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Biomedical subjects

David J Gladstone

Publications and source records attributed to David J Gladstone.

14 recordsLinked to original sources
PubMed2006

Intracerebral hemorrhage: outcomes and eligibility for factor VIIa treatment in a National Stroke Registry.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating form of stroke for which the lack of treatment options, high mortality rate, and the tendency to severely disable result in high social and economic burden. METHODS: We analyzed data in the Registry of the Canadian Stroke Network (RCSN). We sought to: (1) provide a descriptive analysis of ICH; (2) determine the proportion of ICH patients that might have been eligible for treatment with recombinant activated factor VII (rFVIIa) using criteria from a recent phase II trial; (3) compare 6-month outcomes of ICH patients with those of ischemic stroke patients, matched for gender, age, and stroke severity. RESULTS: In the RCSN, 11% of all strokes were nontraumatic ICH. The median Canadian Neurological Scale score was 7. A minority (33%) of patients arrived to the emergency department in less than 3 h from onset. In this cohort, in-hospital mortality was 15%. At 6 months, a further 9% of patients had died and 58% had a slight to no disability (Stroke Impact Scale-16 score > or = 75). Approximately 20% of ICH patients would have been eligible for rFVIIa treatment. Compared to ischemic stroke, ICH showed a trend towards increased mortality at discharge (OR: 1.96, CI: 0.99-3.87). At 6-month follow-up, ICH showed increased mortality (OR: 2.27, CI: 1.29-3.97), yet functional outcomes were not significantly different. CONCLUSION: ICH patients had a higher case-fatality rate when compared to acute ischemic stroke, but survivors had similar functional outcomes. In Canada, about one fifth of ICH patients might potentially benefit from rFVIIa if it is approved, with the major exclusion factor being time.

Aged↗
PubMed2006

Turning a stroke into a TIA: curative thrombolysis with combined intravenous and intra-arterial tPA.

Intravenous tissue plasminogen activator (tPA) is standard treatment for eligible patients with acute ischemic stroke, but may be less effective for very severe strokes caused by proximal intracranial artery occlusions. We report the case of a woman with a devastating stroke who recovered completely following emergency revascularization of an occluded proximal middle cerebral artery using a novel treatment approach that combines both intravenous (i.v.) and intra-arterial (IA) tPA. This case illustrates the potential value of the combined i.v.-IA thrombolytic approach, which is an emerging investigational treatment strategy for selected patients with severe acute ischemic stroke.

Female↗
PubMed2006

Acquired Chiari malformation type I following fractionated radiation therapy to the anterior skull base in a 20-month-old boy. Case report.

The authors present the case of a 20-month-old boy who underwent fractionated radiation therapy to the paranasal sinuses and anterior skull base during treatment for nasopharyngeal parameningeal rhabdomyosarcoma. Subsequent magnetic resonance imaging demonstrated progressive development of a Chiari malformation Type I (CM-I) and partial hypoplasia of the posterior fossa. Since the tonsillar herniation was discovered, the child, now 3 years old, remains asymptomatic except for mild, intermittent neck discomfort. For the time being, his family has elected for him to undergo clinical and neuroimaging follow up. The authors believe this is the first report of a progressive acquired CM-I after cranial irradiation in the pediatric population.

