult brain. This hypothesis led us to study oral language processing in illiterate subjects who, for social reasons, had never entered school and had no knowledge of reading or writing. In a brain activation study using PET and statistical parametric mapping, we compared word and pseudoword repetition in literate and illiterate subjects. Our study confirms behavioural evidence of different phonological processing in illiterate subjects. During repetition of real words, the two groups performed similarly and activated similar areas of the brain. In contrast, illiterate subjects had more difficulty repeating pseudowords correctly and did not activate the same neural structures as literates. These results are consistent with the hypothesis that learning the written form of language (orthography) interacts with the function of oral language. Our results indicate that learning to read and write during childhood influences the functional organization of the adult human brain.

Cerebral and cerebellar activation in correlation to the action-induced dystonia in writer's cramp.

The pattern of brain perfusion of four patients with writer's cramp and four control subjects were examined using positron emission tomography scans after [(15)O] butanol injections. Each subject was scanned 12 times to cover three repetitions of four different motor tasks with the right hand. Drawing of horizontal lines and variable durations of the writing of a prelearned text were performed in a pseudorandom order, the latter task commencing either simultaneously with or 30 sec or 120 sec before the tracer injection. The perceived difficulty and signs of dystonia progressed in correlation to the duration of writing. Statistical parametric maps were calculated to test hypotheses of regional specific effects dependent on the performed motor tasks. The patients with writer's cramp had progressively increased activity in the left primary sensorimotor and premotor cortices, the left thalamus, and the cerebellum with a right-side predominance in correlation to the duration of writing. The regions with activity increases thus corresponded to a cerebrocerebellar motor circuit. The duration of writing correlated to a progressive reduction of activity in the patients' left supramarginal and angular gyri (Brodmann areas 40 and 39) and an inferior part of the left temporal lobe (area 20). The control subjects had neither a significant increase or decrease of activity in correlation to the duration of writing. Group-specific differences were confirmed statistically in split-plot interaction analyses.

Accumulation of FDG in axillary sweat glands in hyperhidrosis: a pitfall in whole-body PET examination.

A diabetic male with severe autonomic neuropathy and recently discovered Hodgkin's disease demonstrated bilateral uptake of [2-18F]-2-fluoro-2-deoxy-d-glucose (FDG) in the axillary sweat glands during profuse sweating caused by hypoglycaemia at positron emission tomography examination. It is not yet clear whether the sweating interfered with the distribution of the radiopharmaceutical. Regardless of the cause or mechanism for the uptake, the finding is clinically relevant. A bilateral symmetrical accumulation of FDG in the axillae of a tumour patient does not necessarily indicate malignant involvement of the lymph nodes.

Alcohol activates the cerebral reward system in man.

OBJECTIVE: We investigated the effect of 0.07% alcohol on regional brain activity at rest and during cognitive performance in order to elucidate the anatomical substrate for the effects of alcohol in man as well as to clarify the interaction between changes in cerebral activity induced by cognitive performance and alcohol inebriation. METHOD: Regional cerebral blood flow (3D-PET, 15O Butanol) was measured in 13 male, nonalcoholic volunteers. Each subject was scanned 12 times, three scans in each of the following four situations: sober/rest, sober/test and inebriated/rest, inebriated/test. We used statistical parametric mapping and a computerized brain atlas for localization. RESULTS: Alcohol induced a sense of inebriation and elation as well as a relative increase of the cerebral blood flow in medial parts of the temporal lobes, in the anterobasal parts of the anterior cingulate cortex including the septal region. In addition, there was an increase of blood flow in midline parts of the lower brain stem. Relative decreases of flow were observed in the cerebellum and in the occipital cortex bilaterally. In the sober state, a computerized perceptual maze test and a (silent) serial seven test induced two distinct neocortical activation patterns that were specific to the tasks. Alcohol did not change these patterns and the test performance was also uninfluenced. CONCLUSIONS: A moderate dose of alcohol selectively activates target structures that pertain to the so-called cerebral reward system and the ascending reticular activating system. Alcohol (approximately 0.07%) appears to have only minor effects in the neocortical systems that are involved in on-line cognitive activity. This apparent independence between the subcortical alcohol target and the neocortical cognitive mechanisms is a new finding that appears to be of importance for an understanding of the effect of moderate doses of alcohol on the brain.

Cerebral effects of nicotine during cognition in smokers and non-smokers.

For the smoker, nicotine has a positive effect on attention, cognition and mood. Conversely, nicotine abstinence is characterized by uncomfortable psychological effects such as impaired attention, but also irritability. We postulated that nicotine exerts an effect on cerebral areas important for attention and mood. Regional cerebral blood flow (rCBF), as an index for cerebral activity, was measured in both smokers and non-smokers. They were scanned during performance of a psychometric task with and without i.v. infusion of nicotine (1-methyl-2-[3-pyridyll] pyrrolidine). Nicotine induced rCBF decreases in the anterior cingulate cortex and the cerebellum, and concomitant increases in the occipital cortex. The changes were similar in nature and magnitude in smokers and non-smokers. Thus, specific changes were induced in areas pertaining to the anterior attention system and to higher order visual cortex. We conclude that these effects on cerebral activity provide insights into the desired positive effects of nicotine on cognition as well as the negative effects experienced during nicotine abstinence.

Coexistence of attention-based facilitation and inhibition in the human cortex.

