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Biomedical subjects

D L Arnold

Publications and source records attributed to D L Arnold.

At least 73 records · Page 4Linked to original sources
PubMed1999

Magnetic resonance spectroscopy: imaging axonal damage in MS.

Recent observations made using magnetic resonance spectroscopy to measure the axonal marker N-acetylaspartate have emphasized the fact that substantial axonal damage occurs in multiple sclerosis, in addition to demyelination. The axonal damage is present both in lesions and normal appearing white matter, progresses over time, and correlates with clinical disability. These observations, together with observations demonstrating that adaptations of sodium channels can restore conduction in demyelinated axons, have led to the hypothesis that axonal damage may be responsible for a significant proportion of the chronic disability that accrues in MS.

Axons↗
PubMed1999

Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders.

The use of magnetism in medicine has a long and colorful history since its legendary discovery in the Western world by the shepherd Magnes. More recent use of magnetism has centered on nuclear magnetic resonance. Magnetic resonance spectroscopy (MRS) provides chemical information on tissue metabolites. Both hydrogen 1 (1H) and phosphorus 31 resonances have been used to study brain tissue, but the magnetic resonance sensitivity for protons is far greater than it is for phosphorus. One of the most important contributions of 1H-MRS to clinical neurology is its ability to quantify neuronal loss and to demonstrate reversible neuronal damage. 1H-magnetic resonance spectroscopy has been found to be a useful research tool in elucidating the pathophysiology underlying certain diseases. This review focuses on the use of proton MRS to study various neurologic diseases, including epilepsy, multiple sclerosis, brain tumors, human immunodeficiency virus 1-associated neurologic disorders, as well as cerebrovascular, neurodegenerative, and metabolic diseases. It highlights the contributions of 1H-MRS to the diagnosis and the monitoring of these neurologic diseases that make it a useful adjunct in patient management.

Aspartic Acid↗
PubMed1999

Short-term aerobic training response in chronic myopathies.

We have previously demonstrated that patients with mitochondrial myopathies can benefit from short-term aerobic exercise training. In this study, we compared the responses to short-term aerobic training of patients with mitochondrial myopathies, patients with nonmetabolic myopathies, and sedentary normal subjects. Training consisted of 8 weeks of treadmill exercise at 70% to 85% of estimated maximum heart rate reserve. All groups showed significant improvements in estimated aerobic capacity as well as heart rate and blood lactate at submaximal exercise intensities. The increase in estimated aerobic capacity was greater in the mitochondrial myopathy patients than in the other two groups. Phosphorus magnetic resonance spectroscopy demonstrated increased oxidative capacity of muscle in patients with mitochondrial myopathies in response to this training but not in patients with other, nonmetabolic myopathies or sedentary control subjects. A self-assessed measurement of functional status (SF-36) suggested improved quality of life associated with the training. This study demonstrates that short-term aerobic training at low intensity can benefit patients with nonmetabolic myopathies but to a lesser extent than patients with mitochondrial myopathies.

Adolescent↗
PubMed1999

Fitting cytosolic ADP recovery after exercise with a step response function.

Phosphorus magnetic resonance (MR) spectroscopy was used to measure the recovery kinetics of calculated cytoplasmic metabolically active adenosine diphosphate (ADP) after exercise in normal subjects and patients with mitochondrial myopathies. These kinetics have previously been fitted with a single exponential function, despite a complex time-dependent undershoot in many subjects. By considering the transition from ischemic-exercise to perfused-recovery as a step function input, a second-order linear system was developed yielding a step response function to fit the ADP recovery. Using this method, an average improvement in fit of 23% resulted in a significant improvement in the characterization of ADP recovery for all normal subjects with substantial undershoot. The patient group had a comparable improvement in fit of 11%. Fitting the ADP recovery with a second-order step response function can provide significantly better characterization of muscle oxidative metabolism in vivo.

Adenosine Diphosphate↗
PubMed1999

Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy.

