The use of enhanced intrinsic feedback for motor learning in stroke survivors: Clinical trial protocol.

BACKGROUND: Stroke can lead to lasting sensorimotor deficits of the upper limb (UL) persisting into the chronic phase despite intensive rehabilitation. A major impairment of reaching after stroke is a decreased range of active elbow extension, which in turn leads to the use of compensatory movements. Retraining movement patterns relies on cognition and motor learning principles. Implicit learning may lead to better outcomes than explicit learning. Error augmentation (EA) is a feedback modality based on implicit learning resulting in improved precision and speed of UL reaching movements in people with stroke. However, accompanying changes in UL joint movement patterns have not been investigated. The objective of this study is to determine the capacity for implicit motor learning in people with chronic stroke and how this capacity is affected by post-stroke cognitive impairments. METHODS: Fifty-two subjects who have chronic stroke will practice reaching movements 3×/wk. for 9 wk. in a virtual reality environment. Participants will be randomly allocated to 1 of 2 groups to train with or without EA feedback. Outcome measures (pre-, post- and follow-up) will be: endpoint precision, speed, smoothness, and straightness and joint (UL and trunk) kinematics during a functional reaching task. The degree of cognitive impairment, lesion profile, and integrity of descending white matter tracts will be related to training outcomes. CONCLUSIONS: The results will inform us which patients can best benefit from training programs that rely on motor learning and utilize enhanced feedback. TRIAL STATUS: Ethical approval for this study was finalized in May 2022. Recruitment and data collection is actively in progress and is planned to finish in 2026. Data analysis and evaluation will occur subsequently, and the final results will be published.

Development of MS Binding Assays targeting the binding site of MB327 at the nicotinic acetylcholine receptor.

The bispyridinium compound MB327 has been shown previously to have a positive pharmacological effect against poisoning with organophosphorous compounds (OPCs). The mechanism by which it exerts its therapeutic effect seems to be directly mediated by the nicotinic acetylcholine receptor (nAChR). In the present study, the development of mass spectrometry based binding assays (MS Binding Assays) for characterization of the binding site of MB327 at the nAChR from Torpedo californica is described. MS Binding Assays follow the principle of radioligand binding assays, but do not, in contrast to the latter, require a radiolabeled reporter ligand, as the readout is in this case based on mass spectrometric detection. For [2H6]MB327, a deuterated MB327 analogue employed as reporter ligand in the MS Binding Assays, an LC-ESI-MS/MS method was established allowing for its fast and reliable quantification in samples resulting from binding experiments. Using centrifugation for separation of non-bound [2H6]MB327 from target-bound [2H6]MB327 in saturation and autocompetition experiments (employing native MB327 as competitor) enabled reliable determination of specific binding. In this way, the affinities for [2H6]MB327 (Kd=15.5±0.9µmolL-1) and for MB327 (Ki=18.3±2.6µmolL-1) towards the nAChR could be determined for the first time. The almost exactly matching affinities for MB327 and [2H6]MB327 obtained in the MS Binding Assays are in agreement with potencies previously found in functional studies. In summary, our results demonstrate that the established MS Binding Assays represent a promising tool for affinity determination of test compounds towards the binding site of MB327 at the nAChR.

In vitro pharmacological characterization of the bispyridinium non-oxime compound MB327 and its 2- and 3-regioisomers.

The primary toxic mechanism of organophosphorus compounds, i.e. nerve agents or pesticides, is based on the irreversible inhibition of acetylcholinesterase. In consequence of the impaired hydrolysis, the neurotransmitter acetylcholine accumulates in cholinergic synapses and disturbs functional activity of nicotinic and muscarinic acetylcholine receptors by overstimulation and subsequent desensitization. The resulting cholinergic syndrome will become acute life-threatening, if not treated adequately. The current standard treatment, consisting of administration of a competitive mAChR antagonist (e.g. atropine) and an oxime (e.g. obidoxime, pralidoxime), is not sufficient in the case of soman or tabun intoxications. Consequently, alternative therapeutic options are necessary. An innovative approach comprises the use of compounds selectively targeting nAChRs, especially positive allosteric modulators, which increase the population of the conducting receptor state. MB327 (1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) di(iodide)) is able to restore soman-blocked muscle-force in preparations of various species including human and was recently identified as "resensitizer". In contrast to the well-studied MB327, the pharmacological efficacy of the 2- and 3-tert-butylpyridinium propane regioisomers is unknown. As a first step, MB327 and its 3-regioisomer (PTM0001) and 2-regioisomer (PTM0002) were pharmacologically characterized using [3H]epibatidine binding assays, functional studies by solid supported membranes based electrophysiology, and in vitro muscle-force investigations of soman-poisoned rat hemidiaphragm preparations by indirect field stimulation technique. The results obtained from targets of different complexity (receptor, muscle tissue) showed that the pharmacological profiles of the 2- and 3-regioisomers were relatively similar to those of MB327. Furthermore, high concentrations showed inhibitory effects, which might critically influence the application as an antidote. Thus, more effective drugs have to be developed. Nevertheless, the combination of the methods presented is an effective tool for clarifying structure-activity relationships.

