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Properties of thermally grown aluminum oxide tunnel barriers are investigated and reported.

Background: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS., Objective: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure., Design: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization., Results: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS., Conclusions: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNbeta-1a (Avonex) in relapsing- remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing--remitting MS.

Background: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value., Methods: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis., Results: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months., Conclusions: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

This randomized, double-blind, placebo-controlled study was aimed at detecting cerebrovascular effects of isradipine and enalapril in patients with moderate hypertension depending on the presence and grade on unilateral stenosis of internal carotid artery (ICA). We evaluated carotid vascular resistance by using Doppler analysis and regional cerebral blood flow (rCBF) by using 133Xe-clearance technique before and after a single 5-mg oral dose of isradipine, enalapril, or placebo. Their effects were randomly and consecutively tested in 73 patients with essential hypertension subdivided into three groups: without carotid occlusive lesions, with moderate (50-75%), and with severe (76-99%) unilateral asymptomatic ICA stenosis. There were no differences in age, gender, and antihypertensive effects of the drugs between these three subgroups. Three major variants of cerebrovascular drug effects were observed: absence of changes (variant I), decrease in carotid vascular resistance with increase in rCBF and elimination of side-to-side asymmetry (variant II), and increase in carotid vascular resistance with further reduction of rCBF ipsilaterally ICA stenosis, and increased side-to-side asymmetry (variant III). Frequency of variant III was significantly higher in patients with severe ICA stenosis. Enalapril produced variant I of cerebrovascular effects in most patients examined; variant III was observed only in 13% of patients with severe ICA stenosis. Isradipine produced variant I of cerebrovascular effects much less frequently than did enalapril. For this drug, variant II was most typical in patients without ICA stenosis and with moderate ICA stenosis. In 43.5% of patients with severe ICA stenosis, however, isradipine produced reduction of cerebral perfusion. Presumably the presence of ICA stenosis, especially >75%, increases the risk of cerebrovascular disorders in antihypertensive therapy. In patients with severe ICA stenosis, treatment with enalapril appears to be safer than that with isradipine.

Regional cerebral blood flow (rCBF) in 75 patients with arterial hypertension and symptoms of chronic ischemic cerebrovascular disorders was studied by using the 133Xenon infusion technique and a 30-detector setup. A baseline decrease in the mean hemispheric blood flow (rCBFh) with elevated deviations of rCBF from rCBFh were observed in the hemispheres. A single oral dose of either nifedipine or nicardipine induced various changes in rCBF. The drug effects regarding changes in the mean value of the hemispheric blood flow and the flow distribution were classified into 4 types. A decrease in the deviation of rCBF from the hemispheric mean CBF accompanied by an increase in the total brain blood flow was considered to be the most beneficial drug effect. This positive reaction was found more frequently when patients were given nicardipine. In some patients both drugs induced nonbeneficial changes in rCBF with an increase in the number of ischemic and hyperemic regions. It was hypothesized that such variants of drug effects may result in the deterioration of brain perfusion, contributing to development of focal brain ischemic damages. The effects of drugs were similar after both single doses and 2-week monotherapy. It is suggested that the analysis of drug effects on regional CBF distribution may be useful for estimating clinical importance of changes in cerebral hemodynamics during antihypertensive therapy.

Background and Purpose: This study was performed to study the dynamics of polymorphonuclear leukocyte (PMNL) accumulation in human cerebral infarction and its association with neurological outcome and brain lesion., Methods: A total of 88 patients diagnosed as having hemispheric ischemic stroke were examined. PMNL accumulation was studied using technetium-99m hexamethylpropyleneamine oxime (99mTc HMPAO)-labeled leukocyte brain single-photon emission computed tomography (SPECT). Volume of brain infarction was evaluated by CT scan. The Mathew Scale was used for neurological assessment. Dynamics of PMNL accumulation was studied at 3 to 6, 6 to 12, and 12 to 24 hours and 6 to 9, 28 to 30, and 90 days after stroke onset. In parallel, at admission, at 6 to 9 days, and at 28 to 30 days neurological outcome and infarction volume were evaluated., Results: Generally, PMNL accumulation progressively increased during 6 to 24 hours after stroke, remained at a high level up to 6 to 9 days and then declined. With the use of cluster analysis, all patients were subdivided into three groups: patients with severe PMNL accumulation that dramatically increased within 12 hours after stroke onset and persisted even at 28 to 30 days (group A); those with moderate PMNL accumulation that significantly decreased at 30 days (group B); and those with mild PMNL accumulation that decreased at 6 to 9 days (group C). Baseline neurological deficit and brain tissue damage at admission appear to be at a similar level for all groups of patients. In dynamics, however, in patients with severe PMNL accumulation, neurological outcome was worse and infarction volume larger than in patients with less marked PMNL accumulation., Conclusions: The present clinical study confirms that PMNLs intensively accumulate in the regions of cerebral infarction. The present study revealed that this accumulation correlated with the severity of the brain tissue damage and poor neurological outcome.