A key function of attention is to select an appropriate subset of available information by facilitation of attended processes and/or inhibition of irrelevant processing. Functional imaging studies, using positron emission tomography, have during different experimental tasks revealed decreased neuronal activity in areas that process input from unattended sensory modalities. It has been hypothesized that these decreases reflect a selective inhibitory modulation of nonrelevant cortical processing. In this study we addressed this question using a continuous arithmetical task with and without concomitant disturbing auditory input (task-irrelevant speech). During the arithmetical task, irrelevant speech did not affect task-performance but yielded decreased activity in the auditory and midcingulate cortices and increased activity in the left posterior parietal cortex. This pattern of modulation is consistent with a top down inhibitory modulation of a nonattended input to the auditory cortex and a coexisting, attention-based facilitation of task-relevant processing in higher order cortices. These findings suggest that task-related decreases in cortical activity may be of functional importance in the understanding of both attentional mechanisms and task-related information processing.

Brief episodes of ventricular fibrillation do not influence postischemic cerebral perfusion assessed by positron emission tomography.

OBJECTIVES: To establish the defibrillation threshold in patients receiving an implantable cardioverter defibrillator, at least three episodes of ventricular fibrillation are induced and converted back to regular rhythm, using direct current countershocks. The aim of this study was to examine the influence of repeated short episodes of ventricular fibrillation on global and regional cerebral perfusion. DESIGN: A prospective, descriptive study. SETTING: A positron emission tomography laboratory at a university hospital. PATIENTS: Four patients, admitted for defibrillation threshold tests 2 yrs after the implantation of a cardioverter defibrillator, were included in the study. Global and regional cerebral blood flow was measured by cerebral positron emission tomography, using an 15O-labeled tracer under propofol-induced general anesthesia. Electroencephalograms (EEGs) were concomitantly recorded. INTERVENTIONS: Induction and conversion of ventricular fibrillation. MEASUREMENTS AND MAIN RESULTS: No effect on global cerebral perfusion was observed after induced ventricular fibrillation lasting 21 +/- 3 secs. The average global cerebral perfusion was 23 +/- 1 mL/100 g/min after induction of anesthesia and 31 +/- 8 mL/100 g/min and 24 +/- 2 mL/100 g/min immediately after the termination of the first and second ventricular fibrillation episodes, respectively. Ten minutes after the second and the third threshold tests, global cerebral perfusion was 21 +/- 1 mL/100 g/min and 21 +/- 2 mL/100 g/min, respectively. Regional cerebral perfusion and EEGs were not influenced. CONCLUSION: Short episodes of ventricular fibrillation did not induce any measurable effects on global and regional cerebral perfusion detectable by positron emission tomography 30 secs and 10 mins after restitution of sinus rhythm.

Alternative positron emission tomography with non-conventional positron emitters: effects of their physical properties on image quality and potential clinical applications.

The increasing amount of clinically relevant information obtained by positron emission tomography (PET), primarily with fluorine-18 labelled 2-deoxy-2-fluoro-D-glucose, has generated a demand for new routes for the widespread and cost-efficient use of positron-emitting radiopharmaceuticals. New dual-head single-photon emission tomography (SPET) cameras are being developed which offer coincidence detection with camera heads lacking a collimator or SPET imaging with specially designed collimators and additional photon shielding. Thus, not only satellite PET imaging units but also nuclear medicine units investing in these new SPET/PET systems need to examine all available alternatives for rational radionuclide supplies from host cyclotrons. This article examines 25 "alternative" positron-emitting radionuclides, discusses the impact of their decay properties on image quality and reviews methods for their production as well as for their application in imaging techniques.

Signed and spoken language perception studied by positron emission tomography.

Sign and spoken language seem to be localized in the same brain areas. They elicit similar regional cerebral blood flow (rCBF) patterns, even though sign language is dependent on spatial information. We investigated sign and spoken language perception in a group of healthy bilingual subjects. Four videotaped activation conditions were used during PET imaging: (1) sign language, (2) spoken language, (3) spoken language with mouth covered, and (4) spoken language on a sound track while showing a motionless face. Spoken language (condition 4) activated significantly the perisylvian cortex (Brodmann areas 22 and 43) bilaterally. Sign language activated the visual association areas (Brodmann areas 37 and 19) but did not selectively activate parietal regions. A reciprocal relationship was observed between the level of activation in visual language perception areas and that in auditory perception areas. We conclude that when healthy bilingual subjects use the visual route for sign language perception, the functional anatomy overlaps that of language processing containing both auditory and visual components.

N-methylquipazine: carbon-11 labelling of the 5-HT3 agonist and in vivo evaluation of its biodistribution using PET.

N-Methylquipazine (2-[1-(4-methyl)-piperazinyl)quinoline)) was labelled with carbon-11 by reacting [11C]methyl iodide with the nor-compound, quipazine. Radiochemical conversions were 79 +/- 7%, based on the alkylating agent. The total synthesis time including purification was 40 to 45 min. N-[Methyl-11C]methylquipazine thus synthesized was >99% radiochemically pure, and the specific activity ranged between 12-37 GBq/mumol. Dynamic imaging with PET was used to examine in vivo its distribution in rat and monkey. In rat the organ uptake at intermediate times was: liver > heart > whole brain > or = lung > extracerebral tissue. Brain uptake and wash-out were rapid: A maximum was reached in 2 to 3 min with subsequent decrease to approximately equal to 50% the peak value by 13 min. In monkey the tracer uptake was heterogeneous and high in regions known to contain 5-HT3 receptors but also in regions devoid of these receptors. Tissue kinetics were similar for all regions (initial rapid accumulation with tmax < or = 7 min, followed by slow decrease with all regions approaching the level of the cerebellum at 30 to 35 min). Pretreating with quipazine significantly decreased only the ratio of uptake in the medulla oblongata compared to the cerebellum. Although the nonspecificity of its binding limits the usefulness of N-[methyl-11C]methylquipazine, both its kinetic behavior and the blocking results indicate that a more selective arylpiperazine might prove to be a more attractive tracer for PET studies of 5-HT3 receptors.