Acute stroke care in non-urban emergency departments.

OBJECTIVE: To evaluate the practice patterns for stroke care in rural emergency departments (ED). METHODS: The authors prospectively evaluated clinical practice decisions for all ED patients in two non-urban East Texas communities using active and passive surveillance methods. Data collected included demographics, risk factors, symptoms, and treatment. Data analysis consisted of descriptive statistics and logistic regression analysis. RESULTS: During the study period, 429 patients presented with validated strokes. Risk factors included hypertension (65%), previous stroke (41%), coronary artery disease (33%), diabetes (25%), current smoking (17%), and atrial fibrillation (11%). In the ED, neurology consultation occurred in 32%, head CT in 88%, and ECG in 85%. Heparin was used in 9%, and 5% received aspirin. Blood pressure was lowered in 19% from a mean high of 189(+/-38)/97(+/-26), average reduction 34 points (18%) systolic. Motor symptoms were more likely to prompt a neurology consultation (OR = 2.47). Heparin was used more commonly for patients with atrial fibrillation (OR = 2.93). Socioeconomic factors did not alter care. IV recombinant tissue plasminogen activator was used in 1.4% of ischemic stroke cases. CONCLUSIONS: Acute stroke care in this representative non-urban community frequently does not follow published guidelines or clinical trial results. Whereas a high percentage of patients receive CT, aggressive blood pressure treatment occurs commonly and at pressures below current recommendations. The use of heparin is common, more so than aspirin treatment. These facts argue for educational interventions aimed at non-urban physicians to improve evidence-based medical practice.

Diabetic neuropathies.

Diabetes mellitus is a systemic disorder with a significant impact on the peripheral nervous system. Over half of the 15 million patients with diabetes mellitus in the United States have some form of diabetic neuropathy. Individuals with diabetes may develop acute or subacute painful polyneuropathy, proximal motor neuropathy, autonomic neuropathy, compression neuropathy, focal neuropathy, and chronic polyneuropathy. Studies have shown that optimizing diabetic control provides the greatest likelihood of either preventing or slowing the development of diabetic neuropathy.

Activation of emergency medical services for acute stroke in a nonurban population: the T.L.L. Temple Foundation Stroke Project.

BACKGROUND AND PURPOSE: Activating emergency medical services (EMS) is the most important factor in reducing delay times to hospital arrival for stroke patients. Determining who calls 911 for stroke would allow more efficient targeting of public health initiatives. METHODS: The T.L.L. Temple Foundation Stroke Project is an acute stroke surveillance and intervention project in nonurban East Texas. Prospective case ascertainment allowed chart abstraction and structured interviews for all hospitalized stroke patients to determine if EMS was activated, and if so, by whom. RESULTS: Of 429 validated strokes, 38.0% activated EMS by calling 911. Logistic regression analysis comparing those who called 911 with those who did not activate EMS found that individuals who were employed were 81% less likely to have EMS activated (OR 0.19, 95% CI 0.04 to 0.63). Of the 163 cases in which 911 was called, the person activating EMS was: self (patient), 4.3%; family member of significant other, 60. 1%; paid caregiver, 18.4%; and coworker or other, 12.9%. Significant associations between the variables age group (P=0.02), insurance status (P=0.007), and living alone (P=0.05) with who called 911 was found on chi(2) analysis. CONCLUSIONS: Educational efforts directed at patients themselves at risk for stroke may be of low yield. To increase the use of time dependent acute stroke therapy, interventions may wish to concentrate on family, caregivers, and coworkers of high-risk patients. Large employers may be good targets to increase utilization of EMS services for acute stroke.

Comparison of stroke hospitalization rates among Mexican-Americans and non-Hispanic whites.

