Superoxide dismutase activity in cisternal cerebrospinal fluid after aneurysmal subarachnoid haemorrhage

Summary It has been recognised that the level of superoxide dismutase (SOD) significantly increases in CSF as the result of cerebral ischaemic damage. The aim of this study was to correlate the CSF levels of SOD enzymatic activity to the patterns of subarachnoid haemorrhage with regards to ischaemic complications due to vasospasm.A series of 78 patients operated on for intracranial aneurysms was studied; all patients were monitored with serial TCD measurements every second day after SAH. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern nearest to the aneurysm. SOD activity was assayed spectrophotometrically.Mean cisternal CSF level of SOD in 12 control cases (12.99±2.33 U/ml) is significantly higher (p < 0.01) than in 26 patients operated on between day 1 and 3 from last SAH episode (4.44±0.7 U/ml) and in 40 patients treated by delayed surgery (7.64±0.92 U/ml). In 13 patients presenting neurological deterioration related to arterial vasospasm mean cisternal SOD level was 12.23±1.86 U/ml; in 27 cases without vasospasm mean level was 5.43±0.7 U/ml (p < 001).The present results suggest that (a) cisternal CSF levels of SOD significantly decreases after SAH, probably in relation to an impaired synthesis in the brain compartment and that (b) a substantial elevation of SOD levels is evident in patients suffering ischaemic complications vasospasm-related. Biochemical events in the brain compartment could influence the expression and release of anti-oxidant enzymes in CSF after SAH.     

S-100 protein in cerebrospinal fluid of patients with subarachnoid haemorrhage: A potential marker of brain damage

Summary Concentrations of S-100 protein in cerebrospinal fluid (CSF) were measured by a recently developed radioimmunoassay (RIA) in 45 patients with subarachnoid haemorrhage (SAH), 44 with verified ruptured aneurysm. In each of 43 patients 2–15 serial CSF samples were analysed, and in the remainder 1 sample was examined. The concentrations of S-100 protein proved to be related to the brain damage caused by the SAH, indexed as outcome (Glasgow Outcome Scale). The S-100 concentrations were related to the severity of the haemorrhage and to the development of delayed ischaemic deterioration. Delayed ischaemic deterioration (vasospasm) was usually accompanied by an increase in CSF S-100 concentration after 4 days. Patients in whom no S-100 value exceeded 20 ng S-100 per ml during the course of the disease had a favourable outcome, whereas patients in whom one or several CSF samples contained more than 100 ng/ ml became severely disabled or vegetative or died. The present study suggests that CSF S-100 analysis may be used as an objective and early measure of the degree of brain damage sustained by the SAH patient.     

Anti-phospholipid antibodies and cerebral vasospasm following subarachnoid haemorrhage

Summary Delayed ischaemic deficits due to cerebral vasospasm contribute to the high morbidity and mortality rates associated with subarachnoid haemorrhage. We evaluated the usefulness of measuring anti-phospholipid antibodies (aPLs) for prediction of the occurrence of symptomatic vasospasm and the outcome after subarachnoid haemorrhage. 32 consecutive patients with subarachnoid haemorrhage due to ruptured cerebral aneurysms were studied. They were admitted and operated on within 72 hours after the onset of subarachnoid haemorrhage. aPLs such as lupus anticoagulants, anti-cardiolipin IgG and anti-cardiolipin IgM were measured repeatedly after admission. Furthermore, platelet count, platelet aggregability and plasma platelet factor 4 were also measured. Eleven among the 32 patients (34.4%) showed positive in the examination for aPLs. Although aPLs could not predict symptomatic vasospasm, once symptomatic vasospasm occurred, patients with aPLs frequently demonstrated cerebral infarction and there-fore their outcome was worse. aPLs were associated with a severe initial clinical grade and SAH grade on CT scan. Therefore it may explain the association of aPLs with worse outcome. aPLs were detected between 1 and 7 days. Four of 6 patients (67%) with aPLs became negative between 7 and 13 days after subarachnoid haemorrhage. The mechanism of transient aPLs is unclear but it is more likely to occur in the severer grade patients. The reduction in platelet count, the increased platelet aggregability, and the increased plasma platelet factor 4 concentration were also observed in aPLs-positive patients with symptomatic vasospasm.     

