Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data

BACKGROUND: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. METHODS: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. RESULTS: Enrollment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. CONCLUSION: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.     

The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria

This is an independent reanalysis of a randomised, placebo-controlled parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex) for the prophylaxis of migraine. The original protocol and analysis had a number of major shortcomings. In order to follow regulatory requirements, an independent reanalysis of the original data was performed. Following a 4-week baseline phase, 33 patients were randomised to treatment with two capsules 25 mg butterbur twice a day and 27 to placebo. The mean attack frequency per month decreased from 3.4 at baseline to 1.8 after 3 months (p = 0.0024) in the verum group and from 2.9 to 2.6 in the placebo group (n.s.). The responder rate (improvement of migraine frequency > or =50%) was 45% in the verum group and 15% in the placebo group. Butterbur was well tolerated. This small trial indicates that butterbur may be effective in the prophylaxis of migraine.     

The validity of adolescent types of alcohol use

BACKGROUND: Alcohol is the most frequently used substance among adolescents with different patterns of consumption. Various types of adolescent alcohol use have been proposed, but only a few studies have looked for external validation of these types. METHOD: Data from 794 adolescents participating in the Zurich Adolescent Psychology and Psychopathology Study (ZAPPS) were used to evaluate the discriminant validity of the classification of four types of adolescent drinkers: abstainers, social drinkers, heavy drinkers, and problem drinkers. Data were based on questionnaires dealing with substance abuse, emotional and behavioral problems, life events, coping capacity, self-related cognitions, perceived parental behavior, perceived school environment, and the social network. RESULTS: There was a clear differentiation of the problem drinkers' group on almost all dimensions of the emotional and behavioral problems questionnaires, with the heavy drinkers' profile situated in between on some dimensions, and the abstainers and social drinkers almost ideally meeting the expectation of a mean normal population profile. Problem drinkers were also marked by high life impact scores, low self-esteem, high self-awareness, low perceived parental acceptance and high amount of rejection by the parents, and various indicators of a stressful and less rewarding school environment. Again, the heavy drinkers were positioned on an intermediate level on some of these scales, whereas the abstainers and social drinkers scored more normally. CONCLUSION: These findings support the validity of the distinction of various adolescent alcohol use types.     

Apoptotic genes in cancer therapy

Induction of apoptosis in malignant cells is a major goal of cancer therapy in general and of certain cancer gene therapy strategies in particular. Numerous apoptosis-regulating genes have been evaluated for this purpose. Besides the most prominent p53 gene others include p16, p21, p27, E2F genes, FHIT, PTEN and CASPASE genes. Recently, the potential for therapy of an adenoviral gene, E1A, known for a long time for its apoptosis-inducing activity, has been discovered. In experimental settings, these genes have proven their tumor-suppressive and apoptosis-inducing activity. Clinical trials are currently being performed with selected genes. By far the most studies transfer the p53 gene using retro- or adenoviral vectors. Disease stabilization or other benefits were observed in a limited number of patients when p53 was applied alone or in combination with cytotoxic drugs. A second proapoptotic gene that has entered clinical trials is adenovirus E1A. Here, too, disease stabilization as well as/or local regression in one case have been demonstrated in selected patients. In all cases, side effects were tolerable. To further improve E1A as a therapeutic transgene, we have deleted transforming domains from the adenovirus 5 and 12 13S cDNAs. Mutants were derived which had completely lost their transforming activity in combination with the E1B oncogene but retained a pronounced tumor-suppressive activity. Cells transduced with these constructs showed a highly reduced ability to grow in soft agar, and tumor growth in nude mice could be substantially suppressed. Outgrowing tumors had lost E1A expression when analyzed in Western blots. These E1A constructs may represent valuable tools for cancer gene therapy in the future.     

Differential gene expression in human cerebrovascular malformations

OBJECTIVE: We sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions. METHODS: Total ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis. RESULTS: The gene discovery method identified 42 genes that were significantly up-regulated and 36 genes that were significantly down-regulated in CCMs as compared with AVMs and STAs (P = 0.006). Similarly, 48 genes were significantly up-regulated and 59 genes were significantly down-regulated in AVMs as compared with CCMs and STAs (P = 0.006). The confirmation analysis showed significant differential expression (P < 0.05) in 11 of 15 genes (angiogenesis factors, receptors, and structural proteins) that previously had been reported to be expressed differentially in CCMs and AVMs in immunohistochemical analysis. CONCLUSION: We identify numerous genes that are differentially expressed in CCMs and AVMs and correlate expression with the immunohistochemistry of genes implicated in cerebrovascular malformations. In future efforts, we will aim to confirm candidate genes specifically related to the pathobiology of cerebrovascular malformations and determine their biological systems and mechanistic relevance.     

