Biomedical subjects
Publications and source records attributed to H Landolt.
The age distribution and incidence of loss of heterozygosity (LOH) of 1p and 19q was analyzed in 85 oligodendroglial tumors WHO II and III. The peak of tumor manifestation was in the age group of 35 to 55 years. There was no association between age at diagnosis and LOH incidence. We conclude that the prognostic effect of age on survival is not mediated by LOH 1p/19q.
This illustrative case shows a meningocele created by erosion of the sacrum by a perineurial cyst. It is the first report of a large presacral mass consisting of a perineurial cyst and a meningocele simultaneously. We describe a hypothesis for the pathogenesis of this particular constellation of circumstances and present a successful surgical option based on the assumed pathogenesis.
Experiments were carried out to test the hypothesis that lactate reduces the neurotoxicity of glutamate in vivo. MAP2 immunohistochemistry was used to measure lesion size, and microdialysis to measure the changes in glucose and lactate in the extracellular compartment. After implantation of a microdialysis probe 100 mM glutamate with or without 6 mM lactate was added to the perfusion medium and infused into the cortex of unanesthetized rats. Infusion of 100 mM glutamate for a period of 30 min produced a lesion of 6.05 +/- 0.64 mm(3), an increase in lactate of 124 +/- 19% above basal and a 21 +/- 9% reduction of glucose below basal level. When 6mM L-lactate was perfused together with 100 mM glutamate there was a significant reduction in the size of the lesion and there was no reduction in dialysate glucose. When L-lactate was replaced with D-lactate the lesion size and the increase in dialysate lactate were greater than after glutamate alone. The neuroprotective role of L-lactate is attributed to its ability to meet the increased energy demands of neurones exposed to high concentrations of glutamate.
The aim of this study was to use quantitative microdialysis to estimate the true extracellular concentrations of glucose and lactate in minimally disturbed human brain. These values are important as criteria for microdialytical monitoring in critical care patients and for determining therapy. Microdialysis procedures were carried out during tumor operations, the probe being inserted distant from the site of manipulation in minimally disturbed tissue. Two methods were used: 1. The zero net flux method of Lönnroth. 2. The low flow method (10 mm membrane length, flow rate 0.3 microliter min-1, high in vivo recovery). Both methods gave similar values of about 2000 microM for lactate and slightly less for glucose (1700 microM). Glucose levels correspond with those measured by other methods in humans, allowing for the fact that our patients were anesthetised. Extracellular glucose levels were positively correlated with blood glucose values measured before the operation, and with extracellular lactate. Results confirm that extracellular glucose is zero when blood glucose is about 2 mM.
Iododeoxyuridine (IUdR) uptake and retention was imaged by positron emission tomography (PET) at 0-48 min and 24 h after administration of 28.0-64.4 MBq (0.76-1.74 mCi) of [124I]IUdR in 20 patients with brain tumors, including meningiomas and gliomas. The PET images were directly compared with gadolinium contrast-enhanced or T2-weighted magnetic resonance images. Estimates for IUdR-DNA incorporation in tumor tissue (Ki) required pharmacokinetic modeling and fitting of the 0-48 min dynamically acquired data to correct the 24-h image data for residual, nonincorporated radioactivity that did not clear from the tissue during the 24-h period after IUdR injection. Standard uptake values (SUVs) and tumor:brain activity ratios (Tm:Br) were also calculated from the 24-h image data. The Ki, SUV, and Tm/Br values were related to tumor type and grade, tumor labeling index, and survival after the PET scan. The plasma half-life of [124I]IUdR was short (2-3 min), and the arterial plasma input function was similar between patients (48 +/- 12 SUV*min). Plasma clearance of the major radiolabeled metabolite ([124I]iodide) varied somewhat between patients and was markedly prolonged in one patient with renal insufficiency. It was apparent from our analysis that a sizable fraction (15-93%) of residual