Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Automated Detection of Cerebral Aneurysms on TOF-MRA Using a Deep Learning Approach: An External Validation Study.

BACKGROUND AND PURPOSE: Cerebral aneurysms yield the risk of rupture, severe disability and death. Thus, early detection of cerebral aneurysms is crucial to ensure timely treatment, if necessary. AI-based software tools are expected to enhance radiologists' performance in detecting pathologies like cerebral aneurysms in the future. Our aim was to evaluate the diagnostic performance of an artificial intelligence-based software designed to detect intracranial aneurysms on TOF-MRA. MATERIALS AND METHODS: One hundred ninety-one MR imaging data sets were analyzed using the software mdbrain for the presence of intracranial aneurysms on TOF-MRA obtained using two 3T MR imaging scanners or a 1.5T MR imaging scanner according to our clinical standard protocol. The results were compared with the reading of an experienced radiologist as a criterion standard to measure the sensitivity, specificity, positive and negative predictive values, and accuracy of the software. Additionally, detection rates depending on size, morphology, and location of the aneurysms were evaluated. RESULTS: Fifty-four aneurysms were detected by the expert reader. The overall sensitivity of the software for the detection of cerebral aneurysms was 72.6%, the specificity was 87.2%, and the accuracy was 82.6%. The positive predictive value was 67.9%, and the negative predictive value was 88.5%. We observed a sensitivity of 100% for saccular aneurysms of >5 mm without signs of thrombosis and low detection rates for fusiform or thrombosed aneurysms of 33.3% and 16.7%, respectively. Of 8 aneurysms that were not included in the initial written reports but were detected by the expert reader, retrospectively, 4 were detected by the software. CONCLUSIONS: Our data suggest that the software can assist radiologists in reporting TOF-MRA. The software was highly reliable in detecting saccular aneurysms, while for fusiform or thrombosed aneurysms, further improvements are needed. Further studies are necessary to investigate the impact of the software on detection rates, interrater reliability, and reading times.

[Interdisciplinary neurovascular networks: state of the art]. / Interdisziplinäre neurovaskuläre Netzwerke: eine Standortbestimmung.

BACKGROUND: In order to treat the complete spectrum of neurovascular diseases at a high level of quality, which goes beyond the purely acute treatment of stroke, the German Stroke Society (DSG) together with the German Societies for Neurosurgery and Neuroradiology developed a certification procedure for neurovascular networks (NVN). Structurally, a NVN consists of a coordinating center with at least three neurovascular network partners with a certified stroke unit. From 2018 to 2020 a total of 15 NVN have so far been audited and certified according to this new standard. OBJECTIVE: How efficient are the NVN? Are high standards maintained? MATERIAL AND METHODS: The reports of the audits were analyzed. The data were taken from the period 2017-2019. RESULTS: The 15 NVN treated a total of 86,510 stroke patients in the years examined and were networked with a total of 107 partner clinics, which were situated an average of 25 km from the coordinating center and transferred a total of 2726 patients. The coordinating centers performed 2463 thrombectomies and treated 2383 patients with nontraumatic intracerebral bleeding. In 712 patients with acute aneurysmatic subarachnoid hemorrhages endovascular treatment was carried out and clipping in 401. The audit was successful in the majority of the NVN. CONCLUSION: The certification process of NVN has been successfully established and the audits proved to be a useful instrument for quality control and improvement. The 15 NVN are highly efficient and treat more than one quarter of stroke patients in German stroke units.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

[Ability to drive with cerebrovascular diseases : Position paper of the German societies DGNB, DGN, DGNC, DGNR, DSG and GNP]. / Fahreignung bei Hirngefäßerkrankungen : Positionspapier der DGNB, DGN, DGNC, DGNR, DSG und GNP.

The regulations for ability to drive with cerebrovascular diseases in the German Driving License Regulations (Fahrerlaubnisverordnung, FeV) and German Guidelines for the Evaluation of Driving Ability of the Federal Highway Research Institute (BASt) are not up to date with the current medical knowledge and are not consistent with comparable regulations regarding cardiovascular diseases. This is particularly true for the assessment of future risks for a sudden loss of control during driving. The present position paper of six medical and neuropsychological societies in Germany presents the current conditions for the assessment of driving ability of patients a cerebrovascular diesease and recommends an estimation of the ability to drive founded on the current state of scientific knowledge. It addresses the following: 1. Physical and mental functional limitations and the possibilities for compensation, which if necessary enable a fitness to drive under conditions or within limits, including the importance of behavioral or personality changes and cognitive deficiencies that interfere with safety. 2. The potential danger due to a sudden loss of control as a result of a transient ischemic attack (TIA) new stroke event, or another cardiovascular event while driving. A summary in the form of a table provides physicians and expert assessors with assistance for the most important cerebrovascular diseases.