Arnold-Chiari Malformation↗
PubMed2005

Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Hemiparesis is the commonest disabling deficit caused by stroke. In animals, dextroamphetamine (AMPH) paired with training enhances motor recovery, but its clinical efficacy is uncertain. METHODS: In a randomized, double-blind, placebo-controlled trial, 71 stroke patients were stratified by hemiparesis severity and randomly assigned to 10 sessions of physiotherapy coupled with either 10 mg AMPH or placebo. Study treatments were administered by 1 physiotherapist, beginning 5 to 10 days after stroke and continuing twice per week for 5 weeks. Outcomes were assessed by 1 physiotherapist at baseline, after each treatment session, at 6 weeks, and at 3 months. The primary outcome was motor recovery (impairment level) on the Fugl-Meyer (FM) scale. Secondary outcomes assessed mobility, ambulation, arm/hand function, and independence in activities of daily living. RESULTS: Baseline hemiparesis was severe overall (mean FM score 27.7+/-20.0). Motor scores improved during treatment in both groups (mean change, baseline to 3 months 29.5+/-16.6). Repeated-measures ANOVA revealed no significant differences in recovery between the treatment groups for the entire cohort (n=67) or for subgroups with a severe hemiparesis (n=43), moderate hemiparesis (n=24), or cortically based stroke (n=26). In the moderate subgroup, there was a significant drug x time interaction for upper extremity motor recovery (F=5.14; P<0.001), although there was a significant baseline imbalance in motor scores in this subgroup. CONCLUSIONS: In stroke patients with a severe motor deficit, 10 mg AMPH coupled with physiotherapy twice per week for 5 weeks in the early poststroke period provided no additional benefit in motor or functional recovery compared with physiotherapy alone. Patients with moderate severity hemiparesis deserve further investigation. Increased intensity and longer duration drug/therapy dosing regimens should be explored, targeting the upper and lower limbs separately.

Aged↗
PubMed2005

Importance of protocol target definition on the ability to spare normal tissue: an IMRT and 3D-CRT planning comparison for intraorbital tumors.

PURPOSE: We selected five intraorbital tumor sites that are frequently found in clinical practice in children diagnosed with orbital rhabdomyosarcoma and performed three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated photon radiotherapy (IMRT) planning. Results of target coverage and doses to critical structures were compared. The goal of this study was to evaluate and to document realistic expectations as to organ-sparing capabilities of modern radiation therapy planning technologies with a focus on lens-sparing irradiation. Furthermore, we investigated potential added benefits of IMRT compared with 3D-CRT and the influence of protocol volume criteria definitions on the ability to obtain normal tissue dose sparing using the orbit as an example of a complex anatomic site. METHODS AND MATERIALS: The five intraorbital tumor sites were placed retrobulbar, temporal, nasal, in the upper inner and upper outer quadrant, the latter two more complex in shape. Gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) were defined in image-fused computed tomography and magnetic resonance data sets. 3D-CRT and IMRT photon plans, using equal beam angles and collimation for direct comparison, were designed to 45 Gy prescription dose according to Intergroup Rhabdomyosarcoma Study Group-D9602 (IRSG-D9602) protocol (Intergroup Rhabdomyosarcoma Study V [IRS-V] protocol) for Stage I, Clinical Group 3 orbital rhabdomyosarcoma. To compare the impact of changed target definitions in IMRT planning, additional IMRT plans were generated using modified volume and dose coverage criteria. The minimum dose constraint (95%) of the PTV was substituted by a required minimum volume coverage (95%) with the prescribed dose. Dose-volume histograms (DVHs) were obtained, including target volumes, lens, optic nerves, optic chiasm, lacrimal gland, bony orbit, pituitary gland, frontal and temporal lobes. RESULTS: Protocol target volume coverage criteria were fulfilled in all cases (5/5) with 3D-CRT and IMRT. Using the protocol criteria, lens sparing was achieved only for two tumor sites (retrobulbar and lateral position) with either planning technique. Mean lens doses were 8.5 and 10.4 Gy for 3D-CRT and 7.5 and 13.2 Gy for IMRT, respectively. The mean lens doses for the other three tumor locations averaged 26.8 Gy. IMRT plans reduced the lens dose in four of five cases by an average of 2.6 Gy compared with 3D-CRT. Modified target protocol prescription markedly reduced mean lens doses by 23-50% and by as much as 18 Gy. Recorded mean lens doses after protocol modification were 26% lower using IMRT plans compared with 3D-CRT. The cold spot as a result of the relaxed volume coverage requirements was within 2% of the original protocol criteria and located at the edge of the PTV, outside the CTV. Compared with 3D-CRT, IMRT resulted in an increase of brain volume receiving 10% (V10) and 20% (V20) of the prescribed dose. CONCLUSION: Strict adherence to IRS-V protocol criteria prohibits at present lens sparing within compliance criteria for the majority of intraorbital tumor locations because of protocol-specific CTV and PTV target definitions. Changing protocol definitions by prescribing to the volume rather than to a dose constraint, IMRT planning significantly reduced lens doses. This was not accomplished to the same degree with 3D-CRT. Our study underlines the importance of appropriate selection of planning objectives to maximize the specific capabilities and advantages of IMRT in terms of sufficient target coverage and simultaneous sparing of critical structures. Our results can add to the ongoing discussion in the design of future 3D-CRT/IMRT protocols.

