Grading of moyamoya disease allows stratification for postoperative ischemia in bilateral revascularization surgery.

BACKGROUND: Moyamoya disease (MMD) may be graded based on DSA, the presence of ischemia in MRI and cerebrovascular reserve capacity allowing the prediction of ischemic symptoms in patients. Cerebral ischemia represents a severe complication in revascularization surgery. Focusing on different clinical features of hemodynamic impairment, MMD grading may allow prediction of ischemic complications. It was the aim to analyze whether MMD grading stratifies for ischemic complications in revascularization surgery for MMD. METHOD: In 37 MMD patients a bilateral, standardized, one-staged revascularization approach consisting of STA-MCA bypass/encephalomyosynangiosis (EMS) and single EMS on the contralateral hemisphere was performed. Clinical data including DSA, MRI and rCBF (Xenon-CT) studies were assessed and used for grading MMD. All patients were observed on the ICU for at least 24 h and received CT imaging on the first postoperative day and in case of neurological deterioration. Ischemic complications were analyzed until the day of discharge and at 6-month follow-up. RESULTS: Grading of MMD revealed 11 hemispheres (15 %) as grade I, 33 hemispheres (44 %) as grade II and 30 hemispheres (41 %) as grade III. Eight ischemic complications were observed (11 %). MMD grading demonstrated a significant correlation with ischemic complications: 0 complications in grade I, 3 in grade II (9 %) and 5 in grade III hemispheres (16 %; p < 0.05, Fisher's exact test). CONCLUSIONS: The proposed grading system allows to stratify for ischemic complications in MMD patients that receive bilateral, one-staged revascularization surgery. Future studies will have to investigate its use for predicting ischemic complications in other revascularization strategies for MMD.

Distinct clinical and radiographic characteristics of moyamoya disease amongst European Caucasians.

BACKGROUND AND PURPOSE: Occlusive cerebrovascular moyamoya disease (MMD) is rare and has been characterized mainly in Asian countries, so far. In recent years, MMD has been increasingly reported worldwide, raising the question whether its clinical presentation would vary amongst different ethnic backgrounds. Here, a homogeneous series of 153 patients with MMD are reported and the specific clinical features of this rare disease amongst European Caucasians are highlighted. METHODS: A total of 153 European Caucasians with MMD who were treated in our institution between 1997 and 2014 were retrospectively identified. Demographic data, clinical symptoms, angiographic characteristics and functional hemodynamic studies were analyzed. RESULTS: Moyamoya disease presented with a female predominance of 2,9:1.,78% presented with a typical MMD, 17% with a unilateral MMD and 5% with an atypical MMD. 16% of our patients belonged to the pediatric population. Overall, 81% and 8.5% of our cohort presented initially with ischaemic and hemorrhagic manifestation, respectively. The rate of hemorrhagic manifestation of MMD amongst the pediatric group was slightly higher (12%). Angiographic analysis revealed steno-occlusive involvement of the posterior circulation in 34% with a higher involvement in pediatric patients (64%) compared to adults (28%). CONCLUSIONS: The characterization of our homogeneous European Caucasian cohort reveals several significant differences compared to Asian cohorts. In contrast, MMD presents similarly amongst European and North American cohorts, suggesting that non-Asian MMD is characterized by distinct clinical features.

Proposal for a new grading of Moyamoya disease in adult patients.

BACKGROUND: Moyamoya disease (MMD) is graded based on digital subtraction angiography (DSA) with limited clinical applications. The aim was to identify clinically relevant parameters that may be used to develop a novel MMD grading system. METHODS: In 40 MMD patients bilateral revascularization surgery was performed. Clinical data including DSA, MRI and regional cerebral blood flow studies were assessed. χ(2) test corrected for dependency of measurements at the same subject and analysis of receiver operating characteristics were used to identify key parameters. Grading system included: DSA (stenosis/occlusion = 1 point; stenosis/occlusion + intracranial compensation = 2 points; stenosis/occlusion + intracranial compensation + extra-intracranial compensation = 3 points), MRI (no sign of ischemia = 0 points; signs of ischemia = 1 point) and cerebrovascular reserve capacity (CVRC > -5% = 0 points; CVRC < -5% = 2 points). MMD grade I referred to 1-2 points, grade II to 3-4 and grade III to 5-6 points. RESULTS: DSA, MRI and CVRC were dependent factors associated with the occurrence of clinical symptoms. Receiver operating characteristics analysis indentified the grading system as superior to each single parameter in predicting clinical symptoms. Fourteen hemispheres were graded as mild (grade I), 35 as moderate (grade II) and 31 as severe (grade III); 21% of grade I, 63% of grade II and 93% of grade III hemispheres were clinically symptomatic. CONCLUSIONS: The proposed grading system allows to stratify for clinical symptomatology in MMD patients. Future studies will have to investigate its value for assessing clinical symptoms and treatment risks.

Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease.

BACKGROUND: The best revascularization strategy for moyamoya disease (MMD) remains unknown. Our aim was to characterize angiographic revascularization effects of a bilateral standardized revascularization approach, consisting of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and encephalomyosynangiosis (EMS) on one hemisphere and single EMS on the contralateral hemisphere of each patient, and to compare the effects of both revascularization strategies on cerebral hemodynamics. METHODS: In 30 patients (18 females/12 males, age 8-63 years), standardized revascularization was performed. Digital subtraction angiography was performed preoperatively and at 7 days, 6 months and 12 months postoperatively. STA-MCA and EMS functions were graded I (poor), II (medium) or III (extensive) according to angiographic aspects. In 20 patients, cerebrovascular reserve capacity (CVRC) was assessed pre- and postoperatively (at 12 months) using xenon CT. RESULTS: After 12 months, STA-MCA/EMS function was grade 1 in 40/40%, grade 2 in 27/26%, and grade 3 in 27/10% of hemispheres, respectively. Twelve months after surgery, single EMS showed grade I in 37%, grade II in 27%, and grade III in 20% of hemispheres. Combined revascularization improved CVRC significantly compared to preoperative measurement (preoperative: 16.5 ± 34.6% vs. postoperative: 60.8 ± 64.22%; p < 0.05). Single EMS did not improve CVRC significantly (preoperative: 21.8 ± 35.9% vs. postoperative: 34.8 ± 63.0%; p < 0.05). CONCLUSIONS: Combined and indirect revascularization may be successfully applied in a bilateral standardized approach. STA-MCA/EMS is superior to single EMS in restoring CVRC in adult MMD patients.

Effect of mouth opening on bypass function after combined revascularization for Moyamoya disease.

Moyamoya disease represents a rare steno-occlusive disease of the internal carotid artery (ICA) with a reactive and pathological basal network of collateral vessels. It may lead to ischemic stroke or intracerebral hemorrhage. Treatment options are either direct or indirect revascularization procedures or a combination thereof. Specialized centers report sufficient revascularization in most patients and low complication rates.Between 2005 and 2008, direct extra-intracranial bypass surgery in combination with encephalomyosynangiosis (EMS) was performed in 71 Moyamoya patients at the Mannheim University Medical Center.Following one case of reversible neurological deficits associated with mouth opening, we prospectively evaluated the effect of mouth opening on bypass function in this patient and four further consecutive patients by digital subtraction angiography.Three out of five patients showed alterations in bypass patency upon mouth opening. The obstruction was located at the junction of the bypass and the temporal muscle. Two temporary occlusions and one case of decreased flow were observed. One patient demonstrated reversible hemiparesis and aphasia.

[Moyamoya disease]. / Enfermedad de moyamoya.

