Intravenous thrombolysis in stroke mimics: results from the SITS International Stroke Thrombolysis Register.

BACKGROUND AND PURPOSE: Patients with stroke mimics (SM), i.e. conditions with stroke-like symptoms, may risk harm if treated with intravenous thrombolysis (IVT). Current guidelines state low risk of intracerebral hemorrhage based on studies comprising a total of <400 SM cases. We aimed to compare safety and outcomes following IVT between patients with acute ischaemic stroke and mimicking conditions. METHODS: We included IVT-treated ischaemic stroke patients in the SITS International Stroke Thrombolysis Register 2003-2017, examined with magnetic resonance imaging 22-36 h after treatment. Outcomes were parenchymal hematoma (PH) after treatment, symptomatic intracerebral hemorrhage (SICH) per Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), Second European Co-operative Stroke Study (ECASS II) and National Institutes of Neurological Disorders and Stroke Study (NINDS) criteria, death and modified Rankin Scale score (mRS) at 3 months. RESULTS: Of 10 436 patients, 429 mimics (4.1%) were identified. The most common types were functional (30.8%), migraine (17.5%) and seizure (14.2%). Patients with mimics had fewer cerebrovascular risk factors and lower median National Institutes of Health Stroke Scale score [7 (interquartile range, 5-10) vs. 8 (5-14), P < 0.001]. Among mimics versus stroke patients, PH was seen in 1.2% vs. 5.1% (P < 0.001), SICH NINDS in 0.5% vs. 3.9% (P < 0.001), SICH ECASS II in 0.2% vs. 2.1% (P = 0.007) and SICH SITS-MOST in 0% vs. 0.5% (P = 0.28). Modified Rankin Scale score 0-1 at 3 months was present in 84.1% vs. 57.7% (P < 0.001) and death within 3 months in 2.6% vs. 5.4% (P = 0.028) of mimics and stroke patients, respectively. CONCLUSIONS: This large observational study indicated that PH and SICH following IVT in patients with SM are uncommon.

Predictors of symptomatic intracranial haemorrhage in off-label thrombolysis: an analysis of the Safe Implementation of Treatments in Stroke registry.

BACKGROUND AND PURPOSE: Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off-label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database. METHODS: This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off-label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed. RESULTS: Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61-78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7-17). A total of 16 740 (30%) patients received off-label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off-label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08-1.80; P = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33-0.78; P = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions. CONCLUSIONS: Thrombolysis appears to be safe with regard to SICH for most of the off-label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk-benefit evaluation should be performed.

Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis.

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.

Impact of the Swedish National Stroke Campaign on stroke awareness.

BACKGROUND: Time delay from stroke onset to arrival in hospital is an important obstacle to widespread reperfusion therapy. To increase knowledge about stroke, and potentially decrease this delay, a 27-month national public information campaign was carried out in Sweden. AIMS: To assess the effects of a national stroke campaign in Sweden. METHODS: The variables used to measure campaign effects were knowledge of the AKUT test [a Swedish equivalent of the FAST (Face-Arm-Speech-Time)] test and intent to call 112 (emergency telephone number) . Telephone interviews were carried out with 1500 randomly selected people in Sweden at eight points in time: before, three times during, immediately after, and nine, 13 and 21 months after the campaign. RESULTS: Before the campaign, 4% could recall the meaning of some or all keywords in the AKUT test, compared with 23% during and directly after the campaign, and 14% 21 months later. Corresponding figures were 15%, 51%, and 50% for those remembering the term AKUT and 65%, 76%, and 73% for intent to call 112 when observing or experiencing stroke symptoms. During the course of the campaign, improvement of stroke knowledge was similar among men and women, but the absolute level of knowledge for both items was higher for women at all time points. CONCLUSION: The nationwide campaign substantially increased knowledge about the AKUT test and intention to call 112 when experiencing or observing stroke symptoms, but knowledge declined post-intervention. Repeated public information therefore appears essential to sustain knowledge gains.

Treatment of acute stroke: an update.