Activation of the coagulation system in the subarachnoid space after subarachnoid haemorrhage: Serial measurement of fibrinopeptide A and bradykinin of cerebrospinal fluid and plasma in patients with subarachnoid haemorrhage

Summary Fibrinopeptide A (FPA) levels as an indicator of thrombin activity in the cerebrospinal fluid (CSF) and plasma of 25 patients with subarachnoid haemorrhage (SAH) were measured serially by radioimmunoassay (RIA). FPA levels in CSF were extremely high on days 0–1 (1253±269 ng/ml, mean ± standard error) but decreased rapidly (11.3±3.9 ng/ml on days 2–4, 10.7±5.9 ng/ml on days 5–7, and 6.3±1.5 ng/ml on days 8–14). In the controls the FPA concentration in CSF was 1.2±0.9 ng/ml (mean ± standard deviation). Plasma FPA levels in patients with SAH showed no statistically significant changes with time.The bradykinin (BK) concentration in CSF and plasma in 27 patients with SAH was measured serially by RIA. The cocentrations in CSF were 122.7±22.7 pg/ml (mean ± standard error) on day 0, 38.6±6.1 pg/ml on day 1,22.7±6.3 pg/ml on day 2, and 17.1±3.0 pg/ml or less thereafter. Plasma BK levels in patients with SAH were higher than those in the control group, but there was no statistically significant change over time.From the measurement of FPA it was apparent that the coagulation system in the subarachnoid space is strongly activated in the early stage of SAH. The formation of BK in CSF after SAH is thought to be due to the contact activation of Hageman factor (intrinsic factor) in the subarachnoid space. Trabeculae as collagen bundles in the subarachnoid space were considered to have a possible role in activating the Hageman factor of the coagulation system in SAH.     

Correlation between CT findings and subsequent development of cerebral infarction due to vasospasm in subarachnoid haemorrhage

Summary We have studied the correlations between computed tomograms (CT), clinical severity at the time of onset, and subsequent development of cerebral infarction due to vasospasm in 32 cases with subarachnoid haemorrhage secondary to rupture of cerebral aneurysms. It was found that the clinical severity could be judged by CT as shown by the amount of blood in subarachnoid space. Furthermore, it was possible to predict the subsequent occurrence of cerebral infarction by sequential findings of CT. A Hounsfield number of the high density area over 60 showed good correlation with the development of cerebral infarction.     

Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH

Summary Objective. Endothelin-1 (ET-1) is postulated to play an important role in the development of cerebral vasospasm (CVS) following SAH. This study was conducted to investigate the time course of ET-release in three different sources: CSF, plasma and microdialysate. Methods. In a prospective study ET-1-concentrations were measured in plasma, cisternal CSF and microdialysate in 20 patients with aneurysmal SAH for at least 8 days after hemorrhage. Results. ET-1 concentration in microdialysate was almost four times higher compared to CSF and plasma. (p<0.001) Only in CSF ET-1-release showed a significant increase over time with highest values on day 5 post ictus (p = 0.03). This was parallel to the increase of transcranial Doppler velocities. ET-1 in plasma and microdialysate did not change over time. Conclusion. ET-1 may have a different biological function in different biological tissues. Only ET-1 in CSF seemed to be associated with CVS. An erratum to this article is available at .     

Vasospasm after traumatic subarachnoid haemorrhage: Transcranial Doppler evaluation. Case report

A case of vasospasm after traumatic subarachnoid haemorrhage (SAH) is reported here. Transcranial Doppler Sonography (TCD) was used to evaluate mean flow velocity (MFV) changes of the basal cerebral arteries related to vasospasm. Accelleration of MFV of the right middle cerebral artery (MCA) indicating vasospasm was first noted on TCD evaluation, and then proved by carotid angiography (CAG). Evaluation of all TCD results revealed that the process of relaxation or normalization of the spastic artery started from the proximal side of the basal intracranial artery and gradually moving to the distal side. This interesting phenomenon could be a common process found in vasospasm cases.     

