Biomedical subjects

D L Arnold

Publications and source records attributed to D L Arnold.

At least 109 records · Page 6Linked to original sources

PubMed1997

Abnormal oxidative metabolism in exercise intolerance of undetermined origin.

Twenty-four patients with exercise intolerance of undetermined origin were examined by muscle phosphorus magnetic resonance spectroscopy (31P-MRS) to test for a possible underlying defect in oxidative metabolism. Results were compared to those of 37 normal controls and 22 patients with well-defined mitochondrial disorders. In 17 (71%) patients with exercise intolerance, ADP recovery after exercise, an index of mitochondrial function, was abnormally slow. The energy state of phosphate-containing metabolites at rest was abnormal in 33% of patients. In 17/22 patients with well-defined mitochondrial disorders, ADP recovery was similarly slow. Abnormalities at rest were slightly more prevalent (50%) in this group of patients. Other 31P-MRS measurements did not add to the overall sensitivity in detecting abnormalities in either of these groups. We suggest that many patients with exercise intolerance of undetermined cause may have impaired muscle oxidative metabolism, that is an important causative factor in the pathophysiology of their symptoms.

Adenosine Diphosphate↗

PubMed1997

Surgical treatment of patients with single and dual pathology: relevance of lesion and of hippocampal atrophy to seizure outcome.

Modern neuroimaging can disclose epileptogenic lesions in many patients with partial epilepsy and, at times, display the coexistence of hippocampal atrophy in addition to an extrahippocampal lesion (dual pathology). We studied the postoperative seizure outcome of 64 patients with lesional epilepsy (median follow-up, 30 months) and considered separately the surgical results in the 51 patients with a single lesion and in the 13 who had dual pathology. In patients with a single lesion, 85% were seizure free or significantly improved (Engel's class I-II) when the lesion was totally removed compared with only 40% when there was incomplete resection (p < 0.007). All three patients with dual pathology who had both the lesion and the atrophic hippocampus removed became seizure free. In contrast, only 2 of the 10 patients with dual pathology undergoing surgery aimed at the lesion or at the hippocampus alone became seizure free (p < 0.05), although 4 of them showed significant improvement (Engel's class II). We conclude that the outcome in patients with single epileptogenic lesions is usually dependent upon the completeness of lesion resection. In patients with dual pathology, surgery should, if possible, include resection of both the lesion and the atrophic hippocampus.

Adolescent↗

PubMed1997

Axonal dysfunction and disability in a relapse of multiple sclerosis: longitudinal study of a patient.

In a 6-year longitudinal study of a patient with relapsing progressive multiple sclerosis (MS), we used proton magnetic resonance spectroscopy to assess N-acetylaspartate (NAA) from a large central brain volume to evaluate the relationship between this marker of neuronal integrity and clinical disability. During the follow-up period, there was one major relapse and its subsequent partial remission. Changes in the brain NAA to creatine ratio correlated strongly with clinical disability (Spearman rank coefficient = -0.73, p < 0.001). We interpret this as evidence that axonal dysfunction or loss contributes to functional impairment of patients with MS. Because the NAA signal in the large volume of interest originated predominantly from white matter that appeared normal on conventional MRI, these results also suggest that some degree of axonal dysfunction may be widespread in acute, severe relapses.

Adult↗

PubMed1997

Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging.

