CLOTBUST: Design of a Randomized Trial of Ultrasound-Enhanced Thrombolysis for Acute Ischemic Stroke

BACKGROUND: Intravenous tissue plasminogen activator (TPA) therapy can be monitored with 2 MHz transcranial Doppler (TCD). This article describes the design of CLOTBUST (combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic TPA), the first prospective international multicenter randomized clinical trial of noninvasive externally applied ultrasound to enhance systemic thrombolysis in human stroke. SUBJECTS: Patients with acute ischemic stroke eligible for intravenous TPA therapy within 3 hours of symptom onset who have detectable middle cerebral artery occlusion on a prebolus TCD are included in this trial. All patients receive standard 0.9 mg/kg TPA therapy. Patients are randomized (1:1) to either 2 hours of continuous monitoring with TCD or placebo monitoring. FDA-approved portable diagnostic TCD equipment and standard headframes (Marc series, Spencer Technologies, Seattle, WA) are used. Output of TCD units is set at 100% power achievable at depths of insonation that display the worst TIBI flow grade signals. METHODS AND END-POINTS: Acute MCA occlusion on prebolus TCD is defined as thrombolysis in brain ischemia (TIBI) flow grades 0-3. Treating physicians are blinded to randomization assignment, and certified scorers measure stroke severity using the National Institute of Health Stroke Scale (NIHSS). Safety of continuous TCD monitoring is determined by rates of symptomatic (NIHSS score increase by 4+ points) intracerebral hemorrhage within 72 hours after initial symptom onset. Potential enhancement of TPA therapy will be determined using combined primary end-point of early complete recanalization on TCD (TIBI flow grades 4-5), dramatic recovery (NIHSS < or = 3 points), or decline in the NIHSS > or = 10 points repeatedly measured every 30 minutes within 2 hours after TPA bolus. Other end-points include recovery at 24 hours and 3 months, modified Rankin scores (mRS) are obtained at 90 days, and favorable outcome is determined as NIHSS or mRS scores 0-1. CONCLUSIONS: The aim of phase II CLOTBUST trial is to determine the rates of early complete recanalization and dramatic/early clinical recovery in TPA + TCD and TPA groups. The sample size is set at 126 patients since a medium effect size (.50) is anticipated for TPA + TCD group vs TPA alone to achieve combined primary end-point.     

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.     

Les plantes transgéniques (OGM végétaux) : connaissances et inconnues sur les risques d'allergénicité…

Much attention is now being focused on foods from genetically modified plants because of the risk of allergenicity. No such risk has been reported for the first generation of GM plants made resistant to herbicides and insect larvae. Current experiments with hypoallergenic GM plants are reported and discussed in the present paper. The second generation of GM plants will improve the nutritional aspects of natural foods. Transgenic proteins could reach from 4 up to 8% of the total protein content in these foods. Any potential difference in allergenicity between second generation GM plants and the natural varieties must be examined with respect to the risk for food allergy caused by food products made from these plants and the risk for respiratory allergies in the people living near the crops caused by airborne pollen originating from the plants. WHO–FAO directives as well as the Codex Alimentarius proposals and the European Food Safety Authority (EFSA) guidelines recommend that transgenic proteins be screened for homology (by in silico study) and cross-reactivity with known allergens, as well as being examined carefully for modifications of host-plant proteomes. In vivo animal studies are also to be carried out to assess any potential immunogenicity. Lacking adequate safety data, the absence of potential allergenicity of transgenic plants cannot be ruled out. This is why data that do not meet the recommended safety criteria required for commercialization of GM plants do not allow us to rule out absolutely the risk that may be associated with products that are going to be commercialized. Therefore, it is essential that commercialized GM plants be monitored. We propose the establishment of public reference serum banks based on up-to-date WHO–FAO recommendations concerning the selection of sera according to precise criteria. We also propose establishing a system of allergovigilance linking national and European health and food safety agencies and a network of university hospital-based clinical and laboratory reference centres, together with a network of clinical allergists, responsible for the creation of the serum banks. Allergists working through these networks would be able to identify new sensitizations to transgenic foods in the population, just as they now identify new types of food allergies, which, in this case, would be GM foods. Such a project is now being established in France.     

NURSE-MIDWIFERY CARE TO VULNERABLE POPULATIONS Phase I: Demographic Characteristics of the National CNM Sample

The purpose of this article is to describe the extent to which certified nurse-midwives (CNMs) provide care to vulnerable populations in the United States and the source of reimbursement for this care. The data were obtained from the first phase of a national study to address the characteristics of women served and cost of care provided by CNMs. Results were analyzed nationally and by American College of Nurse-Midwives regions. Certified nurse-midwives in all types of practices are providing care to women from populations that are vulnerable to poorer than average outcomes of childbirth because of age, socioeconomic status, refugee status, and ethnicity. Ninety-nine percent of CNMs report serving at least one group of vulnerable women, and CNMs in the inner city and rural practices serve several groups. The vast majority of CNMs are salaried; only 11% receive their primary income from fee-for-service. Fifty percent of the payment for CNM services is from Medicaid and government-subsidized sources whereas less than 20% comes from private insurance. Source of income varies by type of setting in which the CNM attends births. The results suggest that CNMs, as a group, make a major contribution to the care of vulnerable populations.