Platelet-activating factor and antiphospholipid antibodies in subarachnoid haemorrhage

Summary The purpose of this study was to measure plasma platelet-activating factor (PAF) concentration, PAF-acetylhydrolase activities, anti-phospholipid antibody (aPLs) titers, and platelet function in patients with subarachnoid haemorrhage (SAH) and to assess the association of these variables with the development of cerebral vasospasm.Thirty-two patients with SAH due to ruptured cerebral aneurysm were studied. Plasma PAF concentration, PAF-acetylhydrolase activity, platelet count and aggregability, and plasma factor 4 (PF 4) concentrations were measured regularly until approximately 2 weeks after SAH. aPLs, including lupus anticoagulant and anti-cardiolipin IgG and IgM were measured within 3 days after SAH.Plasma PAF concentration in patients with SAH showed the highest value on the occasion during 5 to 9 days after SAH. The concentrations were higher in patients with infarction due to vasospasm than in patients without cerebral infarction on any occasions after SAH. Plasma PAF-acetylhydrolase activities did not change in patients, regardless of the presence of cerebral infarction after SAH. Increased platelet consumption and aggregability and higher concentrations of PF 4 were detected in patients with cerebral infarction and not in patients without cerebral infarction. The patients with cerebral infarction due to cerebral vasospasm had aPLs more frequently than the control volunteers.Our findings indicate that increased plasma PAF and aPLs may contribute to the pathogenesis of cerebral vasospasm after SAH.     

CT与脑脊液炎性细胞因子对外伤性蛛网膜下腔出血后脑血管痉挛的早期诊断意义

目的探讨CT及脑脊液炎性细胞因子对外伤性蛛网膜下腔出血后脑血管痉挛的早期诊断价值。方法50例外伤性蛛网膜下腔出血患者根据据其临床表现和TCD检查分为血管痉挛组及非血管痉挛组，对比其CT的改良Fisher分级及脑脊液中IL-6、TGF水平。结果两组脑脊液中IL-6、TGF水平差异有显著性，且血管痉挛发生率及程度与改良Fisher分级成正比。结论根据早期CT影像及脑脊液中炎性细胞因子的变化可以预测脑血管痉挛的发生，从而指导治疗。     

Increased levels of somatomedins in human lumbar and central cerebrospinal fluid after subarachnoid haemorrhage

Summary The somatomedins, multitargit growth-promoting peptide hormones, were measured with radio receptor assay in cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) in 21 patients and after head injury in 2 patients.In the first group of 10 patients, lumbar (n=8) or central (n=2) CSF was collected on days three, six and nine after SAH. 6 of the 8 patients with SAH showed an increase in somatomedin concentrations ranging between 0.52–1.26 U/ml while 2 patients fell within the normal range between 0.19–0.48 U/ml. In the 2 patients with head injury, the somatomedin concentrations were scarcely detectable.In the second group of 13 patients with SAH, CSF was collected peroperatively during surgical clipping of an aneurysm. These patients fell into two groups: 6 patients who had CSF somatomedin levels within the normal range and 7 patients with pathologically increased somatomedin concentrations ranging between 0.38–1.26 U/ml. Neither the neurological condition nor the cerebral vascular diameter correlated with the somatomedin concentrations. It is suggested that the increased somatomedin levels in CSF after SAH could be a compensatory response in order to stimulate cerebral anabolism after injury.This work was supported by grants from Karolinska Institutet, the Swedish Medical Research Council, Sävstaholmsföreningen, and Loo and Hans Osterman Research Fund.     

Time course of csf lactate level in subarachnoid haemorrhage correlation with clinical grading and prognosis

Summary Cisternal and/or ventricular cerebrospinal fluid (CSF) and arterial blood lactate and acid-base balance were measured serially in 38 patients with aneurysmal subarachnoid haemorrhage (SAH). Based on daily clinical assessment, the patients and accordingly the samples were divided into two groups according to the grading of the World Federation of Neurosurgical Societies (W.F.N.S.). In cisternal CSF, samples of Grade III–V showed significantly higher lactic acidosis than those of Grade I–II. The time course of lactate and pH in poor prognosis groups had a significant tendency of lactic acidosis, especially on the 5th, 6th, 7th day after SAH. Ventricular CSF lactate increased even without CSF acidosis in Groups III–V. Measurement of CSF lactate, especially from the cisterna magna is useful as an indicator of prognosis and changes of intracranial environment following SAH.     