AIMS: To describe the clinical manifestations and to summarise the knowledge currently available about the epidemiology, physiopathology, histopathology, diagnosis and treatment of moyamoya disease. DEVELOPMENT: Moyamoya disease is produced by the spontaneous, progressive occlusion of the circle of Willis with the simultaneous appearance of natural intracranial and extra-intracranial collaterals. Both children and adults can be affected and it is to be found not only in Asia but also in Europe and America, although the frequency is unknown. Its primary lesion is a thickening of the tunica interna in the distal segment of the internal carotids, initially within the anterior portion of the circle of Willis. This results in the appearance of collateral vessels, which are first intracranial (moyamoya vessels) and then extracranial, to offset the critical reduction in regional cerebral blood flow. The most common clinical manifestation is motor-type ischaemic episodes, although it may also be accompanied by intracerebral haemorrhages. It can be diagnosed by means of suitable morphological and functional studies, such as cerebral pan angiography and xenon-CT, in patients with a founded clinical suspicion. Neurosurgical revascularisation is to date the most widely accepted treatment and can bring about a permanent clinical cure. CONCLUSIONS: Moyamoya disease is a rare pathology that can be successfully treated using cerebral revascularisation, provided a timely diagnosis is reached and in indicated patients. Such therapy makes it possible to prevent the repetition of ischaemic events or haemorrhages that usually bring about severe limitations in the individual's personal development.

De novo aneurysm of the anterior communicating artery presenting with subarachnoid hemorrhage 7 years after initial cryptogenic subarachnoid hemorrhage: a case report and review of the literature.

Spontaneous subarachnoid hemorrhage (SAH) is usually caused by a ruptured cerebral aneurysm. Despite the use of initial four-vessel cerebral digital subtraction angiography (DSA), 15 % of all cases remain idiopathic. According to the initial computed tomographic scan, the spontaneous SAH can be divided into a perimesencephalic group associated with a benign nature and a nonperimesencephalic group with a similar clinical course as aneurysmal SAH. We present a case of a 49-year-old man with a de novo aneurysm formation of the anterior communicating artery with SAH 7 years after initial cryptogenic nonperimesencephalic SAH. This observation suggests that in some cases, long-term angiographic studies might be justified.

Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intravital multi-fluorescence videomicroscopy.

Vascular endothelial growth factor (VEGF) plays a fundamental role in mediating tumor angiogenesis and tumor growth. Here we investigate the direct effect of a novel small molecule inhibitor of the Flk-1-mediated signal transduction pathway of VEGF, SU5416, on tumor angiogenesis and microhemodynamics of an experimental glioblastoma by using intravital multifluorescence videomicroscopy. SU5416 treatment significantly suppressed tumor growth. In parallel, SU5416 demonstrated a potent antiangiogenic activity, resulting in a significant reduction of both the total and functional vascular density of the tumor microvasculature, which indicates an impaired vascularization as well as significant perfusion failure in treated tumors. This malperfusion was not compensated for by changes in vessel diameter or recruitment of nonperfused vessels. Analyses of the tumor microcirculation revealed significant microhemodynamic changes after angiogenesis blockage such as a higher red blood cell velocity and blood flow in remnant tumor vessels when compared with controls. Our results demonstrate that the novel antiangiogenic concept of targeting the tyrosine kinase of Flk-1/KDR by means of a small molecule inhibitor represents an efficient strategy to control growth and progression of angiogenesis-dependent tumors. This study provides insight into microvascular consequences of Flk-1/KDR targeting in vivo and may have important implications for the future treatment of angiogenesis-dependent neoplasms.

Characteristic chromosomal imbalances in primary central nervous system lymphomas of the diffuse large B-cell type.

We performed a genome wide screening for genomic alterations on a series of 19 sporadic primary central nervous system lymphomas (PCNSL) of the diffuse large B-cell type by comparative genomic hybridization (CGH). The tumors were additionally analyzed for amplification and rearrangement of the BCL2 gene at 18q21 as well as for mutation of the recently cloned BCL10 gene at 1p22. Eighteen tumors showed genomic imbalances on CGH analysis. On average, 2.1 losses and 4.7 gains were detected per tumor. The chromosome arm most frequently affected by losses of genomic material was 6q (47%) with a commonly deleted region mapping to 6q21-q22. The most frequent gains involved chromosome arms 12q (63%), 18q and 22q (37% each), as well as 1q, 9q, 11q, 12p, 16p and 17q (26% each). High-level amplifications were mapped to 9p23-p24 (1 tumor) and to 18q21-q23 (2 tumors). However, PCR-based analysis, Southern blot analysis and high-resolution matrix-CGH of the BCL2 gene revealed neither evidence for amplification nor for genetic rearrangement. Mutational analysis of BCL10 in 16 PCNSL identified four distinct sequence polymorphisms but no mutation. Taken together, our data do not support a role of BCL2 rearrangement/amplification and BCL10 mutation in PCNSL but indicate a number of novel chromosomal regions that likely carry yet unknown tumor suppressor genes or proto-oncogenes involved in the pathogenesis of these tumors.