Immune Reactions after Trauma

Abstract Activation of the immune system for wound healing following accidental trauma is a well-studied phenomenon. The reaction comprises both the cellular and humoral systems. The various steps in the reaction are all temporally defined and influence each other. The main cells involved are polymorphonuclear granulocytes (PMN), monocytes, and lymphocytes. They interact and adhere to the endothelium via adhesion molecules such as L-selectin and ICAM-1. The humoral mediators discussed in this review are tumor necrosis factor- (TNF-) and its receptors, interleukin-1 (IL-1), IL-6, IL-10 and interferon- (IFN-). The kinetics of the cells appearing and of the cytokines are discussed. The actions of these players are reviewed along with the most recent literature. Furthermore, we attempt to elucidate causal relationships. The immune system can be hyper- or hypoactive. Both exaggerated pro- and antiinflammatory reactions may have the same endpoint: multiple organ dysfunction syndrome (MODS). This knowledge should be used to meticulously monitor the patients immunologic status. Depending on the state, hyper- or hypoinflammatory, the treatment should comprise anti-inflammatory and immune-restoring properties, respectively. What is decisive to survival is timely, adequate management based on the individual patients status.     

R1 – Systemic thrombolysis in German stroke units

BACKGROUND: Systemic thrombolysis with tissue plasminogen activator (t-PA) for treatment of acute ischemic stroke was approved in Germany in 2000. Up to now, only data from single centers have been available for the study of the use of thrombolysis in a hospital-based approach outside controlled trials. We therefore sought to determine the frequency of application and complications as well as the patient outcome after t-PA treatment in clinical routine of specialized stroke centers in Germany. METHODS: Within the German Stroke Data Bank Collaboration, 6234 consecutive patients with ischemic stroke were prospectively documented in 20 stroke centers between 1998 and 1999. The patients were centrally followed via telephone interview after 3 months and 1 year to assess global functional outcome using the Modified Rankin Scale. RESULTS: 250 patients (4 %) received systemic t-PA treatment during the study period. The baseline characteristics of these patients were comparable to large clinical trials and phase IV studies. Symptomatic and asymptomatic parenchymal hemorrhage occurred in 22 patients (8.8 %) and was fatal in 3 patients. Follow-up data after 3 months were obtained in 82.4 % of all patients, of which 35 % had a favorable functional outcome (mRS /= 4) and 17 % had died. CONCLUSION: The results of our study agree with the assumption that thrombolytic therapy can be performed safely and effectively in daily clinical practice. Nevertheless, the small proportion of patients receiving thrombolysis even in specialized stroke centers calls for further improvement of acute stroke management in Germany.     

Effects of cardiac contusion in isolated perfused rat hearts

Myocardial contusion is frequently suspected after blunt chest trauma, but the exact mechanisms of resulting cardiac dysfunction and the time course for enzymatic alterations have not yet been fully understood. Therefore, we investigated pathophysiological aspects of myocardial contusion in a controlled animal model. Male Wistar rat hearts were studied in an isolated perfusion model and were divided into two groups: control (n = 4) and heart contusion (n = 6) groups. The cardiac contusion was produced by a single blow with a weighted pendulum (m = 44 g, height = 20 cm). Functional implications of the contusion were examined in an "isolated perfused heart" model. Troponin 1 concentrations were determined in the perfusate. Cardiac contusion resulted in an increase of coronary perfusion pressure (CPP) of 9 mmHg (P < 0.05, 20 min postcontusion versus baseline and control), followed by a significant increase of left ventricular end-diastolic pressure (LVEDP) of 6 mmHg (P < 0.05, 20 min postcontusion versus baseline and control). Heart contusion was followed by an early increase of troponin 1 (+0.82 ng/mL). The troponin 1 concentration decreased again and, after 20 min, baseline levels were reached. The control group showed no such changes. In this model, high troponin 1 levels after cardiac contusion suggest direct damage to the myocardium. First functional response was shown by the alteration of the coronary perfusion, followed by impaired diastolic function, which persisted even after lowering of the troponin 1 levels.     

Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.