Surgery is a safe and effective treatment for patients with temporal lobe epilepsy (TLE) who do not respond adequately to anticonvulsant medication and in whom the seizure generator can be identified and safely removed. Proton MR spectroscopic imaging (MRSI) can image and quantify neuronal damage in patients with TLE based on reduced signals from N-acetylaspartate (NAA), a compound localized exclusively in neurons. We performed proton MRSI in patients with TLE before and after surgical treatment to determine whether NAA or other resonance intensities changed in the temporal lobes of patients with TLE after surgery, and whether these changes correlated with surgical outcome. N-acetylaspartate resonance intensity relative to creatine (NAA/Cr) was abnormally low preoperatively in at least one temporal lobe in all 14 patients examined. It was low ipsilaterally in the patients who became seizure free and bilaterally in those who did not. Postoperatively, it increased to the normal range on the side of surgery in all patients who became seizure free. In the one patient who became seizure free and who had low NAA/Cr in both temporal lobes before surgery, NAA/Cr values in the contralateral, unoperated temporal lobe also increased to the normal range. In contrast, NAA relative intensity ratios did not change in those patients who continued to have seizures after surgery. The creatine resonance intensity (Cr) in the temporal lobes was high, relative to the brainstem, in seven patients preoperatively. After surgery, the Cr remained high in two patients, both of whom continued to have seizures. We conclude that NAA (and Cr) abnormalities in TLE do not result solely from neuronal loss and gliosis but can be reversible after postsurgical control of seizures. This implies that the NAA and Cr abnormalities in patients with TLE, at least in part, are dynamic markers of both local and remote physiologic dysfunction associated with ongoing seizures.

Adolescent↗

PubMed1997

Function and organization in dysgenic cortex. Case report.

Cerebral dysgenesis is a subject of interest because of its relationship to cerebral development and dysfunction and to epilepsy. The authors present a detailed study of a 16-year-old boy who underwent surgery for a severe seizure disorder. This patient had dysgenesis of the right hemisphere, which was composed of a giant central frontoparietal nodular gray matter heterotopia with overlying large islands of cortical dysplasia around a displaced central fissure. Exceptional insight into the function, biochemistry, electrophysiology, and histological structure of this lesion was obtained from neurological studies that revealed complementary information: magnetic resonance (MR) imaging, [18]fluoro-2-deoxy-D-glucose positron emission tomography (PET), functional PET scanning, proton MR spectroscopic (1H-MRS) imaging, intraoperative cortical mapping and electrocorticography, in vitro electrophysiology, and immunocytochemistry. These studies demonstrated compensatory cortical reorganization and showed that large areas of heterotopia and cortical dysplasia in the central area may retain normal motor and sensory function despite strikingly altered cytoarchitectonic organization and neuronal metabolism. Such lesions necessitate appropriate functional imaging studies prior to surgery and cortical mapping to avoid creating neurological deficits. Integrated studies, such as PET, 1H-MRS imaging, cortical mapping, immunocytochemistry, and electrophysiology may provide information on the function of developmental disorders of cerebral organization.

Adolescent↗

PubMed1996

Impairment of muscle mitochondrial oxidative metabolism in McArdles's disease.

Impairment of muscle glycogenolysis in McArdle's disease (myophosphorylase deficiency) leads to exercise intolerance and exercise-induced myalgia. The pathophysiology of these symptoms is not entirely clear. We used phosphorus magnetic resonance spectroscopy to measure muscle phosphate metabolite concentrations and intracellular pH during brief ischemic exercise and in the period of aerobic metabolic recovery after exercise, with special attention to cytoplasmic adenosine 5'-diphosphate (ADP). In 5 patients with McArdle's disease, calculated muscle intracellular ADP concentrations at the beginning of recovery were higher than in normal control subjects (70-425 mmol/L, control mean: 73 +/- 40 mmol/L, P < 0.05). The half-time for intracellular ADP recovery after exercise, an index of maximal mitochondrial oxidative phosphorylation, was 0.16 +/- 0.07 in normal controls and was independent of metabolic state or intracellular pH. ADP recoveries were abnormally slow in all patients with McArdle's disease (range: 0.32-0.83 min, mean = 0.2 min, P < 0.0001). These results are indicative of a limitation in the rate of oxidative phosphorylation in muscle of patients with McArdle's disease, most likely due to impaired substrate delivery to mitochondria. This impairment of mitochondrial function may contribute to the exercise-related symptoms in McArdle's disease.