Effect of intra-arterial papaverine on regional cerebral blood flow in hemodynamically relevant cerebral vasospasm.

BACKGROUND AND PURPOSE: It remains controversial whether the intra-arterial administration of papaverine (IAP) is effective in reversing vasospasm-associated cerebral hypoperfusion after aneurysmal subarachnoid hemorrhage. The aim of the present study was to continuously assess regional cerebral blood flow (rCBF) during and after IAP with the use of quantitative, bedside thermal diffusion flowmetry. METHODS: Eight patients with cerebral vasospasm after subarachnoid hemorrhage (mean flow velocity >120 cm/s; angiographic vessel constriction >33%; hemispheric cerebral blood flow [CBF] <32 mL/100 g per minute) were prospectively entered into the study. Before IAP, thermal diffusion microprobes were implanted into the white matter of each affected vascular territory (n=10) for rCBF monitoring. During and after IAP (300 mg papaverine/50 mL saline over 1 hour), mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, thermal diffusion rCBF (TD-rCBF), and cerebrovascular resistance (CVR) were recorded continuously. RESULTS: IAP significantly increased TD-rCBF from 7.3+/-1.6 to 37.9+/-6.6 mL/100 g per minute (mean+/-SEM), indicating reversal of cerebral hypoperfusion. This TD-rCBF response was dependent on the degree of cerebral vasospasm and reduced perfusion within the vascular territory. Long-term analysis of TD-rCBF, however, demonstrated that this beneficial effect of IAP on cerebral hypoperfusion was only transient: within 3 hours after treatment, TD-rCBF and CVR returned to baseline values. Furthermore, a lack of correlation between transcranial Doppler sonography and thermal diffusion flowmetry suggested that transcranial Doppler sonography is not suited for CBF-based neuromonitoring after IAP. CONCLUSIONS: IAP is not effective in permanently reversing cerebral hypoperfusion in patients with cerebral vasospasm. The need to validate alternative therapeutic strategies that seek to improve cerebral perfusion in vasospasm warrants continued development of CBF-based neuromonitoring strategies.

Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse.

The current study follows angiogenesis and microcirculatory changes associated with malignant glioma growth by means of an intravital fluorescence microscopic approach, which allows for the direct and continuous visualization of the glioma microvasculature and its quantitative analysis. Fluorescently labeled C6 rat glioma cells (5 x 10(5)) were implanted into dorsal skinfold chamber preparations of athymic nude mice. Glioma growth, vascularization, microhemodynamics, vascular permeability, and leukocyte-endothelial cell interactions were simultaneously followed over a 22-day observation period using intravital epiillumination microscopy and a multifluorescent labeling technique. Analysis of the process of glioma vascularization revealed three stages with distinct microvascular characteristics: avascular stage (days 0 to 6), lag of glioma growth but initial glioma-induced angiogenesis within the host tissue in peritumoral areas; early vascular stage (days 6 to 14), glioma cell proliferation associated with a spatially homogeneous development of a glioma microvasculature; and late vascular stage (days 14 to 22), exponential tumor growth and expansion (> 400 mm3) with high vascular densities in the peritumoral region and reduced vascularization (microvascular perfusion) in the glioma center. Within the center, the functional vessel length per area correlated inversely with glioma size (P < 0.01). In the peritumoral region, functional vessel length per area was independent of glioma size, indicating persistent, high angiogenic activity throughout the observation period. Thus, the microvasculature of mature gliomas revealed a microvascular zonal division with a progressive reduction of the functional vessel length per area within the tumor center. The perfusion failure of individual microvessels within the glioma center was partly compensated by an increase of diameters (P < 0.05), and thus by an increase of blood flow in these functional microvessels (P < 0.05) over time. Histologic analysis demonstrated both expanding and infiltrating growth patterns, as well as focal necroses on day 22. These are the first data from repeated in vivo analysis of glioma growth, vascularization, and microcirculation.

