Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.

BACKGROUND: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

[Role of matrix metalloproteinase in transformation of subdural effusion into chronic subdural hematoma].

OBJECTIVE: To investigate the role of matrix metalloproteinase (MMP) in the transformation of subdural effusion into chronic subdural hematoma. METHODS: The clinical data of 8 patients with subdural effusion that transformed into chronic subdural hematoma were collected and MMP-2 and MMP-9 levels were detected in the sudural effusion, chronic subdural hematoma and capsules of hematoma using gelatin-zymography. RESULTS: MMP-2 and MMP-9 increased significantly in chronic subdural hematoma as compared with those in subdural effusion (P<0.01), and their levels were also significantly higher in the outer membrane than in the inner membrane of hematoma. CONCLUSION: Subdural effusion is a risk factor for the occurrence of chronic subdural hematoma, in which process MMP plays a role as the promoting factor acting primarily in the outer membrane of the hematoma.

Expression of matrix metalloproteinases in the chronic subdural haematoma membrane.

To study the role of matrix metalloproteinases (MMP) in the development of chronic subdural haematoma, we investigated the expression and activity of MMPs (MMP-1, -2, -3, -7 and -9) and tissue inhibitors of MMP (TIMP-1 and -2) in capsules of chronic subdural haematoma from 10 patients. Outer membranes of chronic subdural haematoma were immunostained for MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2. Moreover, we confirmed MMP activity in membranes by SDS-PAGE zymography and in situ zymography. These results suggest that MMP degrades extracellular matrix in outer membranes of chronic subdural haematoma, which is thought to decrease their integrity followed by direct haemorrhage and exudation of oedematous fluid from membrane vessels into the haematoma cavity.

Enhanced acetylcholinesterase in chronic subdural hematomas.

Hematomas and specimens were studied from 13 surgically-operated chronic subdural hematoma cases. Evacuated hematomas contained elevated potassium ions and slightly increased levels of Acetylcholinesterase (AChE), and the dural specimens including hematoma capsules stained positive for AChE using histochemical methods, especially in the inner membrane of the dura where the Masson Trichrome staining revealed damaged and irregular collagen fibers. This article suggests that the initial dural damage caused by trauma results in minor bleeding, which in turn causes a raised potassium ion concentration in the hemolytic fluid, which may also cause depolarization and elevated AChE in the dura.

Platelet-activating factor (PAF) and the development of chronic subdural haematoma.

Platelet activating factor (PAF) content and PAF-acetylhydrolase (PAFAH) activity were measured in the plasma and haematoma of 34 chronic subdural haematoma (CSH) patients. The plasma PAF level in patients with CSH was higher than that in healthy controls. Although there was no correlation between the plasma PAF levels and the interval between the onset of symptoms and the day of sampling, namely, the interval after bleeding, the haematoma PAF level gradually decreased according to the interval after the onset of symptoms. There was no difference between plasma PAFAH activity in patients with CSH and that in healthy controls, and haematoma enzyme activity gradually increased correlated with the interval between the onset of symptoms and surgery. In addition, the localization of PAF in haematoma capsules was histochemically determined. PAF was solely localized to the peri-sinusoidal vessels in the outer membrane of haematoma capsules. Based on these biochemical and histochemical studies, we speculated that PAF may play a role in the development of chronic subdural haematomas.

Degradation of fibrinogen and fibrin by plasmin and nonplasmin proteases in the chronic subdural hematoma: evaluation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot.

To characterize local hyperfibrinolysis in the pathogenesis of chronic subdural hematoma (CSDH), fibrin degradation products (FDPs) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to identify each FDP fragment (fragments HMW, YY, DY and DD) by immunoblotting. The electrophoretic patterns of FDP in 40 hematomas from 33 patients could be categorized into 3 patterns; (i) type 1, the sharp DY and DD bands; (ii) type 2, the broad DY and DD bands; and (iii) type 3, the sharp DY and DD with two bands with higher molecular weights than fragment DY and DD. The broadening of DY and DD bands was reproduced by incubating the sample containing sharp DD and DY bands with the hemolyzed peripheral blood cells. These results indicated that the hyperfibrinolysis in CSDH could be characterized by the constant and incomplete proteolysis of fibrinogen and fibrin by plasmin and further degradation of FDPs by non-plasmin proteases released from hemolyzed blood cells.

Measurement of serum alkaline phosphatase isozyme I in brain-damaged patients.