Adenosine Diphosphate↗

PubMed1996

ADP recovery after a brief ischemic exercise in normal and diseased human muscle--a 31P MRS study.

The pattern of cytosolic ADP recovery after exercise has not been fully characterized in human skeletal muscle. ADP recovery after brief, ischemic exercise was studied by 31phosphorus magnetic resonance spectroscopy in calf muscles of 33 normal control subjects, four patients with McArdle's disease and 13 patients with mitochondrial myopathy. In normal muscle, the half-time for the initial ADP decline was 0.18 +/- 0.07 min and was unaffected by the pH or the metabolic state at the end of exercise. ADP decreased to below rest values during the second min of recovery in 27 out of 33 control subjects. There was a significant (p < 0.001) linear correlation for both the size (r = 0.65) and duration (r = 0.64) of this ADP undershoot with intracellular pH. Phosphocreatine resynthesis continued during the ADP undershoot. ADP undershoot was also found in patients with mitochondrial diseases (in 11 out of 13), but not McArdle's disease (six patients). Thus ADP recovery follows a complex time course that is partly dependent on pH. Only the initial ADP recovery is independent of pH, which makes it suitable for comparative assessment of muscle mitochondrial function in vivo. As phosphocreatine recovery continues during the ADP undershoot, mitochondrial regulation must be different from that at the onset of recovery. These observations are consistent with variable, changing regulators of mitochondrial metabolism in human skeletal muscle.

Adenosine Diphosphate↗

PubMed1996

Statistics for investigation of multimodal MR imaging data and an application to multiple sclerosis patients.

Magnetic resonance spectroscopy can image axonal damage specifically based on changes in N-acetyl aspartate (NAA), a neuronal marker. We have developed statistical methods for multimodal analysis of MR spectroscopic images. These methods, which are extensions of mixed-effect models, have allowed us to quantify differences in images from different subgroups of patients with multiple sclerosis (MS) and to determine the dependence of chemical pathology on clinical disability, duration of disease and lesions on T2-weighted MRI. Statistical power was improved by using all reliable resonance intensities in the spectroscopic images while taking into consideration the intra-subject correlations. We studied 17 normal subjects, 14 patients with relapsing remitting (RR) MS and 21 patients with chronic progressive (CP) MS. The ratio of resonance intensities of N-acetylaspartate over creatine (Cr) was found to be significantly lower than normal in normal appearing white matter (NAWM) of both RR and CP patients (19.6% in RR, 28.8% in CP), NAA/Cr was decreased even more in MS plaques than in NAWM (44.2% in RR, 17.7% in CP), NAA/Cr was correlated with clinical disability (p < 0.02) and disease duration (p < 0.1). Our results suggest that, in this setting, MRS reflects accumulated neuronal loss or damage and can be used as a measure of disease severity. The methods developed provide opportunities to evaluate the relationship between inflammation, demyelination, axonal loss and clinical disability in future studies.

Aspartic Acid↗

PubMed1996

Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal.

We studied 74 consecutive patients with temporal lobe epilepsy who were treated surgically and in whom the volumes of mesial temporal structures were determined preoperatively by magnetic resonance imaging. We divided the patients into three groups according to the volumetric findings: unilateral (63.5% of the patients), bilateral (23%), or no atrophy (13.5%) of the amygdala-hippocampal formation. Two distinct surgical approaches were used: selective amygdalohippocampectomy (n = 37) or anterior temporal lobe resection (n = 37). Outcome was assessed at least 1 year after surgery, according to Engel's modified classification. Patients with unilateral mesial temporal atrophy had significantly better results compared with the other two groups (p < 0.001): We found excellent results (class I or II outcome) in 93.6% of the patients with unilateral atrophy, in 61.7% of those with bilateral atrophy, and in 50% of the group with no significant atrophy of mesial temporal structures. The two different surgical techniques were equally effective, regardless of the pattern of atrophy. In conclusion, magnetic resonance volumetric studies in temporal lobe epilepsy proved to be an important preoperative prognostic tool for surgical treatment, but they did not provide guidance for selecting one surgical approach compared to the other.