nonincorporated radioactivity (largely [124I]iodide) remained in the tumors after the 24-h washout period, and this fraction varied between the different tumor groups. Because the SUV and Tm:Br ratio values reflect both IUdR-DNA incorporated and exchangeable nonincorporated radioactivity, any residual nonincorporated radioactivity will amplify their values and distort their significance and interpretation. This was particularly apparent in the meningioma and glioblastoma multiforme groups of tumors. Mean tumor Ki values ranged between 0.5 +/- 0.9 (meningiomas) and 3.9 +/- 2.3 microl/min/g (peak value for glioblastoma multiforme, GBM). Comparable SUV and Tm:Br values at 24 h ranged from 0.13 +/- 0.03 to 0.29 +/- 0.19 and from 2.0 +/- 0.6 to 6.1 +/- 1.5 for meningiomas and peak GBMs, respectively. Thus, the range of values was much greater for Ki (approximately 8-fold) compared with that for SUV (approximately 2.2-fold) and Tm:Br (approximately 3-fold). The expected relationships between Ki, SUV, and Tm:Br and other measures of tumor proliferation (tumor type and grade, labeling index, and patient survival) were observed. However, greater image specificity and significance of the SUV and Tm:Br values would be obtained by achieving greater washout and clearance of the exchangeable fraction of residual (background) radioactivity in the tumors, i.e., by increased hydration and urinary clearance and possibly by imaging later than 24 h after [124I]IUdR administration.
These experiments for the first time examine simultaneous changes in glucose and lactate in unanaesthetised animals during moderate hypoxia. Unanaesthetised rats were exposed to moderate hypoxia for a period of 15 min by reducing inspired oxygen to 8%. Changes in glucose and lactate were monitored in rat cortex using microdialysis and a novel dual enzyme-based assay. Samples of dialysate collected at 3-min intervals were assayed for both glucose and lactate. There was an early rapid rise of lactate that reached a peak at the end of the period of hypoxia followed by a steep decline. Glucose showed a very much smaller delayed increase that started during the period of hypoxia and continued beyond it. The origin of the rise in glucose is discussed, using the temporal relationship between the lactate and glucose changes.
The effects of the neuroprotective aminosteroid U74006F (tirilazad mesylate, Freedox) were monitored microdialytically in rat cortex during three 4h periods beginning immediately, 25h and 49h after permanent middle cerebral artery occlusion. Either U74006F or vehicle only was administered 15 min, 2h, 6h, 12h and 24h after operation. The dialysate was analysed for on-line pH, ascorbic acid, uric acid, glucose and lactate. The efficacy of post-ischaemic treatment was shown by: a) lesion volume 53h after operation was significantly smaller in U74006F-treated animals; b) microdialytic findings were very similar to those found previously with pre-ischaemic drug application (reduction in release of ascorbic acid, uric acid and lactate, increased pH); c) an effect of U74006F on lactate release could still be seen on days 2 and 3; and d) increases in uric acid on days 2 and 3, possibly reflecting delayed cell death, were smaller in aminosteroid treated animals.
The effects of the neuroprotective aminosteroid U74389G were monitored microdialytically in rat cortex during 4 h after permanent middle cerebral artery occlusion. Either U74389G or vehicle only was administered one hour before and 2 h after operation. The dialysate was analysed for on-line pH, ascorbic acid, uric acid, glucose and lactate. In aminosteroid treated animals the levels of ascorbic and uric acids were lower in dialysates after occlusion, total release of lactate was significantly reduced and on-line pH was significantly higher than in control animals. Lesion volume at 4 h, which was significantly reduced in treated animals, correlated positively with ascorbic acid release and on-line pH. Results suggest that neuroprotective effects of aminosteroids might be explained by: (a) preservation of intracellular levels of the radical scavenger ascorbic acid with possible concomitant reduction of glutamate release; and (b) reduced lactate release and increased pH which might influence oedema positively. Copyright 1999 Harcourt Publishers Ltd.
