Improvements to the APBS biomolecular solvation software suite

The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that has provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this manuscript, we discuss the models and capabilities that have recently been implemented within the APBS software package including: a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory based algorithm for determining p$K_a$ values, and an improved web-based visualization tool for viewing electrostatics

Neuroprotection and the Ischemic Cascade

Brain ischemia is a process of delayed neuronal cell death, not an instantaneous event. The concept of neuroprotection is based on this principle. Diminished cerebral blood flow initiates a series of events (the “ischemic cascade”) that lead to cell destruction. This ischemic cascade is akin to a spreading epidemic starting from a hypothesized core of ischemia and radiating outward. If intervention occurs early, the process may be halted. Interventions have been directed toward salvaging the ischemic penumbra. Hypothermia decreases the size of the ischemic insult in both anecdotal clinical and laboratory reports. In addition, a wide variety of agents have been shown to reduce infant volume in animal models. Pharmacologic interventions that involve thrombolysis, calcium channel blockade, and cell membrane receptor antagonism have been studied and have been found to be beneficial in animal cortical stroke models. Human trials of neuroprotective therapies have been disappointing. Other than thrombolytics, no agents, have shown an unequivocal benefit. The future of neuroprotection will require a logical extension of what has been learned in the laboratory and previous human trials. A sensible approach to the use of multiple-agent cocktails used in combination with thrombolytics is likely to offer the highest chance for benefit

Early Dramatic Recovery During Intravenous Tissue Plasminogen Activator Infusion

Background and Purpose— Acute-stroke patients receiving standard intravenous tissue plasminogen activator (tPA) have been noted to experience early dramatic recoveries. The prevalence, clinical characteristics, and outcome of patients experiencing dramatic recovery is not well described. Methods— We prospectively studied all patients presenting with acute middle cerebral artery (MCA) stroke syndromes and transcranial Doppler (TCD) evidence of an MCA obstruction. All patients received intravenous tPA per the National Institute of Neurological and Communicative Disorders and Stroke protocol, with serial National Institutes of Health Stroke Scale (NIHSS) scores and continuous TCD monitoring. Dramatic recovery was defined as an improvement of ≥10 NIHSS points or a decrease to an NIHSS score of ≤3 by the end of infusion. Outcome at the end of infusion, at 24 hours, and at long-term follow-up were obtained. The timing and pattern of deficit recovery during dramatic recovery was also studied. Results— Dramatic recovery occurred in 22% of all patients. Compared with patients who did not experience dramatic recovery, those patients who did had significantly lower end-infusion NIHSS (median 2 and range 0 to 16 for dramatic-recovery patients versus median 17 and range 6 to 35 for non–dramatic-recovery patients, P Conclusions— Early dramatic recovery in acute MCA stroke patients treated with intravenous tPA is relatively frequent. The benefit of dramatic recovery is maintained at 24 hours and over the long term. TCD monitoring suggests that dramatic recovery is a result of early restoration of MCA flow during the tPA infusion. The consistent pattern of early clinical recovery may help explain the mechanisms by which thrombolysis improves outcome and could suggest targets for enhancing the therapeutic effect of intravenous tPA

Dramatic Recovery During IV-TPA Infusion: Time Course and Clinical Pattern

Background: Dramatic recovery (DR) during TPA infusion is not well described. Methods: We compared clinical patterns and time course in patients with DR to Non-DR. We prospectively captured acute MCA strokes treated with standard NINDS IV-TPA protocols and performed serial NIHSS exams. DR was defined as a decrease by ≥ 10 NIHSS points or total score of ≤3 by end of TPA infusion.Intracranial flow signals were graded using the Thrombolysis in Brain Ischemia (TIBI) scale. Results: From 9/98–6/00, DR was observed in 12/53 patients(Table). With DR, there was a consistent pattern and time course of recovery: Gaze preference recovered first (8/11 complete; 2/11 partial; 1/11 none); followed by Sensory (4/7 complete; 3/7 partial recovery; 0/7 none) and Leg Strength (8/10 complete; 1/10 partial; 1/10 none). Arm Strength followed next, but was often incomplete (5/12 complete; 6/12 partial;1/12 none) Certain findings had partial improvement later during infusion: Facial strength (3/12 complete; 7/12 partial; 1/12 none);Aphasia (2/7 complete; 4/7 partial; 1/7 none). Dysarthria tended not to improve during infusion(2/7 complete; 0/7 partial; 5/7 none). DR was observed in 22% of patients during IV-TPA infusion and was sustained at 24 hours. The stroke severity and timing to bolus was similiar between DR and Non-DR groups. Early recanalization was the only noted difference. Conclusion: The clinical pattern of DR may result from reperfusion of the white matter tracts supplied by MCA perforators or improved collateral flow. With clot lysis, the observed recovery pattern is referable to vessel anatomy. How DR occurs and why some clinical deficits have delayed recovery needs further study

Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator

Background and Purpose—TIMI angiographic classification measures coronary residual flow and recanalization. We developed a Thrombolysis in Brain Ischemia (TIBI) classification by using transcranial Doppler (TCD) to noninvasively monitor intracranial vessel residual flow signals. We examined whether the emergent TCD TIBI classification correlated with stroke severity and outcome in patients treated with intravenously administered tPA (IV-tPA). Methods—TCD examination occurred acutely and on day 2. TIBI flows were determined at distal MCA and basilar artery depths, depending on occlusion site. TIBI waveforms were graded as follows: 0, absent; 1, minimal; 2, blunted; 3, dampened; 4, stenotic; and 5, normal. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours after administration of tPA. Results—One hundred nine IV tPA patients were studied. Mean±SD age was 68±16 years; median NIHSS score before administration of tPA (pre-tPA) was 17.5. The tPA bolus was administered 143±58 minutes and the TCD examination 141±57 minutes after symptom onset. Pre-tPA NIHSS scores were higher in patients with TIBI grade 0 than TIBI grade 4 or 5 flow. TIBI flow improvement to grade 4 or 5 occurred in 35% of patients (19/54) with an initial grade of 0 or 1 and in 52% (12/23) with initial grade 2 or 3. The 24-hour NIHSS scores were higher in follow-up in patients with TIBI grade 0 or 1 than those with TIBI grade 4 or 5 flow. TIBI flow recovery correlated with NIHSS score improvement. Lack of flow recovery predicted worsening or no improvement. In-hospital mortality was 71% (5/7) for patients with posterior circulation occlusions; it was 22% (11/51) for patients with pre-tPA TIBI 0 or 1 compared with 5% (1/19) for those with pre-tPA TIBI 2 or 3 anterior circulation occlusions. Conclusions—Emergent TCD TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in IV-tPA–treated stroke patients. A flow-grade improvement correlated with clinical improvement

Timing of Recanalization After Tissue Plasminogen Activator Therapy Determined by Transcranial Doppler Correlates With Clinical Recovery From Ischemic Stroke

Background—The duration of cerebral blood flow impairment correlates with irreversibility of brain damage in animal models of cerebral ischemia. Our aim was to correlate clinical recovery from stroke with the timing of arterial recanalization after therapy with intravenous tissue plasminogen activator (tPA). Methods—Patients with symptoms of cerebral ischemia were treated with 0.9 mg/kg tPA IV within 3 hours after stroke onset (standard protocol) or with 0.6 mg/kg at 3 to 6 hours (an experimental institutional review board–approved protocol). National Institutes of Health Stroke Scale (NIHSS) scores were obtained before treatment, at the end of tPA infusion, and at 24 hours; Rankin Scores were obtained at long-term follow-up. Transcranial Doppler (TCD) was used to locate arterial occlusion before tPA and to monitor recanalization (Marc head frame, Spencer Technologies; Multigon 500M, DWL MultiDop-T). Recanalization on TCD was determined according to previously developed criteria. Results—Forty patients were studied (age 70±16 years, baseline NIHSS score 18.6±6.2). A tPA bolus was administered at 132±54 minutes from symptom onset. Recanalization on TCD was found at the mean time of 251±171 minutes after stroke onset: complete recanalization occurred in 12 (30%) patients and partial recanalization occurred in 16 (40%) patients (maximum observation time 360 minutes). Recanalization occurred within 60 minutes of tPA bolus in 75% of patients who recanalized. The timing of recanalization inversely correlated with early improvement in the NIHSS scores within the next hour (polynomial curve, third order r2=0.429, P300 minutes. Conclusions—The timing of arterial recanalization after tPA therapy as determined with TCD correlates with clinical recovery from stroke and demonstrates a 300-minute window to achieve early complete recovery. These data parallel findings in animal models of cerebral ischemia and confirm the relevance of these models in the prediction of response to reperfusion therapy