The authors performed a prospective, community-based pilot stroke surveillance project in Nueces County, TX. Mexican-Americans showed a trend toward higher completed ischemic stroke hospitalization rates compared with non-Hispanic whites. Mexican-Americans were more commonly uninsured (p = 0.007) and were less likely to receive neuroimaging (p = 0.001). Additional studies are needed to confirm this finding and to determine the role of stroke risk factors and access to care variables.

Stroke prevention: cardiac and carotid-related stroke.

The aim of this article is to discuss cardiac sources of stroke as well as the management of symptomatic and asymptomatic carotid stenosis. The authors detail the risks of cardioembolic stroke in the following conditions: aortic arch atheroma, atrial fibrillation, atrial myxoma, atrial septal aneurysm, dilated cardiomyopathy, infective endocarditis, left ventricular thrombus, mitral annular calcification, mitral valve prolapse, patent foramen ovale, prosthetic heart valves, valvular strands, and the optimal medical management for these conditions. The indications for carotid endarterectomy, angioplasty, and stenting are also outlined.

Accuracy and criteria for localizing arterial occlusion with transcranial Doppler.

The authors determined transcranial Doppler (TCD) accuracy for the proximal internal carotid artery (ICA), distal ICA, proximal middle cerebral artery (MCA), distal MCA, anterior cerebral artery (ACA), posterior cerebral artery (PCA), terminal vertebral artery (tVA), and basilar artery (BA) occlusion in cerebral ischemia patients. Detailed diagnostic criteria were prospectively applied for TCD interpretation independent of angiographic findings. Of 320 consecutive patients referred to the neurosonology service with symptoms of cerebral ischemia, 190 (59%) patients also underwent angiography (MRA or DSA). 48 of those 190 patients had angiographic occlusion and 12 of those 48 patients had involvement of multiple vessels. Median time from TCD until angiography was performed was 1 hour (41 patients had angiography before TCD). TCD showed 40 true positive, 8 false negative, 8 false positive, and 134 true negative studies with sensitivity 83.0%, specificity 94.4%, positive predictive value 83.0%, negative predictive value 94.4%, and accuracy 91.6% to determine all sites of occlusion. Sensitivity for each individual occlusion site was: proximal ICA 94%, distal ICA 81%, MCA 93% tVA 56%, BA 60%. Specificity ranged from 96% to 98%. TCD is sensitive and specific in determining the site of the arterial occlusion using detailed diagnostic criteria, including proximal ICA and distal MCA lesions. TCD has the highest accuracy for ICA and MCA occlusions. If the results of TCD are normal, there is at least a 94% chance that angiographic studies will be negative.

Specific transcranial Doppler flow findings related to the presence and site of arterial occlusion.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) can localize arterial occlusion in stroke patients. Our aim was to evaluate the frequency of specific TCD flow findings with different sites of arterial occlusion. METHODS: Using a standard insonation protocol, we prospectively evaluated the frequency of specific TCD findings in patients with or without proximal extracranial or intracranial occlusion determined by digital subtraction or MR angiography. RESULTS: Of 190 consecutive patients studied, angiography showed occlusion in 48 patients. With proximal internal carotid artery (ICA) occlusion, TCD showed abnormal middle cerebral artery (MCA) waveforms (AMCAW) in 66.7%, reversed ophthalmic artery (OA) in 70.6%, anterior cross-filling via anterior communicating artery (ACoA) in 78.6%, posterior communicating artery (PCoA) in 71.4%, and contralateral compensatory velocity increase (CVI) in 84.6% of patients. With distal ICA occlusion, TCD showed AMCAW in 88.9%, OA in 16.7%, ACoA in 50%, PCoA in 60%, and CVI in 88.9% of patients. With MCA occlusion, TCD showed AMCAW in 100%, OA in 23.5%, ACoA in 31.3%, PCoA in 23.1%, and CVI in 62.5%. With no anterior circulation occlusion at angiography, TCD showed these parameters in 1.8% to 17. 9%, chi(2) P

Role of reactive oxygen species for hepatocellular injury and heme oxygenase-1 gene expression after hemorrhage and resuscitation.