[Stereotactic laser thermocoagulation in epilepsy surgery]. / Stereotaktische Laserthermokoagulation in der Epilepsiechirurgie.

In common with other stereotactic procedures, stereotactic laser thermocoagulation (SLT) promises gentle destruction of pathological tissue, which might become especially relevant for epilepsy surgery in the future. Compared to standard resection, no large craniotomy is necessary, cortical damage during access to deep-seated lesions can be avoided and interventions close to eloquent brain areas become possible. We describe the history and rationale of laser neurosurgery as well as the two available SLT systems (Visualase® and NeuroBlate®; CE marks pending). Both systems are coupled with magnetic resonance imaging (MRI) and MR thermometry, thereby increasing patient safety. We report the published clinical experiences with SLT in epilepsy surgery (altogether approximately 200 cases) with respect to complications, brain structural alterations, seizure outcome, neuropsychological findings and treatment costs. The rate of seizure-free patients seems to be slightly lower than for resection surgery. Due to the inadequate quality of studies, the neuropsychological superiority of SLT has not yet been unambiguously demonstrated.

Percutaneous nerve field stimulation (PENS) of the occipital region as a possible predictor for occipital nerve stimulation (ONS) responsiveness in refractory headache disorders? A feasibility study.

BACKGROUND: Occipital nerve stimulation (ONS) has been reported to diminish pain levels in intractable chronic headache syndromes of different origin. No reliable objective markers exist to predict ONS responsiveness. This study investigated the predictive value of occipital percutaneous nerve field stimulation (PENS) prior to ONS. METHODS: This trial included 12 patients (CCH, CM, PTH, CH) with chronic refractory headache syndromes eligible for ONS. Repetitive PENS (3 × /10 days) was performed and the headache severity/frequency monitored over four weeks before ONS implantation. Further assessment of PENS/ONS outcomes were stimulation-related complications, perception/tolerance stimulation threshold, the Migraine Disability Scale (MIDAS) and the Beck Depression Inventory (BDI). RESULTS: All PENS responders benefited from ONS. Of the seven PENS-nonresponders with VAS 6.1(±1.1), six experienced significant pain relief from ONS after three months and one patient failed the PENS/ONS trial (VAS 3.7 (±1.6)); (95% CI 3.6 to 5.7, p < 0.001). The VAS baseline was 8.4 (±0.5) and decreased significantly (50% reduction in severity/frequency) in five patients after PENS, while seven failed to improve (VAS 4.9 (±1.1); (95% CI 2.5 to 4.5, p < 0.001). BDI baseline (from 22.6 (±4.2) to 10.6 (±5.9) (95% CI 7.4 to 16.6, p < 0.001)) and MIDAS baseline (from 143.9 (±14.5) to 72.8 (±28.7) (95% CI 1.17 to 2.3, p < 0.001)) significantly declined after ONS. No PENS/ONS-related complications occurred. CONCLUSIONS: Presurgical applied occipital PENS failed to identify ONS responders sufficiently according to our study protocol, thus requiring further specific investigations to determine its predictive usefulness.

Metabolic changes in patients with aneurysmal subarachnoid hemorrhage apart from perfusion deficits: neuronal mitochondrial injury?

BACKGROUND AND PURPOSE: Neuronal damage in aSAH apart from perfusion deficits has been widely discussed. We aimed to test if cerebral injury occurs in aSAH independently from visible perfusion deficit by measuring cerebral metabolites in patients with aSAH without infarction or impaired perfusion. MATERIALS AND METHODS: We performed 3T MR imaging including (1)H-MR spectroscopy, DWI, and MR perfusion in 58 patients with aSAH and 11 age-matched and sex-matched control patients with incidental aneurysm. We compared changes of NAA, Cho, Glx, Lac, and Cr between all patients with aSAH and controls, between patients with and without visible perfusion deficit or infarction and controls, and between patients with and without visible perfusion deficit or infarction by using the Wilcoxon signed-rank test. RESULTS: We found that NAA significantly (P < .005) decreased in all patients with aSAH. Cho was significantly increased in all patients compared with controls (P < .05). In patients without impaired perfusion or infarction, Glx was significantly decreased compared with both controls (P = .005) and patients with impaired perfusion or infarction (P = .006). CONCLUSIONS: The significant decrease of NAA and Glx in patients with aSAH but without impaired perfusion or infarction strongly suggests global metabolic changes independent from visible perfusion deficits that might reflect neuronal mitochondrial injury. Further, impaired perfusion in aSAH seems to induce additional metabolic changes from increasing neuronal stress that might, to some extent, mask the global metabolic changes.