The role of postoperative radiotherapy in patients with low grade gliomas is not established yet. PET with 11C methionine (MET) and 18F fluorodeoxyglucose (FDG) was used to perform cross sectional comparisons as well as within patient follow up studies in 30 operated patients with fibrillary astrocytoma WHO II. Uptake of tracer by tumour was quantified by radioactivity concentration ratios in tumour over contralateral brain (T/C). Comparing patients who did (n=13) or did not (n=17) receive external radiotherapy subsequent to first tumour resection, no differences in MET and FDG T/C between both groups were found during a postoperative period of 94 months (when recurrence and malignant progression of low grade astrocytomas are expected). Malignant progression occurred at a similar rate in both patient groups at a mean (SD) postoperative interval of 46 (26) months. Irrespective of whether radiotherapy was applied or not, malignant tumour recurrences showed higher T/C values (MET: 1.70 (0.64), FDG: 0.98 (0.23)) than recurrences without signs of malignancy (MET: 1.21 (0.21), FDG: 0.82 (0.08)) (Mann-Whitney: MET p=0.086, FDG p=0.035). The data show a relative lack of radiotherapy administered immediately after first tumour resection. In the course of disease, patients with tumours undergoing malignant progression may be identified with PET tracer methods.
We analyzed the biodistribution of the 111In-labelled murine anti-tenascin-C MAb BC-2 after intralesional injection in 15 glioblastoma patients. The activated ligand DTPA was conjugated via the isothiocyanato-benzyl group onto BC-2. Conjugates were labelled with 111In, displaying immunoreactivity greater than 90% and labelling efficiency of 99 +/- 1%. In contrast to i.v. injections, excellent tumor uptake was obtained by direct intralesional injection of conjugates that showed only slow systemic release. In serum, conjugates were found to be intact; in urine, only low-molecular-weight decay products were detected. In 8 patients, outflow from the site of injection into systemic circulation was low; daily activity in the serum and urine was found to be below 2% of the total injected radioactivity; most of the injected activity was retained within the tumor, resulting in effective half-lives of 58 +/- 5 hr. In contrast, higher outflow up to 10% of regionally injected 111In-DTPA-BC-2 MAb into systemic circulation resulted in considerable shortening of the effective half-lives to 20 to 40 hr in 7 patients. This outflow was found to correlate with tumor size and blood/brain barrier disruption. In one patient, HPLC analysis of tumor cyst fluid 3 and 6 days after intralesional injection revealed conjugates to be intact and allowed the estimate of about 70% of the total injected 111In-DTPA-BC-2 to be confined to tumor tissue. We conclude that different outflow patterns can be observed following locoregional injection of 111In-DTPA-BC-2, leading to considerable variations in the effective half-lives of isotopes within the tumor, requiring adjustment of the radiation dose in therapeutic trials.
Using microdialysis combined with suitable analytical methods, levels of metabolites in the extracellular fluid of the cerebral cortex were monitored during neurovascular surgery (9 aneurysm and 5 bypass operations). Our aim was to use microdialysis to detect any local ischaemia which could be caused by brain retraction, temporary clipping and dissecting manoevres. For this purpose, parameters were quantified whose levels in the dialysate are known to be influenced by ischaemia (on-line pH, ascorbic acid, uric acid, glutathione, cysteine, glucose, lactate). In the aneurysm series, the on-line pH fell after introduction of the retractor, and rose after removal: also, in many cases, levels of ascorbic acid, glutathione and lactate increased and glucose decreased. These changes are all in accordance with ischaemic conditions in the region of the probe; they disappeared at the end of retraction, or sometimes even before. During the bypass operations, there were no marked changes in on-line pH or in any of the measured parameters. However, in 2 of these patients ascorbic acid, uric acid and glucose levels were very high during the whole measurement, indicating possible changes in metabolism caused by inadequate perfusion (carotid artery stenosis). We conclude that microdialysis is a sensitive method of detecting intraoperative changes in cerebral metabolism.