Three-dimensional reconstruction of the rat brain cortical microcirculation in vivo.

We used confocal laser scanning microscopy (CLSM) to investigate the morphology and three-dimensional relationships of the microcirculation of the superficial layers of the rat brain cortex in vivo. In anesthetized rats equipped with a closed cranial window (dura mater removed), after i.v. injection of 3 mg/100 g of body weight of fluorescein in 0.5 ml of saline, serial optical sections of the brain cortex intraparenchymal microcirculation were taken. Excitation was at a wavelength of 488 nm (argon laser), and emission was collected above 515 nm. CLSM provided images of brain vessels with sufficient signal-to-noise ratio for three-dimensional reconstructions down to a depth of 250 microns beneath the surface of the brain. Compared to conventional fluorescence microscopy, CLSM has a much higher axial resolution and higher depth of penetration. Laser light-induced intravascular aggregates, irregularities of erythrocyte flow, or microvascular occlusions ("light and dye injury") were not apparent in the current experimental paradigm. CLSM is a promising new tool for in vivo visualization of the cerebral microcirculation. Future studies have to characterize the potential damage to the tissue dye mechanisms.

Cerebral blood flow and cerebrovascular reserve capacity: estimation by dynamic magnetic resonance imaging.

We have developed a new method for estimation of regional CBF (rCBF) and cerebrovascular reserve capacity on a pixel-by-pixel basis by means of dynamic magnetic resonance imaging (MRI). Thirteen healthy volunteers, 8 patients with occlusion and/or high grade stenosis of the internal carotid artery (ICA), and 2 patients with acute stroke underwent dynamic susceptibility-weighted contrast enhanced MRI. Using principles of indicator dilution theory and deconvolution analysis, maps of rCBF, regional cerebral blood volume, and of the mean transit time (MTT) were calculated. In patients with ICA occlusion/stenosis, cerebrovascular reserve capacity was assessed by the rCBF increase after acetazolamide stimulation. Mean gray and white matter rCBF values in normals were 67.1 and 23.7 mL x 100 g(-1) x min(-1), respectively. Before acetazolamide stimulation, six of eight patients with ICA occlusions showed decreased rCBF values; and in seven patients increased MTT values were observed in tissue ipsilateral to the occlusion. After acetazolamide stimulation, decreased cerebrovascular reserve capacity was observed in five of eight patients with ICA occlusion. In acute stroke, rCBF in the central core of ischemia was less than 8 mL x 100 g(-1) x min(-1). In peri-infarct tissue, rCBF and MTT were higher than in unaffected tissue but rCBF was normal. Dynamic MRI provides important clinical information on the hemodynamic state of brain tissue in patients with occlusive cerebrovascular disease or acute stroke.

Dynamic SPECT with Xe-133: regional cerebral blood flow in patients with unilateral cerebrovascular disease: concise communication.

To validate xenon-133 dynamic single photon emission tomography (SPECT) clinically, 74 patients were examined. Strictly unilateral cerebrovascular disease was confirmed in 47 patients by clinical history and by transmission computerized tomography (TCT) and contrast angiography. Twenty-seven were excluded, considered normal. SPECT flow maps were evaluated visually (against TCT) or by automated region of interest (ROI) techniques (12 areas per slice) to measure area flow (AF) (ml/100 g-min) and interhemispherical area flow ratios (AR). These were compared with normal values. Minimum AF in affected hemisphere decreased, and AR-to-normal difference increased, with the severity of the disease. Visually, low-flow areas were detected twice as frequently in SPECT as areas of low density of TCT. In reversible episodes, sensitivity of AF alone ws significantly below the sensitivity of combined evaluation of flow and ratio.

Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery.