Erythropoietin neuroprotection is enhanced by direct cortical application following subdural blood evacuation in a rat model of acute subdural hematoma.

Recombinant human erythropoietin (EPO) has been successfully tested as neuroprotectant in brain injury models. The first large clinical trial with stroke patients, however, revealed negative results. Reasons are manifold and may include side-effects such as thrombotic complications or interactions with other medication, EPO concentration, penetration of the blood-brain-barrier and/or route of application. The latter is restricted to systemic application. Here we hypothesize that EPO is neuroprotective in a rat model of acute subdural hemorrhage (ASDH) and that direct cortical application is a feasible route of application in this injury type. The subdural hematoma was surgically evacuated and EPO was applied directly onto the surface of the brain. We injected NaCl, 200, 2000 or 20,000IU EPO per rat i.v. at 15min post-ASDH (400µl autologous venous blood) or NaCl, 0.02, 0.2 or 2IU per rat onto the cortical surface after removal of the subdurally infused blood t at 70min post-ASDH. Arterial blood pressure (MAP), blood chemistry, intracranial pressure (ICP), cerebral blood flow (CBF) and brain tissue oxygen (ptiO2) were assessed during the first hour and lesion volume at 2days after ASDH. EPO 20,000IU/rat (i.v.) elevated ICP significantly. EPO at 200 and 2000IU reduced lesion volume from 38.2±0.6mm(3) (NaCl-treated group) to 28.5±0.9 and 22.2±1.3mm(3) (all p<0.05 vs. NaCl). Cortical application of 0.02IU EPO after ASDH evacuation reduced injury from 36.0±5.2 to 11.2±2.1mm(3) (p=0.007), whereas 0.2IU had no effect (38.0±9.0mm(3)). The highest dose of both application routes (i.v. 20,000IU; cortical 2IU) enlarged the ASDH-induced damage significantly to 46.5±1.7 and 67.9±10.4mm(3) (all p<0.05 vs. NaCl). In order to test whether Tween-20, a solvent of EPO formulation 'NeoRecomon®' was responsible for adverse effects two groups were treated with NaCl or Tween-20 after the evacuation of ASDH, but no difference in lesion volume was detected. In conclusion, EPO is neuroprotective in a model of ASDH in rats and was most efficacious at a very low dose in combination with subdural blood removal. High systemic and topically applied concentrations caused adverse effects on lesion size which were partially due to increased ICP. Thus, patients with traumatic ASDH could be treated with cortically applied EPO but with caution concerning concentration.

Intra-operative subcortical electrical stimulation: a comparison of two methods.

OBJECTIVE: For intra-operative subcortical electrical stimulation of the corticospinal tract, two techniques - originally described for cortical stimulation - have evolved: the 50-Hz-stimulation first described by Penfield in 1937 and the high-frequency multipulse train stimulation technique first described by Taniguchi in 1993. Motor thresholds of both methods in combination with a bipolar and monopolar stimulation technique and their reliability for eliciting motor evoked potentials (MEPs) were studied. METHODS: Data were obtained in 20 patients (50±17 years; 10 females) undergoing tumour resection under general anaesthesia. Both 50-Hz-stimulation of 1-s duration and a multipulse stimulation (5 pulses interstimulus interval 4 ms, 0.5-Hz repetition rate) were applied with a bipolar probe (1.5-mm ball tip, 8-mm interelectrode distance) and a monopolar probe (1.5-mm-diameter tip). MEPs were recorded in muscles contralateral to the stimulated hemisphere. Comparison of different stimulation modalities was performed at the site where monopolar multipulse stimulation technique elicited MEPs with the lowest stimulation intensity (constant current monophasic cathodal stimulation, individual pulse width 0.5 ms, max. 25 mA). RESULTS: MEPs were elicited by monopolar multipulse stimulation with an intensity of 8±3.9 mA (21/21 stimulation sites); monopolar 50-Hz stimulation with 12±5.4 mA (18/21 stimulation sites); bipolar multipulse stimulation with 14±8.1 mA (12/21 stimulation sites) and bipolar 50-Hz stimulation with 15±6.3 mA (11/21 stimulation sites). CONCLUSIONS: Stimulation intensities for eliciting MEPs are significantly lowest for the monopolar multipulse stimulation (p<0.025). Monopolar compared to bipolar stimulation resulted in eliciting MEPs in a higher number of tested patients (Fisher's p<0.0001). SIGNIFICANCE: Subcortical stimulation with a monopolar probe and a multipulse stimulation is most efficient for the purpose of identifying the corticospinal tract. This is explained by the more radiant electric field properties of the monopolar probe compared to the bipolar probe.