Adult↗

PubMed1996

Prevalence of endometriosis in rhesus (Macaca mulatta) monkeys ingesting PCB (Aroclor 1254): review and evaluation.

A total of 80 menstruating rhesus monkeys (Macaca mulatta) were equally and randomly divided among groups receiving 0, 5, 20, 40, or 80 mu g of Aroclor 1254/kg body weight/day during a 6-year toxicological-reproduction study. During the first 3 years of the study, 4 of the treated monkeys became moribund and were euthanized; 3 had endometriosis. This finding suggested a possible link between the PCB treatment and the occurrence of endometriosis. However, neither a laparoscopic examination of the control and high-dose monkeys nor the necropsy data provided evidence for a possible link between the PCB treatment and the observed incidence (37% (6/16) of controls; 25% (16/64) of treated monkeys and/or the severity of the endometrial lesions. Additional clinical and historical data not contained in previous reports are presented to facilitate independent evaluation of the relationship between PCB ingestion and endometriosis. We conclude that the incidence and severity of the endometriosis lesions observed in the rhesus monkeys utilized in this study did not have any relationship with the dosages of Aroclor 1254 they ingested.

Animals↗

PubMed1996

Accurate, noninvasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy.

Although conventional proton magnetic resonance imaging has increased our ability to detect brain tumors, it has not enhanced to nearly the same degree our ability to diagnose tumor type. Proton magnetic resonance spectroscopy is a safe, noninvasive means of performing biochemical analysis in vivo. Using this technique, we characterized and classified tissue from normal brains, as well as tissue from the five most common types of adult supratentorial brain tumors. These six tissue types differed in their pattern across the six metabolites measured. 'Leaving-one-out' linear discriminant analyses based on these resonance profiles correctly classified 104 of 105 spectra, and, whereas conventional preoperative clinical diagnosis misclassified 20 of 91 tumors, the linear discriminant analysis approach missed only 1. Thus, we have found that a pattern-recognition analysis of the biochemical information obtained from proton magnetic resonance spectroscopy can enable accurate, noninvasive diagnosis of the most prevalent types of supratentorial brain tumors.

Adult↗

PubMed1996

Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy.

Quantitative measurement of MRI-defined brain lesions can provide an index of the extent and activity of disease in multiple sclerosis patients. However, the relationships between these indices and clinical features are not well-understood. Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures. Recent studies have suggested that with magnetic resonance spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in multiple sclerosis. Here we report results of combined quantitative brain T2-weighted MRI lesion volume and proton MRS examinations that demonstrate heterogeneity of the chemical pathology underlying brain lesions in patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses. We examined 29 patients with disease characterized by either clear relapses with at least partial remissions (RR) or secondary, chronic progression after an earlier history of a more relapsing and remitting course (SP). Total hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group. Central brain N-acetyl aspartate: creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001). The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05), implying a greater average degree of axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without axonal damage or loss in the RR group. Our results emphasize a limitation of using T2-weighted MRI lesion volume alone and suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of lesion pathology in order to better understand its relationship to clinical features of multiple sclerosis.

Adult↗

PubMed1996

Significance of mesial temporal atrophy in relation to intracranial ictal and interictal stereo EEG abnormalities.