In addition to its well established neuroendocrine and neurotransmitter effects, corticotropin releasing factor (CRF) exerts a potent vasorelaxant action. Recently, a CRF-related peptide, urocortin, has been identified in the mammalian brain. In the present study, the cerebral vasomotor action of this peptide and the mechanism underlying its relaxant effect are characterized. Ring segments obtained from the rat basilar artery were used for measurement of isometric force. The relaxant action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium. In segments precontracted with prostaglandin F2alpha, urocortin, CRF and sauvagine induced concentration-related relaxation. The order of potency was as follows (pD2+/-s.e.m. given in brackets): urocortin (9.32+/-0.07) > sauvagine (9.08+/-0.08) > CRF (7.50+/-0.07). Complete relaxation was achieved with each agonist. Relaxation was not affected by removal of the endothelium but was markedly attenuated in segments precontracted with 50 mM K+ Krebs solution. The relaxant effect of urocortin was inhibited by astressin in an apparently competitive manner. A pA2 value of 7.52 was estimated for astressin. Inhibition of urocortin-induced relaxation was also observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD2 in the presence of 300 microM SQ22536, 9.36+/-0.05) and the K+ channel blockers tetraethylammonium (10 mM; pD2, 8.65+/-0.07), iberiotoxin (100 nM; pD2, 8.88+/-0.08) and apamin (10 nM; pD2, 8.94+/-0.07). However, the inhibitory actions of SQ22536 and apamin or iberiotoxin were not additive. The results suggest that urocortin induces relaxation of cerebral arteries by activating CRF-R2 receptors present in the vascular wall. Relaxation appears to be mediated by adenylate cyclase stimulation and activation of Ca2+-dependent K+ channels.

Effects of 30% stable xenon on regional cerebral blood flow in patients with intracranial pathology.

Regional cerebral blood flow was assessed continuously in 22 patients with severe intracranial pathology undergoing xenon-enhanced computed tomography by means of an intraparenchymal thermodiffusion based microprobe. Thirty-four blood flow studies were analysed revealing an overall xenon-induced flow activation from about 12%. Regional CBF rose from 25 +/- 17 ml/100 g/min (mean +/- sd; range: 5.2-41.8 ml/100 g/min) before xenon administration to 28 +/- 21 ml/100 g/min (p = 0.012; range: 6.5-46.4 ml/100 g/min) when "steady-state" during xenon "wash-in" was reached. Flow activation curve demonstrated a logarithmic shape with an increase in rCBF between 3% and 7% within the first 90 seconds of xenon "wash-in", 12% after 160 seconds, and showed no further augmentation until the end of the blood flow study after 310 seconds. It is concluded that xenon inhalation leads to flow augmentation in patients with cerebral insult, which does not exceed flow activation obtained in normal subjects. The impact of the results on xenon-enhanced computed tomography cerebral blood flow calculations remains to be established.

Bedside monitoring of cerebral blood flow by transcranial thermo-dye-dilution technique in patients suffering from severe traumatic brain injury or subarachnoid hemorrhage.

Bedside measurement of cerebral blood flow (CBF) represents an important feature in monitoring of neurointensive care patients which is hard to establish. Therefore, we adopted a recently described thermo-dye-dilution-based approach for monitoring CBF in patients suffering from severe cerebral insults, that is, traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Combined fiberoptic-thermistor catheters were placed in one jugular venous bulb and in the abdominal aorta of 16 patients. Following central venous injection of a 50-mL bolus of precooled indocyanine green (ICG) solution, CBF was determined as a function of the mean transit times of coldness and dye. In addition, measurements of CBF using stable xenon-enhanced computerized tomography (sXe-CT) were simultaneously performed in 10 patients. A total of 272 thermo-dye-dilution measurements yielded 196 valid results, with CBF ranging from 26.2 to 144.8 mL 100 g(-1) min(-1). Reproducibility was fairly good, with the standard deviation within sets of repeated measurements being 6.3 mL 100 g(-1) min(-1) and 9.4 as the mean coefficient of variation. Simultaneously obtained values with sXe-CT displayed a good correlation (r = 0.843, p < 0.01); however, the thermo-dye-dilution method consistently overestimated CBF. Data analysis using the Bland and Altman methodology revealed a large bias of 45.7 mL 100 g(-1) min(-1) with a +/- 2 SD range of 37 mL 100 g(-1) min(-1), indicating a rather poor agreement. The thermo-dye-dilution method proved a reasonably reproducible technique, enabling repeated long-term bedside measurements of CBF in neurointensive care patients with a minimum of time effort. However, a high failure rate was also noted, and consistent overestimation of perfusion was observed in comparison to sXe-CT measurements. Although the thermo-dye-dilution technique has been successfully validated in patients with normal neurovascular function, its applicability for bedside monitoring of CBF appears uncertain in patients suffering from severe TBI or SAH.