Decompressive hemicraniectomy in subarachnoid haemorrhage: the influence of infarction, haemorrhage and brain swelling.

OBJECTIVE: To analyse decompressive hemicraniectomy (DHC) in patients with aneurysmal subarachnoid haemorrhage (SAH) with regard to infarction, haemorrhage or brain swelling. METHODS: DHC was performed in 43 of 787 patients with SAH. Patients were stratified according to (1) primary brain swelling without and (2) with additional intracerebral haematoma, (3) secondary brain swelling without rebleeding or infarcts and (4) with infarcts or (5) with rebleeding. Outcome was assessed according to the modified Rankin scale at 6 months RESULTS: Overall, 36 of 43 patients (83.7%) with DHC and 241 of 744 patients (32.4%) without DHC have been of a poor grade on admission (World Federation of Neurological Societies grading 4-5; p<0.0001). Favourable outcome was achieved in 11 of 43 (25.6%) patients with DHC. There was no difference in favourable outcome after primary (25%) versus secondary (26.1%) DHC (p = 1.0). Subgroup analysis (brain swelling vs bleeding vs infarcts) revealed no difference in the rate of favourable outcome. In a multivariate analysis, acute hydrocephalus (p = 0.02) and clinical herniation (p = 0.03) were significantly associated with unfavourable outcome. CONCLUSIONS: We conclude that primary and secondary hemicraniectomy may be warranted, irrespective of the underlying aetiology-infarction, haemorrhage or brain swelling. The time from onset of intractable ICP to DHC seems to be crucial, rather than the time from SAH to DHC.

Experimental approaches to evaluate endothelin-A receptor antagonists.

A large body of evidence suggests a substantial role of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Recently bosentan, an ET receptor antagonist, has received approval by the Food and Drug Administration (FDA) for use in pulmonary artery hypertension. The ET system may also be involved in cerebrovascular disorders such as stroke and, most notably, development of cerebral vasospasm following subarachnoid hemorrhage. The pathophysiological mechanisms contributing to the development of a cerebral vasospasm after subarachnoid hemorrhage may be taken as a paradigm to explore mechanisms leading to secondary ischemic brain damages in a variety of insults such as stroke and trauma. The present review provides the evidence to evaluate ET receptor antagonists for potential prophylactic and therapeutic use in patients suffering from subarachnoid hemorrhage. The rationale to develop selective ETA receptor antagonists is given with respect to basic and applied studies. This may be useful to better define the desired profile of action of a given compound, and it may also help to design appropriate preclinical and clinical trials, most desirably in close cooperation with pharmaceutical companies and neurosurgical departments.

Effect of endothelin-converting enzyme inhibitors on big endothelin-1 induced contraction in isolated rat basilar artery.

INTRODUCTION: The aim of this study was to investigate whether blocking functional endothelin-converting enzyme (ECE) activity may offer a new approach to inhibit the development of cerebral vasopasm after subarachnoid hemorrhage (SAH) by preventing transformation of big Endothelin-1 (big ET-1) to vasoactive Endothelin-1 (ET-1). METHODS: In vitro, the effect of potential ECE inhibitors was determined by measurement of isometric contractions, induced by big ET-1, in isolated rat basilar arteries. Endothelium intact (E+) and de-endothelialized (E-) segments were examined after pre-incubated with the putative ECE inhibitors: Phosphoramidon (10(-4) M), Captopril (10(-3) M and 10(-4) M) and [(22)D-Val] big ET-1 (16-38) (10(-5) M and 10(-6) M). RESULTS: Application of 10(-4) M Phosphoramidon resulted in a statistically significant decrease in big ET-1 induced contraction in endothelium intact (E+) and de-endothelialized (E-) segments; 10(-3) M Captopril in E- segments caused a statistically significant inhibitory effect; 10(-4) M and 10(-3) M Captopril in E+ segments showed no statistically significant effect; 10(-5) M and 10(-6) M [(22)D-Val] big ET-1 (16-38) in E- segments produced no statistically significant effect. The application of 10(-6) M [(22)D-Val] big ET-1 (16-38) in E+ segments caused increased contractions as shown by the shift to the left of the concentration-effect curve (CEC). CONCLUSION: The present study indicates the existence of functional ECE activity in rat basilar artery, which is different in the endothelium and the smooth muscle layer. This ECE-activity could be inhibited by Captopril and Phosporamidon, suggesting a potency for prevention and therapy of cerebral vasospasm. However, the structural analogue of big ET-1, [(22)D-Val] big ET-1 (16-38), was ineffective in reducing big ET-1 induced vasoconstriction and rather increased contraction in E+ vessels. Therefore further studies of the biochemical nature of the functional relevant cerebrovascular ECE activity are required for better understanding and development of other efficient ECE inhibitors.