Transcranial Doppler diagnosis of cerebral vasospasm following subarachnoid haemorrhage: Correlation and analysis of results in relation to the age of patients

Summary A retrospective analysis was undertaken to determine whether cerebral vasospasm following subarachnoid haemorrhage (SAH) correlates with the age of patients. For at least 3 weeks after bleeding 80 subjects underwent very close follow-up with clinical examination and transcranial Doppler records of the blood velocities within the basal cerebral arteries.Firstly a correlation between measured maximal mean blood flow velocities and age was made. Secondly, according to their age and the maximum of recorded mean velocitites (v), the patients were divided into groups as follows: age 55 years or less, age more than 55 years; and maximum velocity v1<90cm/s, 90cm/s160cm/s.There was a significant correlation of the measured maximum mean velocities and the age of the patients (r =–0.525, p<0.01). With regard to the velocity groups there was a significant (chisquared statistic for contingency tables, p<0.01) difference between both age-groups: 32% (n=18) of the younger fell into group v4 with maximum mean velocities of more than 160cm/s, but none of the older had such. Vice versa, 63% (n=15) of the older compared with only 14% (n=8) of the younger fell into group v1 with maximum mean velocities of less than 90 cm/s. Clinical follow-up also depicted differences between both age groups. 13 of 18 younger patients with maximum mean velocities >160 cm/s exhibited symptomatic vasospasm with a delayed neurological deficit. This typical course did not occur in the older age group.We conclude from this analysis that the increase of blood velocity in the basal cerebral arteries following subarachnoid haemorrhage depends on the age of the patient. Furthermore, young patients will be more prone to a delayed ischaemic deficit. On the other hand, older patients may also suffer ischaemic deficits following subarachnoid haemorrhage but often without measurable vasospasm according to transcranial Doppler criteria and without the typical delayed appearance.     

Changes of endothelin concentration in cerebrospinal fluid and plasma of patients with aneurysmal subarachnoid hemorrhage

To investigate the clinical significance of endothelin (ET), a potent vasoconstrictor peptide, in subarachnoid hemorrhage (SAH) and SAH-related cerebral vasospasm, we measured the ET-like immunoreactivity (ETLI) in plasma and cerebrospinal fluid (CSF) obtained serially from patients with SAH due to ruptured cerebral aneurysm who underwent aneurysmal surgery. The normal ET–LI levels in plasma and CSF (n = 24) were 12.4±2.0 (mean±s.d.) and 9.1±1.2 pg·ml^-1, respectively. Plasma ET-LI levels in patients with SAH before surgery (16.8±7.8 pg·ml^-1, n = 8) were higher than the normal values ( P <0.05), and became further elevated after surgery (22.5±9.4 pg·ml^-1). ET-LI levels in plasma and CSF one day after surgery were 18.7±5.5 and 18.4±6.8 pg·ml^-1 ( P <0.01 vs. normal values), respectively, and declined thereafter. The plasma and CSF ET-LI levels in patients who showed symptomatic vasospasm became concomitantly elevated again. These results suggest that ET is involved in SAH-related vasospasm and raise the possibility that surgical stress influences the vasospasm.     

A study of possible correlation between subarachnoid haemorrhage related vasospasm and the post-bleed blood platelet count chart in a Caucasian population

Summary Introduction. There has been controversy about the aetiology and pathophysiology of subarachnoid haemorrhage (SAH) related vasospasm. Several pathogenic factors like endothelin and adhesion molecules have been discussed. A recently published study concerning an exclusively Asian population suggested a relationship between SAH related vasospasm and the blood platelet count. The aim of our study was to examine this relationship in a European population. Method. We carefully reviewed 88 patients with aneurysmal SAH (54 females, 34 males; mean age 52.5 years, range from 22 to 78 years) treated in our centre with regard to the occurrence of vasospasm and the blood platelet count in a ten day interval after initial SAH. Symptomatic vasospasm was defined as a focal neurological deficit or deterioration in the level of consciousness with or without confirmation of infarction on a CT scan. Thirty-seven patients (42%) developed clinically relevant vasospasm. Results. There was no statistically significant correlation between the blood platelet count chart (maximum and minimum values) and vasospasm or clinical outcome; we also found no gender or age-related influence on the above mentioned relationships. Conclusions. In our opinion there appears to be a difference between Caucasian and Asian populations regarding the influence of platelets in the pathophysiology of SAH and vasospasm.     

Efficacy of topical recombinant human platelet derived growth factor on wound healing in patients with chronic diabetic lower limb ulcers

Background  

Lower extremity ulcers are a serious complication of diabetes mellitus (DM). These ulcers show decreased angiogenic response and production of growth factors. Recombinant human platelet derived growth factor (rhPDGF) has been found to decrease the time to healing. This study was conducted to evaluate its efficacy in the treatment of diabetic foot ulcers.     