Child↗
PubMed2004

Poststroke "pushing": natural history and relationship to motor and functional recovery.

BACKGROUND AND PURPOSE: Patients with hemiparetic stroke have impaired balance control. Some patients ("pushers") are resistant to accepting weight on and actively "push" away from the nonparetic side. This research identified pushers from stroke patients with moderate to severe hemiparesis and examined longitudinal changes in symptoms, level of impairment, and functional independence. METHODS: Prospective sample of hemiparetic stroke patients (n=65) located in Toronto, Canada. Detailed clinical assessments were performed within 10 days postonset, at 6 weeks, and at 3 months. RESULTS: At 1 week after stroke, 63% of patients demonstrated features of pushing. In 62% of pushers, symptoms resolved by 6 weeks, whereas in 21%, pushing symptoms persisted at 3 months. Motor recovery and functional abilities at 3 months were significantly lower among the pushers compared with the nonpushers. Pushers also had a significantly longer hospital length of stay (89 days versus 57 days). It is noteworthy that motor and functional recovery improved significantly over the 3-month study period for both pushers and nonpushers. CONCLUSIONS: Identification of stroke patients with pushing symptoms has prognostic implications for recovery. In light of this potential recovery, rehabilitation specialists need to refine treatment approaches for the pushers to further improve functional outcome.

Activities of Daily Living↗
PubMed2004

Radiation-induced cardiomyopathy as a function of radiation beam gating to the cardiac cycle.

Portions of the heart are often unavoidably included in the primary treatment volume during thoracic radiotherapy, and radiation-induced heart disease has been observed as a treatment-related complication. Such complications have been observed in humans following radiation therapy for Hodgkin's disease and treatment of the left breast for carcinoma. Recent attempts have been made to prevent re-stenosis following angioplasty procedures using external beam irradiation. These attempts were not successful, however, due to the large volume of heart included in the treatment field and subsequent cardiac morbidity. We suggest a mechanism for sparing the heart from radiation damage by synchronizing the radiation beam with the cardiac cycle and delivering radiation only when the heart is in a relatively hypoxic state. We present data from a rat model testing this hypothesis and show that radiation damage to the heart can be altered by synchronizing the radiation beam with the cardiac cycle. This technique may be useful in reducing radiation damage to the heart secondary to treatment for diseases such as Hodgkin's disease and breast cancer.

Angioplasty↗
PubMed2004

Management and outcomes of transient ischemic attacks in Ontario.

BACKGROUND: Canadian data on the characteristics, management and outcomes of patients with transient ischemic attack (TIA) are lacking. We studied prospectively a cohort of consecutive patients presenting with TIA to the emergency department of 4 regional stroke centres in Ontario. METHODS: Using data from the Ontario Stroke Registry linked with provincial administrative databases, we determined the short-term outcomes after TIA and assessed patient management in the emergency department and within 30 days after the index TIA. We compared the TIA patients with a cohort of patients who had ischemic stroke. RESULTS: Three-quarters of the TIA patients were discharged from the emergency department. After discharge, the 30-day stroke risk was 5% (13/265) overall and 8% (13/167) among those with a first-ever TIA; the 30-day risk of stroke or death was 9% (11/127) among the TIA patients with a speech deficit and 12% (9/76) among those with a motor deficit. Half of the cases of stroke occurred within the first 2 days after the TIA. Diagnostic investigations were underused in hospital and on an outpatient basis within 30 days after the index TIA, the rates being as follows: CT scanning, 58% (211/364); carotid Doppler ultrasonography, 44% (162/364); echocardiography, 19% (70/364); cerebral angiography, 5% (19/364); and MRI, 3% (11/364). Antithrombotic therapy was not prescribed for more than one-third of the patients at discharge. Carotid endarterectomy was performed in 2% within 90 days. INTERPRETATION: Patients in whom TIA is diagnosed in the emergency department have high immediate and short-term risks of stroke. However, their condition is underinvestigated and undertreated compared with stroke: many do not receive the minimum recommended diagnostic tests within 30 days. We need greater efforts to improve the timely delivery of care for TIA patients, along with investigation of treatments administered early after TIA to prevent stroke.