Whether temporal lobe epilepsy is the result of an isolated, early injury or whether there is ongoing neuronal dysfunction or loss due to seizures is often debated. We attempt to address this issue by using magnetic resonance techniques. Proton magnetic resonance spectroscopic imaging can detect and quantify focal neuronal dysfunction or loss based on reduced signals from the neuronal marker N-acetylaspartate (NAA), and magnetic resonance imaging (MRI)-based measurements of hippocampal volumes (MRIvol) can quantify the amount of atrophy in this structure. We performed magnetic resonance spectroscopic imaging and MRIvol in 82 consecutive patients with medically intractable temporal lobe epilepsy to determine whether there was a correlation between seizure frequency, or type or duration of epilepsy, with NAA to creatine (Cr) values or hippocampal volumes. Volumes and spectroscopic resonance intensities were categorized as to whether they were measured from the temporal lobe ipsilateral or contralateral to the predominant electroencephalographic focus. Ipsilateral and contralateral NAA/Cr was negatively correlated with duration of epilepsy. Hippocampal volumes were negatively correlated with duration ipsilaterally but not contralaterally. Frequency of complex partial seizures was not correlated with any of the magnetic resonance measures. However, patients with frequent generalized tonic-clonic seizures had lower NAA/Cr bilaterally and smaller hippocampal volumes ipsilaterally than patients with none or rare generalized tonic-clonic seizures. The results suggest that although an early, fixed injury may cause asymmetric temporal lobe damage, generalized seizures may also cause progressive neuronal dysfunction or loss.

Adult↗
PubMed1999

Biological markers in the diagnosis and treatment of ALS.

The care of patients with amyotrophic lateral sclerosis (ALS), which has classically focused on treatment of symptomatology, has now entered an encouraging new era of therapy targeted at the pathophysiology of the disease. However, an objective measure of disease progression and therapeutic response is sorely needed. Quantitative neuromuscular examinations, measurement of pulmonary function, disability scales, and even survival, are limited by variability due to a number of poorly controlled factors. Quantitative electromyography, positron emission tomography scanning, and magnetic cortical stimulation, provide potential objective indicators of disease progression, but require a large number of patients and a long observation period for adequate statistical power. We have examined the role of magnetic resonance spectroscopic imaging in detecting acute changes in motor cortical metabolism in response to riluzole therapy. N-acetylaspartate (NAA), the most prominent signal in proton spectra of normal brain, is a neuron-specific molecule. ALS patients were found to experience a significant increase in the NAA/creatine ratio within 3 weeks of initiation of riluzole therapy. As glutamate can trigger the generation of reactive oxygen species in neurons, we speculate that acute changes in NAA levels may reflect oxidative injury to mitochondria where NAA is synthesised. The advent of a useful test for upper motor neuron metabolic compromise may provide an objective, non-invasive, short duration measure with which to screen the efficacy of potential therapeutic agents for ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1999

In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis.

To test for axonal damage or dysfunction in white matter tracts remote from acute demyelinating lesions, we used brain proton magnetic resonance spectroscopic imaging to measure changes in N-acetyl aspartate (NAA), an index of neuronal integrity, in the white matter of the normal-appearing hemisphere of three patients with large, solitary brain demyelinating lesions of the type seen early in multiple sclerosis. During the acute phase of their disease, all patients showed normal ratios of NAA to creatine (Cr) resonance intensity throughout the hemisphere contralateral to the lesion. However, on examination 1 month later, all of the patients showed abnormally low NAA/Cr resonance intensity ratios (reduction of NAA/Cr by 22-35%) in voxels of the contralateral hemisphere which were homologous to the demyelinating lesion. Other voxels in the normal-appearing hemisphere showed normal NAA relative resonance intensities. The decrease in NAA/Cr in voxels of the normal-appearing hemispheres resolved in all patients after 6 months, with a time course similar to that observed for NAA from voxels within the lesions. We conclude that effects of damage or dysfunction to axons traversing inflammatory lesions can be transmitted over long distances in the normal-appearing white matter. Such remote, secondary effects may be an expression of dysfunction of axons in projection pathways or of the reorganization of functional pathways seen in brains recovering from an acute injury.

Acute Disease↗
PubMed1999

Surgical outcome in patients with epilepsy and dual pathology.

