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Biomedical subjects

R H Brown

Publications and source records attributed to R H Brown.

At least 109 records · Page 6Linked to original sources
PubMed1998

Pilot study of myoblast transfer in the treatment of Becker muscular dystrophy.

We evaluated myoblast implantation therapy in three subjects with Becker muscular dystrophy who received 60 million myoblasts in one tibialis anterior (TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for 1 year. Strength of the implanted and control TA muscles was measured before and after treatment using a gauge to record TA contraction force. Our protocol controlled for the effects of cyclosporine and myoblast injections. In this pilot study, myoblast implantation did not improve strength of the implanted TA muscles.

Adult↗
PubMed1998

Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy.

A patient with progressive exercise intolerance, proximal weakness, and complex III deficiency in skeletal muscle had a missense mutation in the cytochrome b gene of mitochondrial DNA (G15762A). The mutation, which leads to the substitution of a highly conserved amino acid (G339E), was heteroplasmic (85%) in the patient's muscle and was not present in 100 individuals of different ethnic backgrounds. These data strongly suggest that this molecular defect is the primary cause of the myopathy.

Adult↗
PubMed1997

Surface composition of Kuiper belt object 1993SC.

The 1.42- to 2.40-micrometer spectrum of Kuiper belt object 1993SC was measured at the Keck Observatory in October 1996. It shows a strongly red continuum reflectance and several prominent infrared absorption features. The strongest absorptions in 1993SC's spectrum occur near 1.62, 1.79, 1.95, 2.20, and 2.32 micrometers in wavelength. Features near the same wavelengths in the spectra of Pluto and Neptune's satellite Triton are due to CH4 on their surfaces, suggesting the presence of a simple hydrocarbon ice such as CH4, C2H6, C2H4, or C2H2 on 1993SC. In addition, the red continuum reflectance of 1993SC suggests the presence of more complex hydrocarbons.

Acetylene↗
PubMed1997

Amyotrophic lateral sclerosis. Insights from genetics.

Amyotrophic lateral sclerosis (ALS) is among the most dire neurological diseases. The essential clinical feature of the disorder is relentless, lethal paralysis, usually beginning in midadult years. The disease is caused by a slow, progressive loss of motor neurons in the brain and spinal cord. It usually begins focally and then spreads. In most cases, there is concurrent involvement of corticospinal (upper) and spinal (lower) motor neurons, although in some instances the spinal motor neuron features predominate. Involvement of the spinal motor neurons produces muscle denervation of the affected muscles and fasciculations, followed by muscle atrophy. When corticospinal motor neurons degenerate, the weakness is accompanied by spasticity. The mean age at onset of ALS is 55 years; the mean duration is about 4 years. The incidence of new cases is approximately 1 per 100,000 population. The total number of cases is about 5 per 100,000 population. In the United States, it is estimated that there are 20,000 to 30,000 cases. About 10% of cases are inherited as an autosomal dominant trait; familial and sporadic ALS are clinically indistinguishable.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.

We registered 366 families in a study of dominantly inherited amyotrophic lateral sclerosis. Two hundred ninety families were screened for mutations in the gene encoding copper-zinc cytosolic superoxide dismutase (SOD1). Mutations were detected in 68 families. The most common SOD1 mutation is an alanine for valine substitution in codon 4 (50%). We present clinical and genetic data concerning 112 families with 395 affected individuals. The clinical characteristics of patients with familial amyotrophic lateral sclerosis arising from SOD1 mutations are similar to those lacking SOD1 defects. Mean age at onset was earlier (Wilcoxon test, p = 0.004) in the SOD1 group (46.9 years [standard deviation, 12.5] vs 50.5 years [11.5] in the non-SOD1 group). Bulbar onset was associated with a later onset age. The presence of either of two mutations, G37R and L38V, predicted an earlier age at onset. Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times (Wilcoxon test, p = 0.0007). The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival. This information suggests it will be productive to investigate other genetic determinants in amyotrophic lateral sclerosis and to use epidemiological characteristics of the disease to help discern molecular mechanisms of motor neuron cell death.