Positron emission tomography (PET) studies measuring glucose utilization have demonstrated cerebral hypometabolism in Alzheimer's disease (AD). The anatomic and biochemical basis for this observation remains unknown. We have examined the distribution in the hippocampal formation of the neuron-specific glucose transporter 3 (Glut3) protein. Using quantitative immunohistochemistry, we find a large reduction (49.5%) in Glut3 immunoreactivity in the outer portion of the molecular layer of the dentate gyrus in AD brains. This region corresponds to the terminal zone of the perforant pathway, whose cells of origin in layer II of the entorhinal cortex are selectively destroyed in AD. Because glucose uptake reflects metabolic demand, these results suggest a decrement of functional activity in the deafferented dentate gyrus granule cells. Generalizing from this observation, decreased glucose uptake seen on PET studies may reflect, in part, decreased glucose transport and utilization in functionally deafferented cortical fields.

The activity of cytochrome oxidase (CO), the terminal enzyme of the electron transport chain, has been reported to be decreased in the brains of individuals with Alzheimer's disease (AD). In experimental models, CO activity decreases following functional deafferentation of neural circuits. CO is a holoenzyme composed of 13 nuclear- and mitochondrial-encoded subunits and experimental data indicate that the change in CO activity following deafferented is controlled primarily by regulation of mitochondrial CO gene expression. It has been proposed that the hippocampal formation is deafferented in AD. We therefore hypothesized that an alteration in mitochondrial CO gene expression might underlie the reduction in CO activity in AD. Using in situ hybridization, we found a selective reduction in mRNA levels for a mitochondrial-encoded subunit, CO II, with preservation of mRNA for a nuclear-encoded subunit, CO IV, in the hippocampal formation of individuals with AD. The reduction in CO II mRNA levels was seen both in regions with neurofibrillary tangles, senile plaques, and neuronal loss and regions relatively spared from these neuropathological changes. These data suggest that the reduction in CO activity in brain regions from individuals with AD may be a result of an alteration in mitochondrial CO gene expression that extends beyond neurons directly affected by structural pathology.

An encephalopathy characterized by confusion, stupor, and mutism frequently occurs during administration of the chemotherapeutic drug ifosfamide (IFX). We investigated two patients who developed encephalopathy during IFX infusion. Both exhibited a rapid and near-complete restoration of baseline mental status functioning concurrent with EEG improvement after administration of intravenous diazepam. We recommend an EEG and trial of benzodiazepines in patients with IFX encephalopathy.

In Alzheimer's disease, the relationship between structural alterations such as neurofibrillary tangles and senile plaques and neuronal function is unknown. Cytochrome oxidase, the terminal enzyme of the electron transport, is a marker of neuronal functional activity. Its activity is diminished in experimentally deafferented neurons. Based on evidence that the molecular layer of the dentate gyrus is deafferented in the brains of individuals with Alzheimer's disease, we hypothesized that cytochrome oxidase activity would be diminished in this region secondary to reduced glutamatergic input. Using cytochrome oxidase histochemistry, we found a change in the distribution of cytochrome oxidase in the molecular layer of the dentate gyrus and a decrease in activity in both the dentate gyrus and hippocampal subfields in Alzheimer's disease. In contrast, we found relatively little structural pathology in the dentate gyrus, CA4, and CA3 in these individuals. These results suggest that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo changes in metabolic function as neural systems fail.

Exposure of neonatal Balb.B mice to a variant of Gross murine leukemia virus, termed WB91-GV, resulted in selective white matter infection within the central nervous system. Viral antigens were detected in brain sections of animals inoculated by either intracerebral or intraperitoneal routes, but were only seen in mice exposed within the first day after birth. This distinct tropism was confirmed by virus replication and gp70 expression in isolated glial cultures in vitro. Analysis of gp70 expression in highly enriched glial subpopulations indicated that oligodendrocytes and perhaps a subset of astrocytes were the targets of this infection.