We studied 31 consecutive patients with temporal and extratemporal epilepsy who underwent presurgical evaluation with stereotaxic depth EEG (SEEG) to assess the relationships between amygdalo-hippocampal (AM-HF) atrophy and the location of SEEG seizure onset and SEEG interictal abnormalities. Scalp EEG recordings with sphenoidal electrodes had shown bitemporal ictal or interictal epileptic abnormalities in all. Patients underwent high quality MRI scans, including MRI volumetric measurements of mesial temporal structures. None had foreign tissue lesions. The final conclusions of the SEEG investigation coincided with the lateralization obtained by MRI volumetric measurements in the eight patients who had significant unilateral atrophy of the amygdala, hippocampus or both (> 2 SD below the mean of controls). In these patients with unilateral atrophy, all or > 75% of clinical seizures originated from the atrophic side. The seven patients with bilateral, but significantly asymmetrical, mesial atrophy had bilateral seizure onsets with > 70% originating from the more atrophic side in four, from the less atrophic side in two, and without predominance in one. The one patient with severe bilateral symmetrical atrophy had seizures originating equally from both sides. Five patients had no atrophy on MRI, but depth electrodes revealed predominant unilateral ictal temporal onsets in four of them. There was no significant correlation between the frequency of SEEG interictal spikes and the amount of AM-HF atrophy. However, we found a significant correlation between the severity of SEEG background disturbance in AM and HF and the degree of atrophy of these structures. Patients with unilateral atrophy were more frequently free of seizures after surgery than those with bilateral or no atrophy (P < 0.05). We conclude that unilateral mesial atrophy predicts ipsilateral mesial SEEG seizure onset despite bitemporal extracranial EEG foci. However, in patients with significant bilateral mesial atrophy, SEEG seizures may originate from either side, even in the presence of significant asymmetry. Finally, the identification of unilateral mesial atrophy has prognostic importance.

Adult↗

PubMed1996

Combined aerobic training and dichloroacetate improve exercise capacity and indices of aerobic metabolism in muscle cytochrome oxidase deficiency.

There is no generally effective therapy for mitochondrial myopathies. In this study, we measured responses to combined aerobic training and oral dichloroacetate (DCA) therapy in a 25-year-old woman with a mitochondrial myopathy caused by cytochrome oxidase deficiency. The patient trained for 14 weeks, and DCA therapy was begun after 8 weeks. Independent indices of aerobic capacity and oxidative metabolism showed substantial improvement. Venous lactate concentrations at rest, and after a constant amount of work, decreased by approximately 50% after 8 weeks of aerobic training, and by more than 70% with the combination of training and DCA treatment. Heart rate at rest and after a constant amount of submaximal work decreased progressively. Aerobic capacity on a graded submaximal exercise test improved by 71% from baseline by the end of the treatment period. 31P magnetic resonance spectroscopy measurements of rate constants for recovery of muscle phosphocreatine increased 1.7-fold and metabolically active adenine diphosphate increased 2.8-fold after 8 weeks of training alone, and 4.5-fold and 23.0-fold after 14 weeks of training plus DCA treatment. Responses to the SF-36 Health Survey suggested a marked reduction in handicap. Thus, in this open study of a patient with cytochrome oxidase deficiency, a combination of aerobic training and DCA treatment resulted in substantial improvements in biochemical indices, exercise performance, and handicap. We conclude that exercise limitation in patients with mitochondrial myopathy may arise from effects of chronic deconditioning in addition to the effects of primary mitochondrial dysfunction and may be partially reversed by training and administration of DCA.

Adult↗

PubMed1995

Chemical pathology of acute demyelinating lesions and its correlation with disability.

We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline-containing compounds, lactate, and myo-inositol inside the lesion acutely. Decreases in relative resonance intensities of N-acetylaspartate and creatine were seen both in and around the magnetic resonance imaging-detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo-inositol resonance intensities normalized during the follow-up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N-acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N-acetylaspartate resonance intensities and both brain lesion volumes (r = -0.80, p < 0.0001) and clinical disability (r = -0.73, p < 0.0001). As N-acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.

Adult↗

PubMed1995

Reversible decreases in N-acetylaspartate after acute brain injury.