Adult↗
PubMed1997

Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis.

The pathogenesis of neuronal degeneration in both sporadic and familial amyotrophic lateral sclerosis (ALS) associated with mutations in superoxide dismutase may involve oxidative stress. A leading candidate as a mediator of oxidative stress is peroxynitrite, which is formed by the reaction of superoxide with nitric oxide. 3-Nitrotyrosine is a relatively specific marker for oxidative damage mediated by peroxynitrite. In the present study, biochemical measurements showed increased concentrations of 3-nitrotyrosine and 3-nitro-4-hydroxyphenylacetic acid in the lumbar and thoracic spinal cord of ALS patients. Increased 3-nitrotyrosine immunoreactivity was observed in motor neurons of both sporadic and familial ALS patients. Neurologic control patients with cerebral ischemia also showed increased 3-nitrotyrosine immunoreactivity. These findings suggest that peroxynitrite-mediated oxidative damage may play a role in the pathogenesis of both sporadic and familial ALS.

Adult↗
PubMed1997

Postischemic infusion of Cu/Zn superoxide dismutase or SOD:Tet451 reduces cerebral infarction following focal ischemia/reperfusion in rats.

Oxygen-free radicals play a major role in neuronal cell injury following cerebral ischemia/reperfusion. The free-radical scavenging enzyme, Cu/Zn superoxide dismutase (SOD-1), ameliorates various types of brain injury resulting from temporary CNS ischemia. We have compared the cerebroprotective properties of human SOD-1 (hSOD-1) with a novel recombinant SOD-1 hybrid protein, SOD:Tet451, composed of hSOD-1 linked to the neuronal binding fragment of tetanus toxin (TTxC). Following 2 h of temporary middle cerebral artery occlusion, rats infused with equivalent activities of either hSOD-1 or SOD:Tet451 for the initial 3 h of reperfusion showed reductions in cerebral infarct volume of 43 and 57%, respectively, compared to saline-treated controls (P < 0.01). Serum hSOD-1 concentrations in rats receiving SOD:Tet451 were seven-fold higher than those in rats receiving the native enzyme. Animals treated with SOD:Tet451 also demonstrated an extended persistence of hSOD-1 in the bloodstream during drug washout as compared to animals given free enzyme. Immunohistochemical examination of brain sections from an SOD:Tet451-treated ischemic rat showed positive immunoreactivity in the ipsilateral cerebral cortex using either anti-TTxC or anti-human SOD-1 antibodies. Our results document that both hSOD-1 and SOD:Tet451 significantly reduce brain infarct volume in a model of transient focal ischemia/reperfusion in rats. Additionally, our findings suggest that the cerebroprotective effects of SOD-1 may be enhanced by neuronal targeting as seen with the hybrid protein SOD:Tet451.

Animals↗
PubMed1997

Good teeth, bad teeth and fear of the dentist.

Studies of dental fear and oral disease suggest that conditioning processes are important in the acquisition of dental fear. At this time, however, definitive conclusions are premature as all research on the etiology of dental fear has been retrospective in design, with most confined to analogue or clinic samples. This study redressed these limitations by prospectively investigating the relationship between oral health (i.e. caries experience) at age 5 and 15 yr and the report of dental fear at age 18 in a large, unselected birth cohort. Caries experience at age 5 was not related to the development of dental fear in late adolescence. In contrast, caries experience at age 15 was significantly, and specifically, related to the report of dental fear at age 18. A ratio of caries severity at age 15, indicating the extent of multi-surface involvement, was inversely related to dental fear at age 18. This intriguing finding suggests that relatively brief dental treatment occasioned by low levels of dental disease may result in the incubation of dental fear in some individuals and that longer episodes of treatment may facilitate fear habituation. Theoretical and practical implications of these findings are discussed.

Adolescent↗
PubMed1997

Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.

