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Biomedical subjects

D L Arnold

Publications and source records attributed to D L Arnold.

At least 127 records · Page 7Linked to original sources
PubMed1995

Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 2. Reproduction and infant findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated within each room to one of five dose groups (four females/dose group/room). Each day, the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their adipose tissue. Commencing on test month 37, each female was paired with an untreated male until either an impregnation occurred or the 29-month breeding phase of the study was completed. The females continued to receive their daily test dose during mating and gestation. To preclude an infant ingesting the mother's dosing capsule, dosing of the dam was discontinued when a nursing infant was approximately 7 wk old. Treatment was restarted when the infant was weaned at 22 wk of age. At parturition, and every 4 wk until weaning, milk and blood samples were obtained from the dam and a blood sample was obtained from the infant for PCB analysis. When the infant was 20 wk old, immunological testing was initiated and an adipose sample was obtained from the infant and dam for PCB analysis. Subsequently, further adipose and blood samples were obtained from the infant and blood specimens were obtained from the dam for PCB analysis. Concurrently, each infant was subjected to anthropometric measurements and detailed clinical examinations until it was approximately 122 wk old. At 122 wk some of the control and all of the treated infants were killed humanely and autopsied. A statistical analysis of the reproduction data provided evidence for a significant decreasing dose-related trend in conception rates and a significant increasing dose-related trend in foetal mortality. Several comparisons between impregnated and non-impregnated females did not implicate 'age' as a confounding factor regarding these results. The major findings with the infants involved some immunological test differences and mild clinical manifestations of PCB ingestion.

Administration, Oral↗
PubMed1995

Proton magnetic resonance spectroscopic images and MRI volumetric studies for lateralization of temporal lobe epilepsy.

We obtained 2D magnetic resonance (MR) spectroscopic images (MRSI) and MRI volumetric measurements (MRIV) of amygdala and hippocampus in 30 consecutive patients with temporal lobe epilepsy (TLE) being evaluated for surgical treatment. Both MRSI and MRIV lateralization showed good agreement with the current gold standard of clinical-EEG lateralization. Each exam separately correctly lateralized 25 out of 30 patients with no false lateralization. Combining both exams, lateralization could be achieved in 28 out of 30 patients. The two patients with no significant asymmetry had bitemporal EEG abnormalities, and bilateral damage on both MRIV and MRSI. There was a good correlation between the magnitude of the MRSI and MRIV asymmetry (Pearson coefficient = 0.83; p < .0001). Both MRSI and MRIV were normal in our patients with seizures originating outside the temporal lobes. Both MRIV and MRSI can lateralize TLE in 83% of patients. Combination of the two modalities allows lateralization in 93% of patients. Patients who cannot be lateralized generally have symmetrical bitemporal abnormalities; they are not incorrectly lateralized. The structural and chemical pathologic abnormalities seen in TLE seem to be associated with the seizure focus, and may be as, or even more, reliable than a few recorded seizures in predicting the side from which most seizures originate.

Adult↗
PubMed1995

Glutaric acidemia type II: neuroimaging and spectroscopy evidence for developmental encephalomyopathy.

Glutaric acidemia type II is associated with neonatal hypoketotic hypoglycemia, metabolic acidosis, profound hypotonia, progressive cardiomyopathy, and early death. Deficiency of either electron transfer flavoprotein or electron transport flavoprotein:ubiquinone oxidoreductase leads to intramitochondrial accumulation of metabolites of compounds oxidized by enzymes that transfer electrons to flavoprotein. No detailed results of antemortem neuroimaging or magnetic resonance spectroscopy have been described previously. We investigated a patient with typical neonatal onset glutaric acidemia type II without obvious dysmorphogenesis or renal malformations. Cranial tomographic scan revealed hypoplastic temporal lobes and marked widening of the sylvian fissures ("bat-wing" appearance). Cranial magnetic resonance imaging documented underdeveloped frontal and temporal lobes with delayed myelination and hypoplasia of the corpus callosum. 31P-Magnetic resonance spectroscopy of muscle was grossly abnormal with a very low energy state consistent with mitochondrial dysfunction. 1H-Magnetic resonance spectroscopy of brain revealed elevated intracerebral lactate concentration and abnormally high choline/creatine ratio suggestive of dysmyelination. These findings constitute the first in vivo evidence of a developmental encephalomyopathy in glutaric acidemia type II.