In an aorta-coronary bypass operation, the heart is excluded from the circulation for many minutes, leading to ischemia. During this time the heart is cooled in order to mitigate damage. Microdialysis has been shown to be very suitable for detecting ischaemic changes e.g. in brain. We therefore used this method to study the time courses of several neurochemical parameters which have been shown to indicate ischaemia in animal models (ascorbic acid, glutathione, cysteine, uric acid, glucose, lactate and pH), during such a bypass operation. Three patients were investigated, the microdialysis probe being inserted into the interventricular septum of the heart. Our results show that microdialysis is technically feasible in the human heart in a clinical setting, although the operation becomes more demanding for the surgeon. All the above-mentioned parameters could be detected in the heart muscle. Some of them showed changes characteristic of ischaemia, and the effects of cooling on the metabolism could also be noted. Long term measurements are planned to enable delayed damage to be disclosed.
Glutamate, a major neurotransmitter in the brain, is also involved in pathophysiological processes resulting in secondary lesions following ischaemia or trauma. In the present study we investigated the relationship between glutamate excitotoxicity free radical induction (indicated by ascorbic acid level) and glucose-lactate metabolism. Monosodium glutamate was applied through microdialysis probes (500 mM in perfusate) into the cortex of rats for 30 minutes and ascorbic acid (ASC), glucose (GLUC) and lactate (LAC) were measured in dialysates. Glutamate produced a cortical lesion with an average volume of 12.7 +/- 1.4 mm3. Analysis of dialysates revealed a significant increase of ASC (325 +/- 52% of baseline) and LAC (677 +/- 86%) in the core lesion. In the lesion periphery a non-significant and short-lasting elevation was measured for both parameters with a second microdialysis probe (about 1.3 mm frontally to the first probe). A concomitant decrease of GLUC was found in both probes, reaching 29 +/- 8% and 60 +/- 7% of basal levels in the core and periphery of the lesion, respectively. In addition, we studied the delivery characteristics of several glutamate concentrations (10, 100 or 1000 mM in perfusate) during a 90-minute application into the cortex. The delivery of glutamate from the perfusate to the brain was about 33-38% in the first 30 min and afterwards 11 25% of the total in the perfusate. The results show that cortical application of glutamate changes the composition of the extracellular fluid, which could contribute to the development of the lesion.
Before microdialysis (MD) can be introduced into the clinic as an improved method of cerebral monitoring, certain ethical, methodological and clinical factors must be considered. Access to the brain for probe insertion is offered by craniotomy or by routine intracranial pressure (ICP) monitoring and the additional lesion is minimal. Care must be taken that the two devices do not interfere with each other. In contrast to ICP monitoring, MD provides information about multiple aspects of brain metabolism. We can monitor either still intact tissue to prevent additional damage, or injured brain to decide on and control therapies. The parameters used must reflect pathological changes an early stage, and the analysis should be available on-line or immediately after sample collection. The effects off factors such as tube length and flow rate on the behaviour of the chosen parameters (in our case on-line pH, radical scavengers and uric acid) in the MD set-up must be investigated in vitro and in animal models before use in the clinic. The range of non-pathological values of parameters of interest in human brain should be known For this purpose we took measurements during an extracranial-intracranial bypass operation, and were able to compare values with those in a severely damaged brain. The mutual chronology of parameter changes and clinical events must be clear. Future aspects include the use of low-flow methods offering nearly 100% recovery, improved analytical methods, and combination of MD with other monitoring methods to obtain more exact information.