Stroke is the second leading cause of global mortality after coronary heart disease, and a major cause of neurological disability. About 17 million strokes occur worldwide each year. Patients with stroke often require long-term rehabilitation following the acute phase, with ongoing support from the community and nursing home care. Thus, stroke is a devastating disease and a major economic burden on society. In this overview, we discuss current strategies for specific treatment of stroke in the acute phase, focusing on intravenous thrombolysis and mechanical thrombectomy. We will consider two important issues related to intravenous thrombolysis treatments: (i) how to shorten the delay between stroke onset and treatment and (ii) how to reduce the risk of symptomatic intracerebral haemorrhage. Intravenous thrombolysis has been approved treatment for acute ischaemic stroke in most countries for more than 10 years, with rapid development towards new treatment strategies during that time. Mechanical thrombectomy using a new generation of endovascular tools, stent retrievers, is found to improve functional outcome in combination with pharmacological thrombolysis when indicated. There is an urgent need to increase public awareness of how to recognize a stroke and seek immediate attention from the healthcare system, as well as shorten delays in prehospital and within-hospital settings.

Thrombolytic therapy for acute stroke in Austria: data from the Safe Implementation of Thrombolysis in Stroke (SITS) register.

BACKGROUND: We aimed at determining the safety and efficacy of IV alteplase in Austrian versus non-Austrian centres as documented in the Internet-based registers Safe Implementation of Thrombolysis for Stroke - MOnitoring STudy (SITS-MOST) and - International Stroke Thrombolysis Register (SITS-ISTR). METHODS: We analysed patient data entered in the registers SITS-MOST and SITS-ISTR in the period December 2002 to 15 November 2007. RESULTS: Compared to the non-Austrian cohort (n=15153), the Austrian cohort (n=896) was slightly older [median, interquartile range (IQR): 70, 60-77 years vs. 69, 60-76 years, P=0.05] and included more women (44.6% vs. 41.0%, P=0.03). Austrian patients had a significantly shorter stroke onset-to-treatment time (OTT; median, IQR: 135, 105-160 min vs. 145, 115-170 min, P<0.0005). Symptomatic intracerebral haemorrhages were observed in 1.6% of Austrian and 1.7% of non-Austrian patients (P=0.82). At 3 months, 50.8% of Austrian and 53.0% of non-Austrian patients were independent (P=0.23), but death was less frequent in Austrian patients (12.1% vs. 14.9%, P=0.03). Multivariate analyses adjusted for demographic and baseline characteristics confirmed lower mortality at 3 months in the Austrian cohort (odds ratio 0.81, 95% confidence intervals 0.71-0.92, P=0.001). Longer OTT was associated with increased mortality at 3 months, with a hazard ratio of 1.02 (95% CI 1.01-1.03; P=0.005) for each 10-min increase in OTT. CONCLUSIONS: The implementation of intravenous alteplase for acute stroke has been safe and efficacious in Austrian centres. OTT and mortality were significantly lower in Austrian patients compared to non-Austrian SITS centres.

Safe implementation of thrombolysis in stroke-monitoring study in Italy.

BACKGROUND AND PURPOSE: The safe implementation of thrombolysis in stroke-monitoring (SITS-MOST) study was an unique opportunity to test in Italy, where only few centres were expert in thrombolytic treatment before, safety and efficacy of i.v. alteplase within 3 h of ischaemic stroke outside the setting of clinical trials. METHODS: In Italy to participate in the study the clinical centres had to possess organizational and structural characteristics certified by Regional Health Authorities. RESULTS: Seventy-one centres were activated, 56 (79%) treated patients of which 41 (73%) had never used thrombolysis before the study. Globally, 586 patients were included. Baseline median National Institute of Health Stroke Scale of Italian patients was 13 vs. 12 in other European centres (P = 0.0001). Symptomatic intracerebral haemorrhage as per the NINDS/Cochrane definition, mortality and independence (modified Rankin Scale 0-2) rates at 3 months occurred respectively in 6.7% (95% CI: 4.8-9.1), 11.7% (9.2-14.6) and 51.6% (47.4-55.7) of Italian patients compared with 7.3% (6.7-8.0) (P = 0.56), 11.2% (10.4-12.1) (P = 0.75) and 55.1% (53.8-56.4) (P = 0.09) in the European patients and in 8.6% (40/65; 6.3-11.6), 17.3% (14.1-21.1) and 50.1% (44.5-54.7) of the patients treated in the pooled randomized controlled trials. CONCLUSIONS: The SITS-MOST study showed that in Italy i.v. alteplase is safe and effective in routine clinical use also in non-expert centres.

Intravenous recombinant tissue plasminogen activator for acute stroke in Poland: an analysis based on the Safe Implementation of Thrombolysis in Stroke (SITS) Registry.