Age of Onset↗
PubMed1995

Association of cerebral dysgenesis and lactic acidemia with X-linked PDH E1 alpha subunit mutations in females.

We describe an infant girl who presented at age 4 1/2 months with developmental delay, infantile spasms, hypotonia, and elevated lactate levels in the blood and cerebrospinal fluid. She had minor dysmorphic features. Muscle phosphorus magnetic resonance spectroscopy demonstrated reduced phosphocreatine and increased inorganic phosphate, suggesting a defect in oxidative energy metabolism. Pyruvate dehydrogenase activity in cultured fibroblasts was reduced (0.35 nmol/mg mitochondrial protein/min; controls 0.7-1.1 nmol/mg mitochondrial protein/min). Immunoblotting demonstrated a reduced amount of pyruvate dehydrogenase (PDH) E1 alpha immunoreactive protein with normal amounts of E2 protein. Single-strand conformational polymorphism analysis of E1 alpha cDNA prepared from fibroblasts disclosed an abnormal migration pattern, suggesting heterozygosity for a mutant allele. Dideoxy-fingerprinting of PCR-amplified genomic DNA was used to localize the mutation to exon 10. Direct sequencing demonstrated a novel 13-bp insertion mutation that would lead to premature termination of the protein product. This study further extends the allelic heterogeneity underlying PDH deficiency. The demonstration of bioenergetic abnormalities in muscle emphasizes that hypotonia in PDH deficiency may have combined peripheral and central etiologies. The results further suggest that the association of cerebral dysgenesis with lactic acidemia in females may be a useful clue to PDH deficiency.

Acidosis, Lactic↗
PubMed1995

Imaging of axonal damage in vivo in Rasmussen's syndrome.

We obtained magnetic resonance spectroscopic images (MRSIs) in three patients with Rasmussen's syndrome. The relative resonance intensity of N-acetylaspartate (NAA) to creatine (NAA:Cr), an index of neuronal loss or damage, was determined for various regions within the brain, and the affected:unaffected hemisphere asymmetry ratio was determined. All three patients had decreased relative NAA signal intensity over the entire affected hemisphere. The decrease in NAA:Cr involved cortex and white matter, was most prominent in the anterior periventricular region, and showed a tendency to be worse in patients with longer duration of disease. 1 year follow-up MRSI showed further reduction of the relative NAA signal in all patients, indicating progression of the disease. All patients were free of seizures for at least 48 h before the first MRSI, but two of them had epilepsia partialis continua (EPC) during the follow-up examination. There was no significant increase of the lactate resonance intensity, except in the two MRSIs performed during EPC. This indicates that lactate accumulation results from repetitive seizures rather than from the disease process itself. The spatial distribution of the metabolic abnormality on MRSI was more widespread than that of the structural abnormality on MRI. The relative NAA resonance intensity was not reduced in the contralateral hemisphere. Our findings indicate that MRSI can identify and quantify neuronal damage and loss throughout the affected hemisphere of patients with Rasmussen's syndrome, including areas that appear normal on conventional MRI.

Adolescent↗
PubMed1995

Frequency and characteristics of dual pathology in patients with lesional epilepsy.

We studied 167 patients who had identifiable lesions and temporal or extratemporal partial epilepsy. Pathology included neuronal migration disorders (NMDs) (48), low-grade tumors (52), vascular malformations (34), porencephalic cysts (16), and gliotic lesions as a result of cerebral insults early in life (17). MRI volumetric studies using thin (1.5- or 3-mm) coronal images were performed in all patients and in 44 age-matched normal controls. An atrophic hippocampal formation (HF), indicating dual pathology, was present in 25 patients (15%). Abnormal HF volumes were present in those with lesions involving temporal (17%) but also extratemporal (14%) areas. Age at onset and duration of epilepsy did not influence the presence of HF atrophy. However, febrile seizures in early childhood were more frequently, although not exclusively, found in patients with hippocampal atrophy. The frequency of hippocampal atrophy in our patients with low-grade tumors (2%) and vascular lesions (9%) was low. Dual pathology was far more common in patients with NMDs (25%), porencephalic cysts (31%), and reactive gliosis (23.5%). Some structural lesions, such as NMDs, are more likely to be associated with hippocampal atrophy, independent of the distance of the lesion from the HF. In other types of lesions, such as vascular malformations, dual pathology was found when the lesion was close to the HF. A common pathogenic mechanism during pre- or perinatal development may explain the occurrence of concomitant mesial temporal sclerosis and other structural lesions because of either (1) associated developmental abnormalities or (2) predisposition to prolonged febrile convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Short-term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders.