Adrenergic beta-Antagonists↗
PubMed2004

Non-invasive assessment of radiation injury with electrical impedance spectroscopy.

A detailed understanding of non-targeted normal tissue response is necessary for the optimization of radiation treatment plans in cancer therapy. In this study, we evaluate the ability of electrical impedance spectroscopy (EIS) to non-invasively determine and quantify the injury response in soft tissue after high dose rate (HDR) irradiation, which is characterized by large localized dose distributions possessing steep spatial gradients. The HDR after-loading technique was employed to irradiate small volumes of muscle tissue with single doses (26-52 Gy targeted 5 mm away from the source). Impedance measurements were performed on 29 rats at 1, 2 and 3 month post-irradiation, employing 31 frequencies in the 1 kHz to 1 MHz range. Over the first 3 months, conductivity increased by 48% and 26% following target doses of 52 Gy and 26 Gy 5 mm from the HDR source, respectively. Injury, assessed independently through a grid-based scoring method showed a quadratic dependence on distance from source. A significant injury (50% of cells atrophied, necrotic or degenerating) in 1.2% of the volume, accompanied by more diffuse injury (25% of cells atrophied, necrotic or degenerating) in 9% of the tissue produced a conductivity increase of 0.02 S m(-1) (8% over a baseline of 0.24 S m(-1)). This was not statistically significant at p = 0.01. Among treatment groups, injury differences in 22% of the volume led to statistically significant differences in conductivity of 0.07 S m(-1) (23% difference in conductivity). Despite limitations, the success of EIS in detecting responses in a fraction of the tissue probed, during these early post-irradiation time-points, is encouraging. Electrical impedance spectroscopy may provide a useful metric of atrophy and the development of fibrosis secondary to radiation that could be further developed into a low-cost imaging method for radiotherapy monitoring and assessment.

Animals↗
PubMed2002

Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions.

BACKGROUND: Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored. Summary of Review- In part 1, we review key challenges and complexities in translational stroke research by focusing on the "disconnect" in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often been limited by inappropriately long time windows, insufficient statistical power, insensitive outcome measures, inclusion of protocol violators, failure to target specific stroke subtypes, and failure to target the ischemic penumbra. In part 2, we explore new concepts in ischemic pathophysiology that should encourage us also to think beyond the hyperacute phase of ischemia and consider the design of trials that use multiagent therapy and exploit the capacity of the brain for neuroplasticity and repair. CONCLUSIONS: By recognizing the strengths and limitations of animal models of stroke and the shortcomings of previous clinical trials, we hope to move translational research forward for the development of new therapies for the acute and subacute stages after stroke.

Cell Death↗
PubMed2002

The fugl-meyer assessment of motor recovery after stroke: a critical review of its measurement properties.

Measurement of recovery after stroke is becoming increasingly important with the advent of new treatment options under investigation in stroke rehabilitation research. The Fugl-Meyer scale was developed as the first quantitative evaluative instrument for measuring sensorimotor stroke recovery, based on Twitchell and Brunnstrom's concept of sequential stages of motor return in the hemiplegic stroke patient. The Fugl-Meyer is a well-designed, feasible and efficient clinical examination method that has been tested widely in the stroke population. Its primary value is the 100-point motor domain, which has received the most extensive evaluation. Excellent interrater and intrarater reliability and construct validity have been demonstrated, and preliminary evidence suggests that the Fugl-Meyer assessment is responsive to change. Limitations of the motor domain include a ceiling effect, omission of some potentially relevant items, and weighting of the arm more than the leg. Further study should test performance of this scale in specific subgroups of stroke patients and better define its criterion validity, sensitivity to change, and minimal clinically important difference. Based on the available evidence, the Fugl-Meyer motor scale is recommended highly as a clinical and research tool for evaluating changes in motor impairment following stroke.

Disability Evaluation↗