The authors measured alkaline phosphatase isozyme I (ALP-I) in sera of 24 brain-damaged patients and four with disorders other than brain damage. The study population comprised three patients with postresuscitation encephalopathy, four with ruptured cerebral aneurysms, 14 with acute subdural hematoma and cerebral contusion, and three with nontraumatic intracerebral hemorrhage. ALP-I detected in brain damage is physicochemically different from the other known ALP-Is that appear in patients with obstructive jaundice or hepatoma. In the brain-damaged patients, ALP-I became elevated about 7 days after admission and markedly increased as secondary brain damage developed. Excluding patients who died within 9 days of admission, the maximum serum ALP-I concentration was well correlated with the functional outcome. In cases in which barbiturate therapy was effective, the appearance of ALP-I was delayed and its elevation was suppressed. The results of this study suggest that measurement of serum ALP-I is useful not only in the management but also in predicting the prognosis of brain damage.

Creatine-kinase-BB after severe head-injury as an index of prognosis in relation to nature of trauma and patients age.

Creatine-Kinase-BB (CK-BB) is a brain specific enzyme, with a prognostic value for the patient's outcome after head-injury. We have investigated 76 brain injured patients and attempted to show a correlation of the concentrations of CK-BB and the Glasgow-Outcome-Scale (GOS). Patients with a CK-BB concentration of more than 50 ng/ml died. Patients, who had a CK-BB concentration less than 25 ng/ml showed only minimal neurological deficits. Intracerebral contusions and acute subdural haematomas showed the highest CK-BB concentration, indicating a high degree of braintissue-damage. CK-BB seems to have no correlation with the age of patients. Normalisation of elevated CK-BB levels do not correlate with recovery from neurological deficit.

[Growing factors of chronic subdural hematoma--significance of CK activity in hematoma contents and neomembrane].

The growing mechanism of the chronic subdural hematoma has not fully understood yet, in spite of numerous studies about hematoma neomembranes. However, it is well known that the majority of the chronic subdural hematomas are well healed by a simple irrigation of hematoma. These facts suggested that the hematoma contents could have important growing factors of the chronic subdural hematoma. Thus, LDH and CK activities were estimated in 52 cases of hematoma contents and 15 cases of hematoma neomembranes in order to search growing factors, biochemically. Hematocrit and hemoglobin values in hematoma contents were also examined simultaneously. As a result, hematocrit and hemoglobin values in hematoma contents were gradually increased, these facts might be due to the concentration of hematoma contents. LDH and CK activities in hematoma contents were high around 60 days after the hematoma inducing head trauma, and these enzyme activities were not correlated with hematocrit value. In isozyme analysis of LDH and CK activities, LDH-1,2 and CK-MM showed high values but CK-BB, MB could not be recognized. These findings suggested that LDH activity in the hematoma contents were caused by hemolysis which had been reported to be a main cause, and CK activity might originate from muscular tissues. Therefore, author hypothesized that the CK activity in hematoma contents had originated from the neomembrane, since there was a good correlation between the mature stage of neomembrane and the high level of CK-MM, and the myofibroblast was found in neomembrane recently. CK-MM could be released from the myofibroblast in neomembrane. However, CK activity in hematoma neomembrane could not be recognized, biochemically nor immunohistochemically.(ABSTRACT TRUNCATED AT 250 WORDS)

Predictive value of serum lactate dehydrogenase in head injury.

Serum total lactate dehydrogenase (LDH) was estimated serially for up to 15 days in 110 patients with head injuries who had no extraneural injury. Increase in LDH activity generally indicated the degree of parenchymal brain damage. The prognostic value of LDH was established by correlating its activity with clinical criteria such as duration of unconsciousness and post-traumatic amnesia, type of brain damage, and quality of survival. A significant rise in LDH activity suggested severe brain damage and poor prognosis.

Fibrinolytic enzyme in the lining walls of chronic subdural hematoma.

Active plasmin, available plasmin, and total plasminogen were measured by Enzo-diffusion fibirn plate techniques in 11 cases and level of tissue activator and tissue fibrinolytic activities in another 11 cases with chronic subdural hematoma. The values were too small to be measured in some instances. Anti-plasmin in the hematoma was less than in the blood plasma. The outer membrane contained about three times more tissue activator than the dura mater, although the inner membrane contained none. Increased tissue activator, which exudes from the extremely vascular outer membrane, transforms plasminogen into plasmin in subdural hematoma, so that plasmin breaks down fibrin and fibrinogen and induces continuous hemorrhage.