We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p < 0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p < 0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p < 0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p < 0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.

Acetylcysteine↗
PubMed1995

Mitochondrial disease. Pulmonary function, exercise performance, and blood lactate levels.

Mitochondrial diseases are a heterogeneous group of disorders in which it has been suggested that genetic defects in oxidative phosphorylation lead to specific alterations in exercise performance and lactate metabolism during exercise. To investigate this possibility, we evaluated pulmonary function tests, incremental exercise testing, and serial blood lactate levels in a group of subjects with mitochondrial disease (M) and compared them with a group of patients with nonmitochondrial (N) myopathies and healthy subjects (H). The two groups were demographically comparable and had no significant differences in pulmonary function. Both groups showed similar degrees of reduced exercise tolerance compared with a group of healthy subjects (M: 61.08% predicted VO2max +/- 19.58 SD, n = 13; N: 62.14 +/- 28.89, n = 7; H: 115.17 +/- 19.35, n = 12; p < 0.001). The mitochondrial disease group more frequently showed abnormalities in cardiac response to exercise than did the nonmitochondrial myopathy subjects (M: 12/13, N: 3/7, H: 3/12, p = 0.002). Minute ventilation greater than predicted occurred with similar frequency in both groups. Although resting lactate level was increased in some subjects with mitochondrial myopathy compared with disease controls, there were no differences between groups for peak venous lactate level normalized for oxygen uptake or the rate of lactate clearance. These findings, while confirming the presence of some specific abnormalities in mitochondrial disease, are against the notion that exercise limitation in this condition directly results from specific abnormalities in oxidative metabolism.

Adolescent↗
PubMed1995

Neuroimaging in multiple sclerosis.

Neuroimaging in multiple sclerosis is now dominated by MR imaging. This article will focus primarily on conventional MR imaging studies in multiple sclerosis, but will also discuss briefly some of the more recent advances related to MR imaging. Fast spin-echo imaging, fluid attenuated inversion recovery MR studies, three-dimensional volumetric studies, magnetization transfer, and magnetic resonance spectroscopy as it applies to multiple sclerosis are examined.

Brain↗
PubMed1994

Lateralization of temporal lobe epilepsy based on regional metabolic abnormalities in proton magnetic resonance spectroscopic images.

Magnetic resonance spectroscopic imaging (MRSI) is capable of determining the spatial distribution in vivo of cerebral metabolites, including N-acetylaspartate (NAA), a compound found only in neurons. We used this technique in 10 patients with temporal lobe epilepsy (TLE) to determine the location of maximal neuronal/axonal loss or damage and to evaluate the potential of MRSI for presurgical lateralization. Asymmetry of the relative resonance intensity of NAA to creatine was determined for mid and posterior regions of the temporal lobes defined anatomically and also for "metabolic lesions" defined as the regions of maximal abnormality on MRSI. MRSI revealed decreased relative signal intensity in at least one temporal lobe of all patients. Two patients had a widespread reduction in NAA in both temporal lobes. The region of maximal abnormality was usually in the posterior temporal lobe but sometimes in the mid temporal lobe. The side of lowest NAA was ipsilateral to the clinical electroencephalographic lateralization in all patients. Lateralization based on NAA to creatine correlated with the atrophy of amygdala and hippocampus in 8 patients who showed this on magnetic resonance imaging volumetric measurements. MRSI can demonstrate regional neuronal loss or damage that correlates with clinical electroencephalographic and structural lateralization in temporal lobe epilepsy. The ability to identify a region of maximal metabolic abnormality on spectroscopic images may confer greater sensitivity than that available from single voxel methods. The maximal metabolic abnormality may not be located in a voxel defined a priori, and based on anatomical considerations, without knowledge of the distribution of the metabolic abnormality.

Adult↗
PubMed1994

Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis.