OBJECTIVES: Intravenous thrombolysis was conditionally approved in the European Union (EU) in 2002, under the requirement of entering all patients into Safe Implementation of Thrombolysis in Stroke - Monitoring Study (SITS-MOST). Countries not belonging to the EU by 2002, i.e. Poland were invited to enter data into the SITS International Stroke Thrombolysis Registry (SITS-ISTR). The aim of this study is to compare the safety and efficacy of thrombolysis in the Polish SITS-ISTR stroke patient population with patients registered in SITS-MOST. METHODS: 481 patients in Poland were reported between 2003 and 2007. Baseline and outcome data of Polish patients were compared with SITS-MOST. RESULTS: Most of the baseline characteristics did not differ between the groups. The most important was the onset-to-needle and door-to-needle times were significantly longer in Polish patients, 150 vs 136 min and 82 vs 68 min, respectively (P < 0.001). The symptomatic intracranial haemorrhage and independence rates at 3 months were similar in both populations. Polish patients had a significantly higher 3-month mortality rate, 18.6% vs 11.3% (P < 0.001). CONCLUSIONS: Because of higher mortality the study implies the need to improve the organization of thrombolysis services and provides the rationale to continue the monitoring of treatment in Poland.

The Belgian experience with intravenous thrombolysis for acute ischemic stroke.

PURPOSE: We report the Belgian results of the Safe Implementation of Thrombolysis in Stroke - International Stroke Thrombolysis Register (SITS-ISTR). This prospective observational register evaluates the safety and efficacy of intravenous thrombolysis with rtPA (recombinant tissue Plasminogen Activator) for ischemic stroke in routine clinical practice. METHODS: We compared the baseline characteristics, treatment delay, rate of symptomatic intracerebral hemorrhage and functional outcome at 90 days after treatment between patients enrolled in centres in Belgium and the non-Belgian SITS-registry population. We performed a multivariate analysis to adjust for differences in demographic and baseline characteristics. RESULTS: 743 patients were enrolled in 42 centers in Belgium between December 2002 and December 2007. These patients were older, had more severe stroke were more frequently female and more frequently had hyperlipidemia and atrial fibrillation. The median stroke onset-to-treatment delay was 140 min vs. 145 min. More patients died and were disabled 3 months after the stroke. A slight, non-significant, increase of symptomatic intracerebral hemorrhage (SICH) as per SITS protocol was observed (2.4 vs. 1.6%, p = 0.15). After adjustment for differences in baseline characteristics, functional independence (mRS < or = 2) at 3 months (OR 0.95, 95% CI 0.86-1.05, p = 0.31) was not different from non-Belgian patients, nor was the rate of SICH. However mortality at 3 months in Belgian patients was slightly higher (OR 1.15, 95% CI 1.02-1.29, p = 0.02). CONCLUSION: Intravenous thrombolysis for ischemic stroke is safe and effective in the routine clinical use in Belgium. The higher mortality we observed is not related to a higher rate of SICH.

Stroke in the Middle-East and North Africa: A 2-year prospective observational study of intravenous thrombolysis treatment in the region. Results from the SITS-MENA Registry.

BACKGROUND AND METHODS: Intravenous thrombolysis for acute ischemic stroke in the Middle-East and North African (MENA) countries is still confined to the main urban and university hospitals. This was a prospective observational study to examine outcomes of intravenous thrombolysis-treated stroke patients in the MENA region compared to the non-MENA stroke cohort in the SITS International Registry. RESULTS: Of 32,160 patients with ischemic stroke registered using the SITS intravenous thrombolysis protocol between June 2014 and May 2016, 500 (1.6%) were recruited in MENA. Compared to non-MENA (all p < 0.001), median age in MENA was 55 versus 73 years, NIH Stroke Scale score 12 versus 9, onset-to-treatment time 138 versus 155 min and door-to-needle time 54 min versus 64 min. Hypertension was the most reported risk factor, but lower in MENA (51.7 vs. 69.7%). Diabetes was more frequent in MENA (28.5 vs. 20.8%) as well as smoking (20.8 vs. 15.9%). Hyperlipidemia was less observed in MENA (17.6 vs. 29.3%). Functional independence (mRS 0-2) at seven days or discharge was similar (53% vs. 52% in non-MENA), with mortality slightly lower in MENA (2.3% vs. 4.8%). SICH rates by SITS-MOST definition were low (<1.4%) in both groups. CONCLUSIONS: Intravenous thrombolysis patients in MENA were younger, had more severe strokes and more often diabetes. Although stroke severity was higher in MENA, short-term functional independency and mortality were not worse compared to non-MENA, which could partly be explained by younger age and shorter OTT in MENA. Decreasing the burden of stroke in this young population should be prioritized.