In the past 10 years, the management of brain injury has shown several advances. Besides new diagnostic tools many new tentative approaches have been investigated, such as jugular bulb measurement of oxygen and lactate differences and near-infrared spectroscopy. The latest tool is microdialysis, which uses a probe as an interface to the brain. This method uses internally perfused semi-permeable membrane probes, which allow neurochemical water-soluble substances to be collected outside the brain for further analysis. Since the late 1980s the first results of microdialysis in neurointensive care show that chemical substances such as lactate, glucose, amino acids, metabolites of several biochemical mechanisms and electrolytes are measurable. This heterogeneous approach now waits for validation for clinical use and for the most challenging aspect, the clinical interpretation and use to improve therapy. The aim of this review is to describe the state of the art of this new technique, including our own experiences and concepts.
Using microdialysis, levels of metabolites in the extracellular fluid of the cerebral cortex were monitored during neurovascular surgery (9 aneurysm and 5 extra-intracranial bypass operations). Our aim was to use microdialysis to detect any local ischemia which might be caused by brain retraction or temporary clipping. Parameters were therefore quantified whose levels in the dialysate are known to be influenced by ischemia (on-line pH, ascorbic acid, uric acid, glutathione, cysteine, glucose, lactate, glucose:lactate ratio). In the aneurysm series, on-line pH fell after introduction of the retractor, and in the majority of cases the other parameters also showed changes in accordance with ischemic conditions in the region of the probe. These changes disappeared at the end of retraction, or sometimes even before. During the bypass operations, there were no marked changes in on-line pH or in any of the measured parameters. However, in some of these patients values for the glucose:lactate ratio, ascorbic acid and uric acid lay outside the suggested basal levels for minimally disturbed cortex, indicating possible changes in metabolism caused by inadequate perfusion (carotid artery occlusion). We conclude that microdialysis is a sensitive method of detecting intraoperative changes in cerebral metabolism.
An apparent transient increase in local glucose utilization has been demonstrated in certain brain areas after global and focal ischemia in several models. A coincident transient increase in extracellular glutamate has been shown in the same brain regions in many of these models. To test the hypothesis that an increase in metabolism is an important component of the excitotoxic effect of glutamate, we perfused glutamate at different concentrations (0.01, 0.1, 0.5, 1 M) into the extracellular space, and performed 2-deoxyglucose autoradiography after 90 min of infusion. Furthermore, we infused 14C-labeled glutamate to investigate its diffusion characteristics within the brain using autoradiographic methods. Glutamate at 0.5 and 1 M concentration caused large consistent areas of brain damage with all the histological features of acute infarction, although ischemia does not occur in this model. Glucose utilization was significantly increased (115 +/- 20 vs. 56 +/- 13 mumol/100 g/min in controls p < 0.01) in a sharply demarcated concentric zone, at the boundary between histologically damaged and normal brain, suggesting that viable cells not yet destroyed by glutamate respond by increased glucose metabolism. [14C] Glutamate diffused into the brain in a dose-dependent manner, and the pattern of its diffusion corresponded closely to that of the histological lesion and the zone of increased glucose uptake. We speculate that the increase in glucose use, which is not caused by ischemia in this model, is due to a metabolic response to glutamate and may be due to attempts to restore ionic homeostasis or repair cell damage.
Homeostatic sleep regulation in habitual short sleepers (sleep episode < 6 h, n = 9) and long sleepers (> 9 h, n = 7) was investigated by studying their sleep structure and sleep electroencephalogram (EEG) during baseline conditions and after prolonging their habitual waking time by 24 h. In each sleep episode, total sleep time was > 3 h longer in the long sleepers than in the short sleepers. Sleep deprivation decreased sleep latency and rapid eye movement (REM) density in REM sleep more in long sleepers than in short sleepers. The enhancement of EEG slow-wave activity (SWA; spectral power density in the 0.75-4.5 Hz range) in non-REM sleep after sleep loss was larger in long sleepers (47%) than in short sleepers (19%). This difference in the SWA response was predicted by the two-process model of sleep regulation on the basis of the different sleep durations. The results indicate that short sleepers live under a higher "non-REM sleep pressure" than long sleepers. However, the two groups do not differ with respect to the homeostatic sleep regulatory mechanisms.