Decreases in brain N-acetylaspartate are associated with neuronal loss or dysfunction. We report a longitudinal study in which changes in the N-acetylaspartate to creatine resonance intensity ratio measured by brain proton magnetic resonance spectroscopy were used to follow the progression of brain pathology in 7 patients with multiple sclerosis over an 18-month period. Four of the patients had a history of recurrent relapses and 3 had a secondary progressive course. All had clinical and magnetic resonance imaging evidence of persistent neurological abnormalities. At 6-month intervals proton magnetic resonance spectra were obtained and the N-acetylaspartate-creatine ratio was determined for each patient. The volumes of hyperintense signal from lesions on conventional magnetic resonance images and the Kurtzke Expanded Disability Status Scale scores were determined concurrently. At the onset of the study, the N-acetylaspartate-creatine ratio was significantly (p < 0.05) lower in the central brain volumes from the patients than in 13 normal control subjects. At 12 and 18 months of follow-up, the ratio had decreased further in all patients (p < 0.05), consistent with progressive accumulation of neuronal damage. In contrast to magnetic resonance spectra data, changes in lesion volume on magnetic resonance images or disability status did not reach significance over this period. Subgroup analysis showed that changes (increases or decreases) in the N-acetylaspartate-creatine ratio between consecutive 6-month examinations correlated significantly (r = -0.74, p < 0.005) with changes in lesion volume on magnetic resonance images in patients with a history of relapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspartic Acid↗
PubMed1994

Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin.

Niemann-Pick type C is an autosomal-recessive, neurovisceral storage disorder that results from defective cholesterol esterification. Cholesterol-lowering agents have been demonstrated to decrease hepatic lipids in Niemann-Pick type C patients. The objective was to determine the effects of cholesterol-lowering agents on neurologic features and to develop a noninvasive method of monitoring clinical response. A 9-month-old boy with progressive hepatosplenomegaly and neurodevelopmental delay was studied. Water-suppressed proton magnetic resonance spectra from a supraventricular volume of central white and gray matter revealed an abnormal lipid signal. The patient was treated with cholesterol-lowering agents (i.e., cholestyramine, lovastatin). Repeat standardized neurodevelopmental assessments (Peabody and Griffith scales) at 13 and 19 months were normal and magnetic resonance spectra no longer detected the previously observed lipid resonance. Early treatment of Niemann-Pick type C patients with cholesterol-lowering agents appeared to have short-term beneficial effects. Magnetic resonance spectra provided a noninvasive means of monitoring CNS response.

Brain↗
PubMed1994

Cerebral dysgenesis and lactic acidemia: an MRI/MRS phenotype associated with pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase complex (PDHC) is an intramitochondrial multienzyme complex essential for the aerobic oxidation of glucose. The majority of patients with PDHC deficiency have abnormalities in the major catalytic and regulatory subunit, E1 alpha, which is encoded on the X chromosome. The clinical spectrum of PDHC deficiency is heterogeneous, particularly in heterozygous females, and diagnosis may be difficult. Three affected infant girls with PDHC deficiency were investigated. All had dysmorphic features, microcephaly with profound global developmental delay, and hypotonia. Systemic acidosis was absent, although serum lactate and pyruvate were abnormally elevated. Magnetic resonance imaging revealed hypoplasia of the corpus callosum in all patients. Proton magnetic resonance spectroscopy of brain revealed large increases in relative signal intensities for lactic acid and decreases in the relative signal intensities of N-acetylaspartate, a marker of neuronal damage or less. Phosphorus MRS of muscle revealed abnormally low phosphorylation potentials for all these patients, although the degree of abnormality was variable and not directly correlated with the amount of brain lactate. It is proposed that cerebral dysgenesis and cerebral lactic acidemia as shown by magnetic resonance imaging and proton magnetic resonance spectroscopy are useful diagnostic clues to PDHC deficiency, particularly in females in whom variable patterns of X-inactivation reduce sensitivity of laboratory diagnosis based on the biochemical studies of peripheral tissues. In addition, muscle bioenergetic abnormalities in conjunction with CNS dysfunction may contribute to profound hypotonia in this disorder.

Acidosis, Lactic↗
PubMed1994

Normative hematologic and serum biochemical values for adult and infant rhesus monkeys (Macaca mulatta) in a controlled laboratory environment.