Reactive oxygen species (ROS) generated during hemorrhage and subsequent resuscitation (H/R) may contribute to cellular injury but may also regulate an adaptive cellular response to stress. Heme oxygenase (HO)-1 has been recognized as an important stress-inducible gene conferring protection after H/R. The aim of this study was to determine the contribution of ROS to hepatocellular injury and to induction of HO-1 in parenchymal and nonparenchymal cells after H/R. Anesthetized Sprague-Dawley rats were subjected to reversible H/R with or without coadministration of the potent antioxidant Trolox (6 mg/kg body wt). HO-1 gene expression was determined at baseline, at the end of hemorrhagic hypotension, and after 1, 3, and 5 h of resuscitation on the messenger ribonucleic acid (mRNA) and protein level. Assessment of hepatocellular injury by alpha-glutathione-S-transferase serum levels showed a significant increase after H/R that was attenuated by Trolox (sham: 38 (26-42); H/R: 286 (150-696); Trolox: 14 (2-227) microg/L; median (25th/75th percentile) P<0.05). Injury correlated with induction of HO-1 mRNA (r2 = 0.97) on the whole organ level and with the expression pattern of HO-1-immunoreactive protein in pericentral hepatocytes after H/R. Trolox attenuated H/R-induced increase of HO-1 in hepatocytes. In contrast, nonparenchymal cells showed high constitutive levels of HO-1 mRNA and protein that were increased by sham operation and H/R to a similar extent. HO-1 steady-state transcripts in nonparenchymal cells were not modulated by Trolox. These results suggest a differential regulation of HO-1 gene expression in hepatocytes and nonparenchymal cells. ROS formation seems to contribute to early hepatocellular injury but also serves as an important trigger for HO-1 gene expression in parenchymal cells, which confers delayed protection after H/R.

Race/ethnicity and location of stroke mortality: implications for population-based studies.

BACKGROUND AND PURPOSE: Stroke community surveillance projects often focus on hospital data rates. We hypothesized that not including strokes which occurred in nursing homes or at home would differentially affect race/ethnic stroke rates. METHODS: Texas vital statistics data were studied to compare age-specific (45 to 59, 60 to 74, and >/=75 years) location of stroke death for African Americans (AAs), Hispanic Americans (HAs), and non-Hispanic whites (NHWs). Rate ratios are reported with 95% CIs; NHW is used as the referent group. RESULTS: During 1991 to 1996, there were 52 996 stroke deaths in Texas for individuals aged 45 years and older. HAs in the oldest age group (>/=75 years) were 33% more likely than NHWs to die in the hospital, and HAs aged 45 to 59 and 60 to 74 years were 4% and 10%, respectively, more likely to die in the hospital. AAs aged >/=75 years were 19% more likely to die in the hospital. HAs aged 60 to 74 years were 35% less likely to die in a nursing home, whereas HAs aged >/=75 years were 43% less likely than NHWs to die in a nursing home. AAs aged >/=75 were 33% less likely to die in a nursing home. Death at home was 19% more likely in HAs aged 60 to 74 years. Significant gender differences are also reported. CONCLUSIONS: Using hospital data alone would overestimate stroke mortality in the HA and AA groups. Stroke community surveillance projects should account for ethnic and gender differences in location of death to avoid bias in race/ethnic and gender comparisons.

Yield of transcranial Doppler in acute cerebral ischemia.

BACKGROUND AND PURPOSE: The objective of this study was to evaluate the yield of emergent transcranial Doppler (TCD) for the evaluation of acute cerebral ischemia. METHODS: We performed urgent bedside non-contrast-enhanced TCD in patients with acute cerebral ischemia before or immediately after baseline CT scanning. A fast-track scanning protocol (

Orthostatic intolerance in the chronic fatigue syndrome.

This study aims to investigate the prevalence and pathophysiology of orthostatic intolerance (OI) and its potential contribution to symptoms of a group of unselected patients with chronic fatigue syndrome (CFS). Seventy five patients (65 women, 10 men) with CFS were evaluated. During an initial visit, a clinical suspicion as to the likelihood of observing laboratory evidence of OI was assigned. Laboratory investigation consisted of beat-to-beat recordings of heart rate, blood pressure (Finapres), and stroke volume (impedance cardiograph) while supine and during 80 degrees head-up tilt (HUT), during rhythmic deep breathing (6 breaths/min) and during the Valsalva maneuver. The responses of 48 age-matched healthy controls who had no history of OI were used to define the range of normal responses to these three maneuvers. Forty percent of patients with CFS had OI during head-up tilt. Sixteen exhibited neurally-mediated syncope alone, seven tachycardia (> 35 bpm averaged over the whole of the head-up tilt) and six a mixture of tachycardia and syncope. Eight of 48 controls exhibited neurally-mediated syncope. The responses to the Valsalva maneuver and to deep breathing were similar in controls and patients. On average, the duration of disease and patient age were significantly less and the onset of symptoms was more often subacute in patients with OI than in those without OI. We conclude that there exists a clinically identifiable subgroup of patients with CFS and OI that differs from control subjects and from those with CFS without OI for whom treatment specifically aimed at improving orthostatic tolerance may be indicated.

Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke.

BACKGROUND AND PURPOSE: Five pretreatment variables (P<0.1 univariate analysis), including serum glucose (>300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated <3 hours from onset with intravenous rtPA at 2 institutions to evaluate the role of these variables in predicting ICH. METHODS: Baseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. RESULTS: Symptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1. 08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis. CONCLUSIONS: Serum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.

Neurologic complications after coronary artery bypass grafting.

Although outcomes from coronary artery bypass grafting (CABG) surgery have improved in general, there has been little or no improvement in the incidence of postoperative stroke or neurologic dysfunction. Several studies have identified factors that increase the CABG patient's risk for developing a stroke and neurologic complications. It is important to identify those patients at increased risk and differentiate among stroke, delirium, and seizures. Post-CABG patients need to be monitored for neurological dysfunction with appropriate assessments. Neurologic complications must be appropriately managed to optimize patient recovery.

Thrombolysis, stroke units and other strategies for reducing acute stroke costs.

Stroke is the leading cause of long term disability and the third leading cause of death in the US. Nearly $US40.9 billion (1997 values) are spent each year on direct and indirect stroke-related costs in the US alone. Length of hospital stay, hospital overheads and nursing-related and rehabilitation costs account for the majority of stroke-related expenditures. Intravenous recombinant tissue plasminogen activator (rt-PA) therapy for patients presenting within 3 hours from onset of ischaemic stroke was shown to improve outcome at 3 months by the National Institute of Neurological Disease and Stroke (NINDS) investigators using a dosage of 0.9 mg/kg. When the NINDS rt-PA Stroke Study results were examined using a Markov model, savings of $US4 to $US5 million (1996 values) per 1000 patients treated with rt-PA were projected. These savings were predicted to result from decreases in length of hospital stay, inpatient rehabilitation and nursing home costs, increases in the number of patients discharged directly to home and improvements in quality-adjusted life-years. Furthermore, a recent meta-analysis has documented that the institution of stroke units, consisting of multidisciplinary specialised stroke teams, also decreased length of hospital stay, death and dependency. Because only a minority of patients who have a stroke are currently eligible for thrombolysis, implementation of specialised and standardised stroke care may further enhance cost benefits and improve patient outcomes.

Cerebrovascular and cardiovascular measurements during neurally mediated syncope induced by head-up tilt.

BACKGROUND AND PURPOSE: This study examines changes in systemic hemodynamics and in cerebral blood velocity that occur during neurally mediated syncope (NMS) to determine whether cerebral autoregulation is intact or impaired in patients with recurrent NMS. METHODS: Beat-to-beat recordings of heart rate, blood pressure (volume clamp photoplethysmography), stroke volume (impedance cardiography), and right middle cerebral artery blood velocity (transcranial Doppler sonography) were performed at rest and during 80 degrees head-up tilt. Twelve patients with NMS and 10 healthy control subjects were studied. RESULTS: Baseline values and the initial response to head-up tilt of control subjects and patients with NMS were similar. The mean latency to onset of syncope was 11.8 +/- 11.1 minutes. At syncope, heart rate, systolic and diastolic blood pressure, and diastolic cerebral blood velocity decreased significantly, whereas systolic cerebral blood velocity did not change. Calculated cerebrovascular resistance was significantly reduced from 1.85 +/- 0.60 to 1.32 +/- 0.27 mm Hg/cm per second, whereas the pulsatility index increased from 0.92 +/- 0.16 to 1.52 +/- 0.21. We never observed a change in cerebral blood velocity before the rapid decline in blood pressure, nor did we observe any significant change in respiratory pattern. CONCLUSIONS: The decrease in cerebrovascular resistance during NMS indicates that the integrity of cerebrovascular autoregulation is maintained even when syncope is imminent. The selective loss of diastolic flow during syncope and the increase in pulsatility index are likely caused by collapse of downstream vessels as diastolic blood pressure decreases below the critical closing pressure of cerebral vessels.