Several heritable forms of myotonia and hyperkalemic periodic paralysis (HyperPP) are caused by missense mutations in the alpha subunit of the skeletal muscle Na channel (SkM1). These mutations impair fast inactivation or shift activation toward hyperpolarized potentials, inducing persistent Na currents that may cause muscle depolarization, myotonia, and onset of weakness. It has been proposed that the aberrant Na current and resulting weakness will be sustained only if Na channel slow inactivation is also impaired. We therefore measured slow inactivation for wild-type and five mutant Na channels constructed in the rat skeletal muscle isoform (rSkM1) and expressed in HEK cells. Two common HyperPP mutations (T698M in domain II-S5 and M1585V in IV-S6) had defective slow inactivation. This defect reduced use-dependent inhibition of Na currents elicited during 50-Hz stimulation. A rare HyperPP mutation (M1353V in IV-S1) and mutations within the domain III-IV linker that cause myotonia (G1299E) or myotonia plus weakness (T1306M) did not impair slow inactivation. We also observed that slow inactivation of wild-type rSkM1 was incomplete; therefore it is possible that stable membrane depolarization and subsequent muscle weakness may be caused solely by defects in fast inactivation or activation. Model simulations showed that abnormal slow inactivation, although not required for expression of a paralytic phenotype, may accentuate muscle membrane depolarization, paralysis, and sensitivity to hyperkalemia.

Animals↗
PubMed1997

Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis.

Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8-hydroxy-2'-deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase-1, malondialdehyde-modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Dystrophin-associated proteins and the muscular dystrophies.

Discovery of the gene encoding the protein dystrophin delineated not only the cause of Duchenne dystrophy but also an expanding family of at least eight different dystrophin-associated muscle proteins. These include two that span the membrane (the dystroglycans), at least five within the membrane (the sarcoglycans), and a submembrane protein (utrophin). In recent years, defects in the genes for several of these proteins have been identified in several different muscular dystrophies. The spectrum of clinical deficits associated with these genetic lesions is broad, but typically it encompasses both milder proximal myopathies characteristic of limb-girdle dystrophy and more severe disorders reminiscent of Duchenne dystrophy. These discoveries will provide the basis both for improved understanding of physiology of this complex of proteins at the muscle membrane and for new strategies in the treatment of muscular dystrophy.

Chromosome Mapping↗
PubMed1997

Effect of lung inflation in vivo on airways with smooth muscle tone or edema.

Fibrous attachments to the airway wall and a subpleural surrounding pressure can create an external load against which airway smooth muscle must contract. A decrease in this load has been proposed as a possible cause of increased airway narrowing in asthmatic individuals. To study the interaction between the airways and the surrounding lung parenchyma, we investigated the effect of lung inflation on relaxed airways, airways contracted with methacholine, and airways made edematous by infusion of bradykinin into the bronchial artery. Measurements were made in anesthetized sheep by using high-resolution computed tomography to visualize changes in individual airways. During methacholine infusion, airway area was decreased but increased minimally with increases in transpulmonary pressure. Bradykinin infusion caused a 50% increase in airway wall area and an small decrease in airway luminal area. In contrast to airways contracted with methacholine, the luminal area after bradykinin increased substantially with increases in transpulmonary pressure, reaching 99% of the relaxed area at total lung capacity. Thus airway edema by itself did not prevent full distension of the airway at lung volumes approaching total lung capacity. Therefore, we speculate that if a deep inspiration fails to relieve airway narrowing in vivo, this must be a manifestation of airway smooth muscle contraction and not airway wall edema.

Animals↗
PubMed1997

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo.

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83(2): 366-370, 1997.-Inflammatory changes and airway wall thickening are suggested to cause increased airway responsiveness in patients with asthma. In five sheep, the dose-response relationships of individual airways were measured at different lung volumes to methacholine (MCh) before and after wall thickening caused by the inflammatory mediator bradykinin via the bronchial artery. At 4 cmH2O transpulmonary pressure (Ptp), 5 microg/ml MCh constricted the airways to a maximum of 18 +/- 3%. At 30 cmH2O Ptp, MCh resulted in less constriction (to 31 +/- 5%). Bradykinin increased airway wall area at 4 and 30 cmH2O Ptp (159 +/- 6 and 152 +/- 4%, respectively; P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased airway luminal area (13 +/- 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH2O, postbradykinin, the maximal airway narrowing was not significantly different (26 +/- 5%; P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect on the MCh-induced airway constriction. We conclude that inflammatory fluid leakage in the airways cannot be a primary cause of airway hyperresponsiveness.