N-Acetylaspartate (NAA), which constitutes the major proportion of the dominant resonance in proton MR spectra of brain, is localized in mature brain exclusively in neurons and neuronal processes. A decrease in NAA has been observed in many cerebral pathologies and has usually been interpreted as an index of irreversible neuronal loss. The authors report a follow-up study of six patients with acute brain damage (four from demyelinating lesion and two from mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]). All patients underwent serial MR spectroscopy examinations. The four patients with acute demyelinating lesions initially showed decreases in NAA in the centers of the lesions that ranged between 34-72% of values from homologous brain volumes in the other hemisphere. All four patients subsequently showed substantial recovery of NAA as their clinical status improved. The two patients with MELAS syndrome had large decreases of NAA signal (50% and 20% of normal values, respectively) from their occipital lobe lesions during the acute stroke-like episodes. After the acute phase of the illness a progressive increase of NAA in the same volumes was seen in both patients (to 76% and 60% of normal values, respectively). These results demonstrate that significant recovery of NAA can occur after acute brain damage. The potential contribution of reversible neuronal dysfunction (as well as neuronal loss) must be considered in the interpretation of decreases in the NAA resonance associated with acute brain pathology.

Acute Disease↗

PubMed1995

Postmortem tissue levels of polychlorinated biphenyls in female rhesus monkeys after more than six years of daily dosing with Aroclor 1254 and in their non-dosed offspring.

Polychlorinated biphenyl (PCBs) analyses were made on prenecropsy blood samples and postmortem adipose, liver, kidney, and brain tissues from female rhesus monkeys fed a daily dose of 0, 5, 20, 40, or 80 micrograms Aroclor 1254/kg body weight for approximately 6 years. During this time, the females were bred with non-dosed males. All resulting offspring were nursed for 22 weeks and fed no additional PCBs until they were necropsied at approximately 120 weeks after birth. PCBs were also measured in necropsied infant tissues to determine PCB levels due to intake of PCB-contaminated milk from the dosed dams, in addition to in utero exposure. Polychlorinated biphenyl levels in all tissues of the adult monkeys increased with their dosage. The highest PCB levels were found in adipose tissue and the lowest levels were found in the brain. Polychlorinated biphenyl residues in the cortex of the kidney were lower than in the medulla, while in the brain no appreciable differences were observed between the occipital and frontal lobes. Necropsy tissues of infants from dosed dams contained more PCBs than those nursed by controls, but less than tissues from stillborn infants. Although no differences were observed between PCB tissue levels from monkeys having offspring and those having no offspring, those having a stillborn infant had higher PCB levels in their tissues than those with a viable infant. Similarly, monkeys that were euthanized because of poor health had higher PCB levels in their tissues than those necropsied at the conclusion of the study and showed a dramatic shift from tetra- and hexachlorobiphenyls to penta- and heptachlorobiphenyls in their tissues. The PCB distribution pattern in tissues from a dosed mother/infant pair differed considerably. A larger percentage of heptachlorobiphenyls was found in the infant than in its dam. The adipose/blood PCB ratio in the adult monkeys remained remarkably constant.

Adipose Tissue↗

PubMed1995

The elimination and estimated half-lives of specific polychlorinated biphenyl congeners from the blood of female monkeys after discontinuation of daily dosing with Aroclor 1254.

The levels of thirty polychlorinated biphenyl congeners in the blood of female rhesus monkeys, previously dosed with Aroclor 1254 for over six years, were monitored every two weeks during the first year and monthly during the subsequent two years after dosing was discontinued. Both blood lipid and polychlorinated biphenyl congener levels generally declined during this post dosing period. The percent distribution of the PCB congeners during the post dosing period remained relatively constant with more than half of all polychlorinated biphenyls consisting of the mono-orthochlorine substituted biphenyls. The contribution of the mono-orthochlorine substituted biphenyls was significantly different for one out of three monkeys in two of the three dose groups, during the post dosing period. Half-life, estimations for nine of the congeners ranged from 0.3-7.6 years.

Animals↗