High-resolution MRI can detect dual pathology (an extrahippocampal lesion plus hippocampal atrophy) in about 5-20% of patients with refractory partial epilepsy referred for surgical evaluation. We report the results of 41 surgical interventions in 38 adults (mean age 31 years, range 14-63 years) with dual pathology. Three patients had two operations. The mean postoperative follow-up was 37 months (range 12-180 months). The extrahippocampal lesions were cortical dysgenesis in 15, tumour in 10, contusion/infarct in eight and vascular malformation in five patients. The surgical approach aimed to remove what was considered to be the most epileptogenic lesion, and the 41 operations were classified into lesionectomy (removal of an extrahippocampal lesion); mesial temporal resection (removal of an atrophic hippocampus); and lesionectomy plus mesial temporal resection (removal of both the lesion and the atrophic hippocampus). Lesionectomy plus mesial temporal resection resulted in complete freedom from seizures in 11/15 (73%) patients, while only 2/10 (20%) patients who had mesial temporal resection alone and 2/16 (12.5%) who had a lesionectomy alone were seizure-free (P < 0.001). When classes I and II were considered together results improved to 86, 30 and 31%, respectively. Our findings indicate that in patients with dual pathology removal of both the lesion and the atrophic hippocampus is the best surgical approach and should be considered whenever possible.

Adolescent↗
PubMed1999

Spatial mapping of T2 and gadolinium-enhancing T1 lesion volumes in multiple sclerosis: evidence for distinct mechanisms of lesion genesis?

It is generally believed that most T2-weighted (T2) lesions in the central white matter of patients with multiple sclerosis begin with a variable period of T1-weighted (T1) gadolinium (Gd) enhancement and that T1 Gd-enhancing and T2 lesions represent stages of a single pathological process. Lesion probability maps can be used to test this hypothesis by providing a quantitative description of the spatial distribution of these two types of lesions across a patient population. The simplest prediction of this hypothesis would be that the spatial distributions of T1 Gd-enhancing and T2 lesions are identical. We generated T1 Gd-enhancing and T2 lesion probability maps from 19 patients with relapsing-remitting multiple sclerosis. There was a significantly higher probability (P = 0.001) for T2 lesions to be found in the central relative to the peripheral white matter (risk ratio 4.5), although the relative distribution of T1 Gd-enhancing lesions was not significantly different (P = 0.7) between central and peripheral white matter regions (risk ratio 0.6). Longitudinal data on the same population were used to demonstrate a similar distribution asymmetry between new T1 Gd-enhancing and new T2 lesions that developed over the course of 1 year. Alternative hypotheses to explain this observation were tested. We found no spatial difference in the likelihood of development of persistent T2 lesions following T1 Gd enhancement. The relative distribution of T1 Gd-enhancing lesions was shown to be independent of the dose of Gd contrast agent and the frequency of scanning. Our findings suggest that a proportion of the periventricular T2 lesion volume may arise from mechanisms other than those associated with early breakdown of the blood-brain barrier leading to T1 Gd enhancement.

Adult↗
PubMed1999

A dispensable region of the chromosome which is associated with an avirulence gene in Pseudomonas syringae pv. pisi.

Pseudomonas syringae pv. pisi comprises a number of races which fall into two phylogenetically distinct groups (designated I and II). Races are based on cultivar specificity in the host plant, pea (Pisum sativum), and are specified by the presence of avirulence genes. The avirulence gene avrPpiA1 is present on the chromosome of all strains examined in race 2, which belongs to phylogenetic group II. A race 4B strain, from phylogenetic group I, lacks this avirulence gene and a comparative study was made of the chromosome in strains representing these two races. A race 2 cosmid clone (pAV270) carrying avrPpiA1 was used as a basis for collinearity analysis of races 2 and 4B. A region of the chromosome amounting to 8.5 kb and including avrPpiA1 was absent from race 4B compared with race 2. A fragment spanning the junction of the discontinuity in race 4B was isolated, cloned and used to delimit the extent of the additional DNA present in race 2. In both races the borders of the discontinuity contained DNA sequences which showed a high degree of conservation. A 7 bp slightly imperfect direct repeat (CCAGC(T)/(A)T) flanked the additional DNA in race 2, with a single copy in race 4B. The region flanking the additional DNA was present in all races of P. syringae pv. pisi. These results confirm the phylogenetic groupings in P. syringae pv. pisi.

Base Sequence↗
PubMed1999

Relation of interictal spike frequency to 1H-MRSI-measured NAA/Cr.

