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.     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.     

Paramedic and emergency department care of stroke: baseline data from a citywide performance improvement study.

BACKGROUND: Rapid diagnosis and transport by paramedics and efficient, effective emergency management are essential to improving care of acute stroke patients. OBJECTIVES: To measure the performance of paramedics and emergency departments providing care for patients with suspected acute stroke. METHODS: Two stroke centers and 4 other hospitals where most patients with acute stroke in Houston, Tex, are admitted participated. Hospital and paramedic performance data were collected prospectively on 446 patients with suspected acute stroke transported by paramedics between September 1999 and February 2000. RESULTS: Paramedics had a sensitivity of 66%, specificity of 98%, and overall accuracy of 72% in diagnosing stroke. For patients with suspected stroke, 58.5% arrived in the emergency department within 120 minutes of symptom onset; in confirmed cases, that percentage was 67%. Mean total transport time was 42.2 minutes and was significantly longer (P < .001) to inner-city hospitals (44 minutes) than to suburban, community-based centers (39 minutes). Door to computed tomography times were significantly (P < .001) shorter for the 2 stroke centers than the other hospitals. Overall thrombolysis treatment rate among patients with confirmed ischemic stroke was 7.4% (range, 0-19.4%); treatment rates at the 2 stroke centers were 5.9% and 19.4%. CONCLUSIONS: More than half of patients with suspected stroke arrive at hospitals while thrombolytic treatment is still feasible. Although the current rate for thrombolytic treatment in Houston exceeds the national rate, performance of paramedics and hospitals in treating acute stroke can be improved by increasing efficiency and standardizing medical practices.     

Residual Flow Signals Predict Complete Recanalization in Stroke Patients Treated With TPA

BACKGROUND: Residual blood flow around thrombus prior to treatment predicts success of coronary thrombolysis. The authors aimed to correlate the presence of residual flow signals in the middle cerebral artery (MCA) with completeness of recanalization after intravenous tissue plasminogen activator (TPA). METHODS: The authors studied consecutive patients treated with intravenous TPA therapy who had a proximal MCA occlusion on pretreatment transcranial Doppler (TCD). Patients were continuously monitored for 2 hours after TPA bolus. Absent residual flow signals correspond to the thrombolysis in brain ischemia (TIBI) 0 grade, and the presence of residual flow signals was determined as TIBI 1-3 flow grades. Complete recanalization was defined as flow improvement to TIBI grades 4-5. RESULTS: Seventy-five patients with a proximal MCA occlusion had median pre-bolus NIHSS 16 (85% with > or = 10 points). TPA bolus was given at 141 +/- 56 minutes (median 120 minutes). Complete recanalization was observed in 25 (33%), partial in 23 (31%), and no early recanalization was seen in 27 (36%) patients within 2 hours after TPA bolus. Only 19% with absent residual flow signals (TIBI grade 0, n = 26) on pretreatment TCD had complete early recanalization. If pretreatment TCD showed the presence of any residual flow (TIBI 1-3, n = 49), 41% had complete recanalization within 2 hours of TPA bolus (P = .03). CONCLUSIONS: Patients with detectable residual flow signals before IV TPA bolus are twice as likely to have early complete recanalization. Those with no detectable residual flow signals have less than 20% chance for complete early recanalization with intravenous TPA and may be candidates for intra-arterial therapies.     

Strecker stent in stenotic hemodialysis Brescia-Cimino arteriovenous fistulas

Flexible tantalum stents (Strecker) were used as an adjunct to percutaneous transluminal angioplasty (PTA) in the treatment of stenotic arterial or venous limbs of Brescia-Cimino hemodialysis fistulas. The diagnostic procedure was performed using retrograde fistulography. After PTA with unsatisfactory results, stents were placed in 5 patients with significant residual stenoses and poor fistula function. Within the mean follow-up period of 6.4 months (range 3–10 months) all fistulas were functioning. We conclude that Strecker stent is useful in the treatment of stenotic hemodialysis arteriovenous fistulas as an adjunct to PTA.     

Capsular fixation with the Frezzotti-Caporossi intraocular lens

Fixation within the capsular bag appears to be generally, if not unanimously, accepted for optimal positioning of an intraocular lens. It furthermore seems apparent to us that each lens model relates to a specific position within the eye and fixates better according to its particular geometry. In our opinion, the Frezzotti-Caporossi lens represents one of the better solutions for in-the-bag fixation because of the static action of the haptic and the extended contact between loops and the enclosing structures.     

Management of patients supported on the Hemopump cardiac assist system

The Hemopump Cardiac Assist System is a relatively new intraarterial, axial-flow circulatory assist device that offers temporary left ventricular support to patients in refractory cardiogenic shock, without requiring major surgery for insertion. Use of the Hemopump is associated with a low complication rate. Device-related morbidity is extremely rare. Because the Hemopump is safe for use in community hospitals, the number of patients supported by this device is expected to increase. In this report, we present general guidelines for the care of patients supported by the Hemopump. We describe techniques for the management of afterload reduction, supravalvular dislodgement, device malfunction, ventricular ectopy, intracardiac shunting, and inflow cannula obstruction.     

Soman intoxication-induced changes in serum acute phase protein levels,corticosterone concentration and immunosuppressive potency of the serum

We have studied the effect of soman intoxication on serum acute phase reactants (APR) levels, and the relationship of the APR and corticosterone concentrations and the immunosuppressive activity of the serum. One day after the injection of 1.8 LD₅₀ soman the concentrations of ₂-macroglobulin (₂-MG) and ₁-acid glycoprotein (AGP) in the serum of antidote protected rats increased 4- and 7-fold, respectively, whereas those of hemopexin (Hx), haptoglobin (Hp) and cysteine protease inhibitor (CPI) were two to three times higher than in the controls. A similar magnitude of increase of serum acute phase reactants levels was observed when 0.3 LD₅₀ soman was administered at 24-h intervals over the 5-day period. The relationship of changes in the APR concentration, corticosterone level and immunosuppressive activity of the serum was also comparable to that observed in the acute phase response to tissue injury.     

NMDA receptors regulate developmental gap junction uncoupling via CREB signaling

Signaling through gap junctions (electrical synapses) is important in the development of the mammalian central nervous system. Abundant between neurons during postnatal development, gap junction coupling subsequently decreases and remains low in the adult, confined to specific subsets of neurons. Here we report that developmental uncoupling of gap junctions in the rat hypothalamus in vivo and in vitro is associated with a decrease in connexin 36 (Cx36) protein expression. Both developmental gap junction uncoupling and Cx36 downregulation are prevented by the blockade of NMDA glutamate receptors, action potentials and the calcium-cyclic AMP response element binding protein (CREB), and are accelerated by CREB overexpression. Developmental gap junction uncoupling and Cx36 downregulation are not affected by blockade of non-NMDA glutamate receptors, and do not occur in hypothalamic neurons from NMDA receptor subunit 1 (NMDAR1) knockout mice. These results demonstrate that NMDA receptor activity contributes to the developmental uncoupling of gap junctions via CREB-dependent downregulation of Cx36.