Animals↗
PubMed1997

Changes in self-reported dental anxiety in New Zealand adolescents from ages 15 to 18 years.

Little is understood of the natural history of dental anxiety. The aim of this study was to examine three-year changes in self-reported dental anxiety among adolescent participants in the Dunedin Multidisciplinary Health and Development Study. Dental anxiety was estimated at ages 15 and 18 by means of the Corah Dental Anxiety Scale (DAS). A DAS score of 13+ defined high dental anxiety. Participants were assigned to one of four dental-anxiety study groups (Chronic, Incident, Remitted, or Never) on the basis of changes in reported level of anxiety from ages 15 to 18. Results are reported for the 691 participants who completed the DAS at both ages. The sample's overall dental anxiety score decreased significantly from age 15 (mean, 8.79) to 18 (8.52) (paired t test, t = 2.37; P < 0.05). The Chronic and Never groups had small negative DAS increments, the Incident group showed a substantial positive increment, and the Remitted group recorded an even larger negative increment. Multivariate analysis showed that the DAS score at age 15 was the sole predictor of the change in DAS score for the Chronic and Remitted groups, and was a co-predictor for the Incident and Never groups. An episodic dental visiting pattern was a strong predictor of a positive change in DAS score for the Incident group; and for the Never group, a higher DMFS score at age 15 predicted a positive change in DAS score at 18, but being female was predictive of a decrement. This study indicates lower stability of dental anxiety in late adolescence than has been reported from other age groups.

Adolescent↗
PubMed1997

Intrathecal administration of recombinant human superoxide dismutase 1 in amyotrophic lateral sclerosis: a preliminary safety and pharmacokinetic study.

We undertook a safety and pharmacokinetic study of intrathecal (i.t.) recombinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophic lateral sclerosis (ALS). Two sheep received chronic i.t. infusion of rhSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the gene for Cu/Zn SOD1. They both received i.t. infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was safe. Bolus i.t. administration of 0.25 mg rhSOD1 in sheep revealed a mean elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. After chronic i.t. infusion, the initial alpha-phase half-life was estimated as 1.2 hours and the extended beta-phase half-life was 15.0 hours. The mean clearance rate was 25.9 ml per hour and the steady-state volume of distribution was 920.6 ml. Bolus i.t. administration of 20 micrograms of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/- 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distribution of 3.5 +/- 0.4 ml. With chronic i.t. infusion of 5 mg per day, cerebrospinal SOD1 levels increased approximately fortyfold. We detected no benefit of this treatment in the two patients with familial ALS.

Adult↗
PubMed1996

Determination of phenoxy acid herbicides in vegetation, utilising high-resolution gel permeation chromatographic clean-up and methylation with trimethylsilyldiazomethane prior to gas chromatographic analysis with mass-selective detection.

A method for the determination of phenoxy acid herbicides in vegetation samples is described. Macerated samples are extracted with acetone and following filtration and acidification, the herbicides are partitioned into dichloromethane. The herbicides are then cleaned-up using high-resolution gel permeation chromatography before undergoing rapid and efficient methylation using trimethylsilyldiazomethane. The resultant methyl esters are then selectively and sensitively analyzed by gas chromatography with mass selective detection. Silanized glassware was used throughout. The method has been applied to grass samples spiked with four phenoxy acid herbicides; 2,4-D, dichlorprop, MCPA and mecoprop. Recoveries around 100% and reproducibilities of 5% (n = 4) were achieved at two spiking levels, approximately 700 and approximately 140 micrograms/kg.

Chromatography, Gel↗