PURPOSE: Whereas EEG spiking and decreases of the neuronal marker N-acetyl-aspartate (NAA) both localize well the epileptic focus, the significance of the intensity of these variables is unclear. Therefore we investigated whether the frequency of interictal surface spikes is related to the degree of N-acetyl-aspartate/creatine (NAA/Cr) ratio decrease as measured by proton magnetic resonance (MR) spectroscopic imaging (1H-MRSI) in patients with intractable partial epilepsy. METHODS: We retrospectively studied 14 patients, nine with temporal lobe epilepsy and five with frontal lobe epilepsy. Spikes that occurred during prolonged video-EEG monitoring from electrodes placed according to the International 10-20 system were counted blinded to the 1H-MRSI results. Eight electrode positions (F3/4, C3/4, T3/4, T5/6) were assigned to underlying brain subregions in the 1H-MRSI volume of interest. We converted NAA/Cr ratios into z-scores (NAA/Cr(z)) to compared NAA/Cr values directly across subregions. We calculated Spearman rank-order (p) and Pearson product-moment (r) correlations between spike frequency and NAA/Cr(z) values overall, as well as within each brain subregion. RESULTS: We found an overall negative relation between spike-frequency data and NAA/Cr(z) data (p = -0.341). When analyzing only spiking subregions, this negative relation became slightly stronger (p = -0.442; r = -0.338). When data from the eight sites were considered separately, this negative relation remained in most instances. CONCLUSIONS: Our results reveal a trend toward higher interictal spike frequencies on surface EEG in regions of pronounced neuronal metabolic damage or dysfunction. This suggests that both variables parallel an underlying pathologic substrate, although the pathophysiologic processes may be distinct.

Adolescent↗
PubMed1999

Combined magnetization transfer and proton spectroscopic imaging in the assessment of pathologic brain lesions in multiple sclerosis.

BACKGROUND AND PURPOSE: Conventional MR imaging of multiple sclerosis (MS) provides relatively poor pathologic specificity, which has led to the investigation of more sophisticated MR techniques. The purpose of this study was to combine magnetization transfer (MT) imaging and proton MR spectroscopic imaging (MRSI) to evaluate the specific pathologic features of myelination and neuronal integrity in patients with MS and to determine the relationship between these measures within plaques. METHODS: We acquired conventional MR, MT, and proton MRSI data and evaluated clinical disability in 30 patients with MS, whose conditions were categorized as relapsing-remitting, primary progressive, or secondary progressive. The lesions were classified, using a semiautomated edge-following technique, on T2-weighted MR images, and an analysis of MT and proton MRSI data was conducted for lesion regions as well as for tissue that was categorized as normal. RESULTS: The MT ratio (MTR) of normal-appearing white matter in the patients with MS was significantly lower than in the healthy participants, whereas gray matter values were unchanged. MS lesions showed a large reduction in MTR, with old lesions exhibiting a lower MTR than new lesions. The average lesion MTR and the MR spectroscopic imaging-measured relative concentration of N-acetylaspartate, a marker of neuronal integrity, was positively correlated in patients with relapsing-remitting MS. This relationship was strengthened in regions containing new lesions. CONCLUSION: The integrated use of MT and MR spectroscopic imaging provides a more complete description of the pathologic features of MS than does conventional MR imaging alone, and our data suggest that axonal damage occurs in step with new demyelination and is not a late feature of the disease.

Adult↗
PubMed1998

Recovery of N-acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy.

Riluzole, a glutamate antagonist, has been shown to be efficacious in the treatment of patients with amyotrophic lateral sclerosis (ALS), allowing prolonged survival and time to tracheostomy. The efficacy of riluzole in thought to result from reduced glutamate excitotoxicity on motor neurons of patients with ALS, but this has never been demonstrated directly in vivo. N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sublethal injury. To determine whether riluzole reverses sublethal corticomotoneuron damage in patients with ALS we measured NAA/creatine (Cr) relative intensity ratios in the motor cortex before and after treatment with riluzole 50 mg bid. After 3 weeks of riluzole therapy in 11 patients NAA/Cr increased from 2.14 +/- 0.26 to 2.27 +/- 0.24 (p = 0.044), whereas, in 12 untreated patients NAA/Cr decreased from 2.17 +/- 0.20 to 2.08 +/- 0.20 (p = 0.099). Thus the change in NAA/Cr between the treated and untreated groups was 0.22 +/- 0.095 (p = 0.008). The magnitude of increase in NAA/Cr in those treated was not correlated with age, sex, duration of treatment or disease, the presence of probable or definite upper motor neuron (UMN) signs, bulbar features, or pre-treatment NAA/Cr. We conclude that magnetic resonance spectroscopy can provide a novel surrogate measure of neuronal integrity that demonstrates reversal of sublethal UMN injury in patients with ALS within weeks of initiating riluzole therapy.