Disappearing hyperdense middle cerebral artery sign in ischaemic stroke patients treated with intravenous thrombolysis: clinical course and prognostic significance.

BACKGROUND AND PURPOSE: Hyperdense middle cerebral artery sign (HMCAS) on CT is a well known indication of thromboembolic arterial occlusion. Its disappearance after thrombolytic therapy is poorly described. Taking the rate of HMCAS disappearance as a surrogate for MCA recanalisation, its prognostic value after intravenous thrombolysis was examined. METHODS: 1905 stroke patients with HMCAS on admission CT scan in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) were studied. On follow-up CT scans 22-36 h after thrombolysis, HMCAS disappeared in 831 cases, persisted in 788 and was uncertain in 122; follow-up CT was not done in 164 cases. RESULTS: Patients whose HMCAS disappeared were younger (median age 67 years vs 69 years for persistent; p = 0.03), with milder stroke (admission National Institute of Health Stroke Scale (NIHSS) score was 16 vs 17; p<0.005) and were less likely to have early infarct signs on admission CT (26% vs 33%; p<0.005). Patients with disappearing HMCAS were more likely to have early improvement in NIHSS score (median improvement 2 vs 0 at 2 h; 4 vs 1 at 24 h), be independent at 3 months (42% vs 19%), with fewer deaths (15% vs 30%) than those with persistent HMCAS. In multivariate analysis, HMCAS disappearance independently predicted functional independence and survival. Early NIHSS improvement independently predicted HMCAS disappearance. CONCLUSIONS: HMCAS disappeared after intravenous thrombolysis in about half of cases and these patients had twice as good outcomes compared with those with persistent HMCAS. The prognosis in patients with MCA occlusion that persists after intravenous thrombolysis is poor, which may indicate the need for an alternative treatment approach to this subgroup.

Two-dimensional nuclear magnetic resonance study of the beta-casein peptide 1-25: resonance assignments and secondary structure.

The N-terminal 25 amino-acid residue peptide (beta-CN 1-25) obtained from a tryptic digest of bovine beta-casein was studied using two-dimensional NMR techniques. Complete sequence-specific assignment of the 1H-NMR spectrum was performed both in the presence and absence of 22 mM Ca2+. The NMR data supported earlier findings that this segment of beta-casein is highly flexible and adopts multiple conformations. The observed pattern of sequential NOEs indicated that the peptide did not contain stable folded structures. However, the structure was neither that of a fully-extended peptide nor a so-called random coil. The region Ile-12 to SerP-15 showed an enhanced population of extended structure. Furthermore, addition of Ca2+ ions induced chemical-shift changes and apparently decreased the population of conformations with extended structure in the region SerP-18 to Ile-23.

Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized. The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty.

Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise.

Factors controlling cerebral blood flow (CBF) during exercise are complex and incompletely known. Different techniques have shown partly contradictory results of changes in regional and global cerebral perfusion during dynamic exercise in healthy subjects. To elucidate the global CBF response to supine stepwise increasing physical exercise, we measured blood flow in the left common carotid artery (QCCA) and the left internal carotid artery (QICA) simultaneously with the blood flow velocity in the ipsilateral middle cerebral artery (VMCA) using duplex ultrasonography and transcranial Doppler ultrasonography. During moderate exercise intensity (60-67% of maximal capacity), the VMCA increased 14% (P < 0.001), the QICA 17% (P < 0.01), and the QCCA 33% (P < 0.001) compared with baseline values. High physical exercise intensity (80-90% of maximal capacity) tended to reduce VMCA and QICA compared with moderate exercise, in contrast to a continued increase in QCCA. The results indicate an increased global CBF during exercise. This increase was reduced during hard exercise due to a decrease of the arterial PCO2 secondary to hyperventilation.

Spectrophotometry of the CSF (CSF-SPE) and computer tomography (CT) in traumatic head injuries.

Combined examinations with quantitative CSF spectrophotometry (CSF-SPE) and computer tomography (CT) were performed on 53 patients with traumatic head injuries. In cerebral concussion the results were mainly normal in both examinations. In cerebral contusion bleeding patterns were found by CSF-SPE in all subjects, with a special bleeding pattern (S2 pattern) occurring in 86%. CT showed findings described as typical for contusion in 8 of 14 examined patients, the remaining CT scans showing questionable or normal signs. In extra- and intracerebral haematomas, all patients had bleeding patterns on the CSF-SPE. A special bleeding component (H factor) was found in about 72%. The H component was not observed during the first 3 to 4 days after the trauma. All but one patient examined later than the 4th day had an H component with or without an S-pattern. CT demonstrated a haematoma in 14 of 18 verified haematoma patients, while 4 subjects with subdural haematoma (e.g. one third of this group) had questionable CT findings. The combined examinations with CT and CSF-SPE, being complementary to each other, are of great value in the different diagnosis of traumatic head injuries.