Characterization of the contractile and relaxant action of the endothelin-1 precursor, big endothelin-1, in the isolated rat basilar artery.

The presence of functional endothelin converting enzyme (ECE) activity in basilar artery ring segments was investigated by measuring the contractile and relaxant effects of big endothelin (ET)-1. Under resting tension conditions cumulative application of big ET1-1 elicited a concentration-related contraction with the concentration-effect curve (CEC) shifted to the right against ET-1 by a factor of 31 and 29 in segments with the endothelium intact or mechanically removed, respectively. Preincubation with the ET(A) receptor antagonist, BQ123, induced an apparently parallel rightwards shift without affecting the maximum contraction. This shift was more pronounced for ET-1 than for big ET-1. With the putative ECE inhibitor phosphoramidon (10(-3) M) in the bath a small rightwards shift of the CEC for big ET-1 was observed in control segments and a more marked one in de-endothelialized segments. In segments precontracted with prostaglandin (PG) F(2alpha) big ET-1 induced a significant although transient relaxation whereas ET-1 did not. However, in the presence of BQ123 both ET-1 and big ET-1 elicited concentration-related relaxation with a significantly higher maximum effect obtained with big ET-1. The potency was 13 fold higher for ET-1, which is markedly less than that found for contraction. The results, therefore, suggest 1) the presence of functional ECE-activity in the rat basilar artery wall, and 2) differences in the functional ECE activity located in the endothelium and media.

Glioma cell migration is associated with glioma-induced angiogenesis in vivo.

To simultaneously assess glioma cell invasion and glioma angiogenesis in vivo by non-invasive and quantitative means, DiI-labeled C6 glioma spheroids were implanted into the dorsal skinfold chamber preparation of nude mice (n = 6). Heat-inactivated spheroids served as controls to distinguish between active and passive cell spread. Using multi-fluorescent intravital videomicroscopy, glioma cell migration was analyzed on days 1-4, 6, and 10 and spheroid vascularization was analyzed on days 3, 6, and 10 after implantation. Additionally, C6 glioma spheroids were implanted into the chronic cranial window of nude mice as an orthotopic implantation site (n = 4). In the dorsal skinfold chamber, spheroids were vascularized within 10 days and revealed a tumor-specific microvasculature. In parallel, individual glioma cells detached from the spheroid edge and migrated centrifugally demonstrating an affinity to tumor and host vessels. Glioma cells demonstrated a heterogeneous pattern of their regional migratory activity (0.2-9.6 microm/h) which correlated well with regional glioma angiogenesis (r = 0.733). Using the cranial window, glioma cells spread similarly demonstrating an affinity to the perivascular space of pial/subpial vessels with preference to the arteriolar segments. Intravital fluorescence microscopy represents a versatile technique to assess the complex relationship between glioma-driven angiogenesis and glioma cell invasion.

Normal values of cerebrovascular reserve capacity after stimulation with acetazolamide measured by xenon 133 single-photon emission CT.

PURPOSE: To determine whether a standardized stimulation challenge with acetazolamide will be helpful for assessing the vasodilatory capacity in patients with obstructive cerebrovascular disease. METHODS: To establish normative data of the cerebrovascular reserve capacity, a group of 41 control patients was investigated. The regional cerebral blood flow was measured quantitatively before and after stimulation with acetazolamide using the xenon 133 inhalation method and dynamic single-photon emission CT. RESULTS: A significant increase of regional cerebral blood flow was found after administration of 1 g of acetazolamide. By doubling the dose no significant further increase was measured. We found no correlation of either baseline or stimulated flow values with age. However, a linear dependence between the stimulated flow values and their respective baseline values was observed. CONCLUSION: The standardized challenge with acetazolamide seems to be a reliable method to determine cerebrovascular reserve capacity quantitatively.