During the conduct of a long-term toxicity/reproduction study using rhesus monkeys (Macaca mulatta), periodic hematologic and serum biochemical analyses were undertaken on blood obtained from 15 untreated (vehicle control) adult female monkeys over a period of 3 yr, 20 untreated adult males over a period of 6 yr, and 9 infants (5 male, 4 female, whose dams were the vehicle control females) from 12 wk through 2 yr of age. All samples were obtained by femoral puncture. To facilitate handling, ketamine hydrochloride (Ket.HCl) was administered to the males, and for some of the later infant samplings. Complete blood cell counts were performed using electronic cell counters, while reticulocyte counts and leukocyte differentials were assessed manually. The serum biochemistry analyses were performed with automated analyzers. These data were obtained as part of a health monitoring program, with medians and 2.5 to 97.5 percentiles for each parameter indicated. Some monitored parameters were found to be affected by the type of equipment used and by the use of Ket.HCl.

Aging↗
PubMed1994

Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo.

We performed proton magnetic resonance spectroscopic imaging (1H-MRSI) in patients with motor neuron disease (MND) to evaluate the distribution and extent of cortical neuron damage or loss as reflected by decreased N-acetyl (NA) to creatine (Cr) resonance intensity ratios. We examined premotor (superior frontal gyrus), primary motor (precentral gyrus), primary sensory (postcentral gyrus), and parietal (superior parietal gyrus/precuneus) neocortical regions of 12 patients with MND and six normal control subjects. Patients with MND were representative of three syndromes: amyotrophic lateral sclerosis (ALS) with definite lower motor neuron and upper motor neuron signs, MND with probable upper motor neuron signs (PUMNS), and progressive spinal muscular atrophy (PSMA) with lower motor neuron signs only. Compared with healthy controls, ALS patients had a significant decrease in NA/Cr resonance intensity ratios, most prominently in the primary motor cortex (p < 0.001) but also, to varying degrees, in primary sensory (p < 0.01), posterior premotor, and parietal (p < 0.05) regions. Patients classified as ALS-PUMNS showed less prominent reduction in NA/Cr ratios in the same regions; patients with PSMA had normal cortical NA/Cr ratios. Sequential studies in one patient suggested that 1H-MRSI could document progression of the NA/Cr abnormality. Decreased NA/Cr ratios on 1H-MRSI provide an index of cortical motor neuron loss and/or dysfunction in MND patients. Clinical applications of 1H-MRSI could include documenting the extent of upper motor neuron involvement, aiding diagnosis of syndromes presenting with an ALS-like picture, and monitoring disease progression.

Adult↗
PubMed1993

Evidence for mitochondrial dysfunction in patients with alternating hemiplegia of childhood.

Phosphorus magnetic resonance spectra of resting muscle were obtained from 4 patients with alternating hemiplegia of childhood. All patients had abnormally high resonance intensities from inorganic phosphate and an abnormally low calculated cytosolic phosphorylation potential. Two of the 4 patients had abnormally low resonance intensities from phosphocreatine and an abnormally high calculated cytosolic free adenosine diphosphate concentration. These abnormalities are indicative of mitochondrial dysfunction. The combination of a central nervous system disorder and evidence of mitochondrial dysfunction in muscle suggests that alternating hemiplegia of childhood may represent a previously unrecognized phenotype of mitochondrial disease.

Adenosine Diphosphate↗
PubMed1993

Toxicological consequences of Aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 1A. Prebreeding phase: clinical health findings.

A group of 80 menstruating rhesus (Macaca mulatta) monkeys, with an average estimated age of 11.1 +/- 4.1 yr SD, were first randomly allocated to four similar test rooms (20 monkeys/room) and then randomly allocated to one of the five dose groups (four females/dose group/room). Each day, the females self-ingested capsules containing doses of 0, 5, 20, 40 or 80 micrograms Aroclor 1254/kg body weight. After 25 months of daily dosing, approximately 90% of the treated females attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl in their adipose tissue. The test monkeys were monitored daily for health and menstrual status, as well as feed and water consumption. On a weekly basis, each female's body weight was determined and a detailed clinical examination was conducted. Minor treatment effects included a slight, but not statistically significant, decrease in feed and water consumption as well as a decreased feed conversion ratio and a slight increase in the duration of menses. Statistically significant, dose-related treatment effects included inflammation and/or prominence of the tarsal (Meibomian) glands, eye exudate, and various finger and toe nail changes. These results were found at doses lower than those previously reported for non-human primates.

Animal Feed↗