Amphetamines for improving recovery after stroke.

BACKGROUND: Experimental animal research shows that treatment with amphetamines improves recovery after focal cerebral ischaemia. If the effect were similar in humans, amphetamine treatment could have a major impact on recovery from stroke. OBJECTIVES: The objective of this review was to assess the effects of amphetamine treatment in patients with stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2002). In addition, we searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 4 2002), MEDLINE (1966-September 2002), EMBASE (1980-November 2002), and Science Citation Index (1992-December 2002). The reference lists of all relevant articles and reviews were checked, and we contacted researchers in the field to identify further published and unpublished studies. SELECTION CRITERIA: Randomized unconfounded trials comparing amphetamine with placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Seven studies involving 172 patients were included. The quality of the trials varied but was generally high. Based on two trials (85 patients) there was no evidence that amphetamine treatment reduced death or dependence (Peto's odds ratio, [Peto OR] 1.54; 95% Confidence Interval [CI] 0.64 to 3.73). In these two trials, there were imbalances at baseline, with more serious strokes allocated to amphetamine. This imbalance may account for the trend for more deaths at the end of follow-up among amphetamine allocated patients (Peto OR 3.33; 95% CI 0.99 to 11.24). Based on 4 studies (95 patients) there was evidence of a better relative change in motor function according to the Fugl-Meyer motor scale (Weighted Mean Difference, [WMD] -8.17 points; 95% CI -13.58 to -2.76) and based on 1 study (21 patients) there was evidence of a better change in language function as assessed by the Porch Index of Communicative Ability score (WMD -7.51 points; 95% CI -14.42 to -0.60) in amphetamine allocated patients. REVIEWER'S CONCLUSIONS: At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke. The suggested benefits on motor and language function, and the non-significant trend towards increased risk of death, could be related to imbalances in prognostic variables or other bias in studies. Further research in this area is therefore justified.

Effect of rigor temperature on muscle shortening and tenderisation of restrained and unrestrained beef m. longissimus thoracicus et lumborum.

Pairs of muscularis longissimus thoracicus et lumborum (LTL) from young bulls were removed within 1h of slaughter. Small portions of the muscles were placed in a rigormeter to continously follow the isometric tension and isotonic shortening developed, at constant temperatures of 15, 20, 25, 30 and 35°C, as the muscle went into rigor. The bulk LTL was placed in water baths at the same temperature. One of the bulk pairs was tightly restrained by wrapping, to reduce muscle shortening, the other was unrestrained free to shorten. For the bulk samples, shear values were measured using a Warner-Bratzler instrument (1, 7 and 14 days post mortem), and sensory attributes were measured using a sensory panel (7 and 14 days post mortem). Minimum tension and shortening occurred at 15°C. The activation energy for the muscle shortening process was larger than for the isometric tension process. This indicates that the isometric tension data, collected during rigor, does not solely reflect muscle shortening. Thus, a counteracting process that decreases the tension response, most likely ageing is simultaneously detected. Meat that went into rigor at 15°C had least shortening and was always more tender than meat going into rigor at higher temperatures. For meat entering rigor at temperatures higher than 15°C, restraining of the muscle by wrapping, significantly (p<0.05) decreased the amount of muscle shortening and resulted in an improved meat tenderness (p<0.001). It was also observed that at rigor temperatures higher than 15°C the meat tenderness is affected negatively by a reduced ageing capacity. It therefore appears that muscle shortening and enzyme activity both affect tenderness and that both are highly affected by rigor temperature and have the greatest beneficial effect at a rigor temperature of 15°C.

Minimally invasive and non-invasive diagnosis of carotid artery obstructive disease: an evaluation of supraorbital fluorescein angiography and ultrasonic duplex technique.

The carotid arteries of twenty-five patients with transient ischaemic attacks, minor stroke or amaurosis fugax were examined by conventional angiography, the ultrasonic duplex technique and supraorbital fluorescein angiography (SOFA). The results of the last two techniques (non-invasive and minimally invasive, respectively) were compared with the results of angiography. We found that the ultrasonic duplex technique is highly sensitive and specific for both high and low-grade carotid stenoses while the less costly SOFA can only identify stenoses equal to or more than 75%. However, since tight stenosis has proved to be an indication for surgical reconstruction, SOFA - or possibly the still simpler procedure with direct ocular inspection of the supraorbital fluorescence pattern without any recording - would be useful for initial screening in smaller units without access to ultrasonic duplex examination. In this way potential candidates for surgery can be identified without delay and forwarded to larger units for further supplementary examinations.