Cisternal and lumbar CSF levels of arachidonate metabolites after subarachnoid haemorrhage: An assessment of the biochemical hypothesis of vasospasm

Summary Several naturally occurring compounds have been identified in human cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) as possible vasoactive agents involved in the biochemical mechanism of vasospasm. The authors have measured, in 30 patients admitted for SAH, CSF concentrations of two arachidonic acid metabolites, Prostacyclin and Prostaglandin D₂, as representative of vasodilator and vasoconstrictor compounds. CSF samples were made available by lumbar punctures and intraoperative cisternal punctures. Nine patients presented with symptomatic vasospasm: lumbar CSF Prostaglandin D₂ levels are significantly higher than in patients without vasospasm. The Cisternal Prostaglandin D₂ level is significantly higher than the lumbar CSF concentration; CSF Prostacyclin levels do not significantly differ in the two groups of patients. These data suggest the presence of an imbalanced biochemical situation responsible for promoting vasospasm. The evaluation of cisternal levels of arachidonate metabolites support the hypothesis of the clotting phenomenon around the ruptured aneurysm wall as an important predictive pattern of vasospasm onset after SAH, as shown in computed tomography.This research was supported by a grant of the Italian Department of Instruction, Rome, Italy, 1984 and by a grant of Regione Lombardia.     

The early effects of sustained platelet-derived growth factor administration on the functional and structural properties of repaired intrasynovial flexor tendons: an in vivo biomechanic study at 3 weeks in canines

PURPOSE: A bioactive fibrin-based delivery system was used to provide sustained administration of platelet-derived growth factor (PDGF-BB) in a clinically relevant model of intrasynovial flexor tendon repair. We hypothesized that PDGF-BB administered in this manner would improve the sutured tendon's functional and structural properties 3 weeks after repair. METHODS: A delivery system consisting of 30 microL of fibrin matrix, peptide, heparin, and 100 ng of PDGF-BB was incorporated into the repair sites of randomly selected medial or lateral forepaw flexor digitorum profundus tendons of 8 adult mongrel dogs. The remaining forepaw flexor digitorum profundus tendons were repaired without the growth-factor and fibrin-based delivery system and served as controls. The surgically treated forelimbs were treated with controlled passive motion rehabilitation. The animals were killed at 3 weeks, at which time the tendons were tested for range of motion with a motion analysis system and for tensile properties with a materials testing machine. RESULTS: Proximal interphalangeal joint and distal interphalangeal joint rotation values were significantly higher for the PDGF-BB-treated tendons compared with the repair-alone tendons. Excursion values were also significantly higher in the PDGF-BB-treated tendons. There were no significant differences in tensile properties when comparing PDGF-BB-treated with repair-alone tendons. CONCLUSIONS: The functional properties of repaired intrasynovial flexor tendons were significantly improved with the sustained administration of PDGF-BB. The failure to achieve improvements in ultimate load, stiffness, and strain in the experimental group may have been due to suboptimal PDGF-BB dosage or suboptimal release kinetics.     

A primate model for acute and late cerebral vasospasm: Angiographic findings

Summary A subarachnoid haemorrhage (SAH) in the squirrel monkey was produced by injection of blood via a permanently implanted catheter connected to the cisterna magna and a cannula stereotactically inserted into the interpeduncular cistern. Repeated angiographic examinations of the vertebro-basilar and right internal carotid arteries revealed a biphasic vasospasm with a maximal acute spasm at ten minutes and maximal late spasm at six days after blood injection. The present study has shown that a reproducible biphasic vasospasm can be produced in the squirrel monkey and evaluated by repeated angiographic examinations. The model is suitable in the study of basic mechanisms underlying vasospasm in a primate and, due to the size of the animal, autoradiographic evaluation of the cerebral blood flow and metabolism can be performed at an acceptable cost.     

血小板源生长因子对瘢痕成纤维细胞的影响

目的探讨血小板源生长因子（platelet derived growth factor,PDGF）对瘢痕成纤维细胞生物学行为的影响,及其对瘢痕形成和增生的作用机制,为临床预防和治疗瘢痕提供分子及病理学水平的理论依据。方法对瘢痕成纤维细胞及正常皮肤成纤维细胞进行体外培养,采用倒置显微镜、四甲基偶氮唑盐（MTT）测定、流式细胞术等方法进行观察、分析,以研究细胞因子PDGF对瘢痕成纤维细胞生物学行为的影响。结果测定结果显示,与相应的对照组相比,加入细胞因子PDGF后,均显示对细胞起明显的促增殖作用。结论细胞因子PDGF对成纤维细胞的生长趋势与增殖活性有明显的促进作用,刺激了胶原纤维的合成、增生和沉积。