Adult↗
PubMed1998

Intracellular phosphates in inclusion body myositis--a 31P magnetic resonance spectroscopy study.

Muscle phosphorus magnetic resonance spectroscopy was used to study oxidative metabolism at rest and during recovery from exercise in 7 patients with sporadic inclusion body myositis (s-IBM), compared with normal controls (n=8) and mitochondrial myopathies (n=20). At rest, 6/7 patients had elevated inorganic phosphates. Recovery parameters were not different from controls, in contrast with mitochondrial myopathies, who showed abnormal rest and recovery. The normal recovery suggests that mitochondrial oxidative capacity is not impaired in s-IBM.

Aged↗
PubMed1998

In vivo differentiation of astrocytic brain tumors and isolated demyelinating lesions of the type seen in multiple sclerosis using 1H magnetic resonance spectroscopic imaging.

We used computer pattern recognition of proton magnetic resonance spectroscopic image data to differentiate between brain tumors and large, isolated, demyelinating lesions of the type seen in multiple sclerosis. Leave-one-out linear discriminant analyses correctly classified resonance profiles from five acute demyelinating lesions, 20 low-grade astrocytomas, 22 anoplastic astrocytomas, and 24 glioblastomas. Classification of nonacute lesions will require further development, as the metabolic profiles of demyelinating lesions evolve over time.

Adult↗
PubMed1998

A multigeneration study to ascertain the toxicological effects of Great Lakes salmon fed to rats: study overview and design.

Fish from the Great Lakes can be contaminated with a plethora of industrial, agricultural, and environmental chemicals. These chemicals have been associated with reproductive and other toxicological effects in fish and fish-eating birds found in the Great Lakes basin. To obtain more insight into this association, several laboratory studies have been undertaken wherein fish have been incorporated into the experimental diets to determine the effect of their ingestion upon the test animals. In addition, several human epidemiological studies have found correlations between Great Lakes fish consumption and effects in neonates which have been attributed to polychlorinated biphenyls without any appreciable consideration as to what synergistic or antagonistic effects other chemicals or heavy metals may or may not have contributed to the observed findings. Herein is presented the design of a two-generation feeding-reproduction study that incorporated lyophilized chinook salmon (Oncorhynchus tsawytscha) fillets into the diets of Sprague-Dawley rats. The findings of this study will be presented in the sections which follow.

Animal Feed↗
PubMed1998

The toxicological effects following the ingestion of chinook salmon from the Great Lakes by Sprague-Dawley rats during a two-generation feeding-reproduction study.

A two-generation reproduction-feeding study was undertaken with Sprague-Dawley rats to ascertain the effects of ingesting chinook salmon fillets caught in the Credit River, which empties into Lake Ontario (LO), or in the Owen Sound region of Lake Huron (LH). Rats (30/sex/group) were randomly assigned to groups whose dietary protein consisted of casein and/or lyophilized salmon [Group 1: 20% casein (controls); Group 2: 15% casein + 5% LO salmon (LO-5%); Group 3: 20% LO salmon (LO-20%); Group 4: 15% casein + 5% LH salmon (LH-5%); Group 5: 20% LH salmon (LH-20%)]. After 70 days on test, the males and females were mated on a 1:1 basis within diet groups. Approximately 70 days postweaning, one F1 male and one F1 female from 24 litters were mated within diet groups, avoiding sibling matings. At weaning, the F0 and F1 adults and the F1 and F2 neonates not randomly selected for further testing were necropsied. Evaluated parameters included growth, feed consumption, organ weights, reproduction indices, serum chemistry, hematology, and coagulation times. The only statistically significant effects which were present in both generations were increased relative liver and kidney weights of both sexes in the LO-20% and LH-20% groups; the LH-20% females had lower alanine transaminase activity than the controls; the controls had lower creatinine levels than the fish groups and the LO-20% females; the LH-20% and LO-20% males had a lower blood urea nitrogen than the controls; and the LH-20% females had a heavier terminal body weight than the controls and a lower number of red blood cells, hematocrit, hemoglobin values, and mean platelet volume. There was a tendency for the fish-fed groups to grow faster, eat more feed, and have larger litters with heavier pups. Overall, there was little to suggest that the myriad of contaminants in chinook salmon from the Great Lakes presented an appreciable toxicological risk to Sprague-Dawley growth and reproduction.

Animal Feed↗