Mechanisms of action of neuroprotectants in stroke.

During cerebral ischemia, there is excessive activity of excitatory amino acids, especially glutamate. Activation of glutamate receptors leads to a marked increase in intracellular calcium, which in turn leads to activation of intracellular enzymes and neuronal death--the so-called excitotoxic cascade. The calcium antagonist nimodipine, which acts at L-type calcium channels, was tested for a putative neuroprotectant effect in patients with acute ischemic stroke, but no beneficial effect was demonstrated. Glutamate receptors are attractive targets for neuroprotectant drugs because glutamate plays a central role in the excitotoxic cascade. Clinical trials of NMDA (N-methyl-D-aspartate) antagonists have been disappointing, however, and psychiatric side effects seem to be a general problem with this class of drug. Another strategy proposed for interfering with NMDA receptor function is the infusion of magnesium. The NMDA receptor is normally blocked by magnesium ions and will only respond to glutamate when this magnesium-induced block is removed on depolarization. A large clinical trial to investigate possible neuroprotection by magnesium is underway. The NMDA receptor also has a glycine-binding site and a polyamine-binding site, and the cation channel will only open in response to glutamate if glycine and polyamines are already bound to these obligatory modulatory sites. Gavestinel is selective for the glycine-binding site, and eliprodil for the polyamine site, but large international clinical trials have failed to find any beneficial effects in patients with acute ischemic stroke. Neurotoxic free radicals are also generated during cerebral ischemia. Laboratory stroke models suggest that free radical scavengers might be effective neuroprotectants. One of these, NXY-059, was effective in several animal studies, and preliminary studies in human subjects show that plasma concentrations that are neuroprotective in animal models can be achieved and are well tolerated. Lubeluzole interferes with the glutamate-induced neuronal damage mediated through the formation of nitric oxide. However, a meta-analysis of all clinical trials of lubeluzole was unable to detect a neuroprotectant effect of the drug. There is now some evidence that, in addition to necrosis, some neurons die as a result of apoptosis after cerebral ischemia. Several drugs that interfere with the apoptosis cascade, for example, caspase inhibitors, are under investigation. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) is also undergoing a second large clinical trial in patients with major ischemic strokes. This drug's mechanism of action is not completely clear, but it is known to activate a nonbenzodiazepine site on the GABA(A) (gamma-aminobutyric acid) receptor. This causes increased chloride conductance and hyperpolarization. In vitro clomethiazole inhibits ischemia-induced glutamate efflux from cerebral neurons. The first large controlled trial showed it to be well tolerated and suggested a clinically significant effect in patients with deficits of a major stroke.

Neuroprotectants in the treatment of stroke--an overview.

The concept of neuroprotection against the excitotoxic cascade that accompanies ischemic stroke has been proved in animal models. However, no clinical trial has so far shown a statistically significant benefit for a neuroprotectant in patients with acute ischemic stroke on primary end point measures. Some of these failures can be ascribed to poor study design, small sample sizes, or poor choice of primary outcome measures. Trials of NMDA (N-methyl-D-aspartate) antagonists, however, have been troubled by psychotomimetic side effects that may well have meant that the maximal dose that could be tolerated was suboptimal in terms of neuroprotection. Clomethiazole ('ZENDRA'; a trademark, the property of the AstraZeneca group of companies) lacks psychotomimetic side effects and has undergone a large randomized placebo-controlled trial--CLASS (Clomethiazole Acute Stroke Study). This study failed to detect a statistically significant overall effect of clomethiazole. However, a post hoc analysis based on a prospective clinical classification showed that clomethiazole was effective in a subgroup of patients who had deficits of a major stroke. A further clinical trial of clomethiazole in patients with deficits consistent with a major ischemic stroke is currently underway (CLASS-I). In absolute terms, the size of benefit that can be expected from a neuroprotectant may be relatively small, but even small benefits could make the difference between independence and dependence on others for activities of daily living. Even small effects could therefore produce meaningful improvements in quality of life for both patients and their families and could produce significant reductions in long-term costs. The introduction of an effective neuroprotectant will increase the need for stroke to be treated as urgent by both the public and emergency services.