Blood flow velocities in middle cerebral artery branches after subarachnoid hemorrhage.

In a prospective study, 55 patients were examined by transcranial duplex sonography (TCCS) after subarachnoid hemorrhage (SAH) to determine whether additional transcranial duplex examination on the middle cerebral artery M2 segments would aid in the examination of the MCA stem segment. The mean blood flow velocities and pulsatility index were correlated to the occurrence of delayed ischemic neurologic deficits (DIND). Out of 47 patients included, 21 did not experience any delayed deficit (group I), 15 did (group II), and in 11 the extent to which vasospasm contributed to a neurologic deficit was unclear (group III). The highest blood flow velocity and the greatest increase of mean blood flow velocity on 1 day were significantly higher in groups II and III both in M1 and in M2. In 10 patients in group II, where the onset day of DIND was known exactly, Doppler data indicating ischemia before or at the time of DIND were observed in nine. In eight patients, Doppler of the MCA stem alone would have provided enough information to recognize the risk of symptomatic vasospasm; in one patient, only the M2 Doppler gave an indication of ischemic complication. Transcranial duplex sonography may provide additional information to TCD by accurate delineation of M1/M2 vasospasm and therefore may help plan cerebral angiography and neurointerventional treatment.

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.

Evidence for functional endothelin-converting enzyme activity in isolated rat basilar artery: effect of inhibitors.

Endothelin-1 (ET-1) may be involved in the upregulation of cerebroarterial resistance under pathologic conditions, most notably in the development of vasospasm after subarachnoid hemorrhage. Therefore, blocking the contractile action of ET-1 by receptor antagonists may prove to be a new and worthwhile approach. However, decreasing synthesis and release of ET-1 by blocking the endothelin-converting enzyme (ECE) activity may also prove worthwhile. In this study we have therefore investigated the effect of several putative ECE inhibitors in isolated rat basilar artery by measuring isometric contraction after application of big ET-1, the precursor peptide which is not vasoactive in itself. In the presence of phosphoramidon (10(-4) M in segments with an intact endothelium or 5 x 10(-4) M in de-endothelialized segments), there was only a small shift to the right of the concentration-effect curve for big ET-1. Similarly, 10(-3) M thiorphan (a selective inhibitor of the neutral endopeptidase) did not affect big ET-1-induced contraction, both alone and in combination with phosphoramidon (10(-3) M). When the big ET-1 analogue [22Phe]big ET-1[19-37] was applied, an increase in resting tension occurred irrespective of whether or not the endothelium was present. Furthermore, in the presence of 10(-5) M [22Phe]big ET-1[19-37], contraction induced by big ET-1 was not affected in de-endothelialized segments but rather was enhanced in endothelium-intact segments. These results suggest the presence of functional ECE activity in the rat basilar artery wall. However, such activity could not be markedly inhibited with different putative enzyme inhibitors. Therefore, the chemical nature of the cerebroarterial ECE activity must be further elucidated before rational development of efficient ECE inhibitors for treatment of cerebral vasospasm becomes possible.

Support for baby-boom retirees--not to worry.

PIP: Flaws in the discussion of the baby-boom retiree problem make the Social Security problem seem worse than it really is. Problems include the overwhelming emphasis upon fiscal and related financial aspects at the expense of consideration of the output of goods and services, and the almost total neglect of projected real income and productivity rises. Rather, baby-boom retirees can be coped with on the basis of hypothetically reasonable projected magnitudes. It is currently being argued that the future US economy cannot provide Social Security support for the upcoming baby-boom retirees. However, people who support such an argument fail to consider the main determinant of capacity to support. That determinant is the historically established rise in productivity as expressed in per capita output or output per hour of the employed population. Maintaining Social Security pension support through 2030 involves little to no strain upon society, while abolishing such support would cause considerable strain. The authors describe who Social Security supports now and in the future, and explain the capacity of US society to fund Social Security in the decades ahead.^ieng