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Biomedical subjects

R H Brown

Publications and source records attributed to R H Brown.

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

The pharmacokinetics and pharmaco-dynamics of Procysteine in amyotrophic lateral sclerosis.

In 13 subjects with ALS, we studied the safety and pharmacokinetic properties of Procysteine, a cysteine prodrug that increases levels of intracellular glutathione. We found that oral administration of Procysteine was safe. Procysteine enters CSF after both IV and oral dosing and accumulates to significant levels in CSF. We also observed that CSF levels of glutathione fall dramatically with aging.

Administration, Oral↗
PubMed1999

Deletions causing spinal muscular atrophy do not predispose to amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably lethal disease resulting from the premature death of motor neurons of the motor cortex, brainstem, and spinal cord. In approximately 15% of familial ALS cases, the copper/zinc superoxide dismutase gene is mutated; a juvenile form of familial ALS has been linked to chromosome 2. No cause has been identified in the remaining familial ALS cases or in sporadic cases and the selective neurodegenerative mechanism remains unknown. Deletions in 2 genes on chromosome 5q, SMN (survival motor neuron gene) and NAIP (neuronal apoptosis inhibitory protein gene), have been identified in spinal muscular atrophy, a disease also characterized by the loss of motor neurons. These genes are implicated in the regulation of apoptosis, a mechanism that may explain the cell loss found in the brains and spinal cords of patients with ALS. OBJECTIVE: To determine whether the mutations causing neurodegeneration in spinal muscular atrophy are present in patients with ALS in whom the copper/zinc superoxide dismutase gene is not mutated. PATIENTS AND METHODS: Patients in whom ALS was diagnosed were screened for mutations in the SMN and NAIP genes by single strand conformation analysis. RESULTS: We found 1 patient with an exon 7 deletion in the SMN gene; review of clinical status confirmed the molecular diagnosis of spinal muscular atrophy. No mutations were found in the remaining patients. CONCLUSION: The SMN and NAIP gene mutations are specific for spinal muscular atrophy and do not predispose individuals to ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Site of functional bronchopulmonary anastomoses in sheep.

The location of bronchopulmonary anastomoses has long been a topic of discussion, and pre-, post-, and capillary sites have all been demonstrated in postmortem examinations. However, there have been few studies that have provided insight into the patency and function of these anastomoses in the intact lung. To identify these functional sites where the bronchial circulation anastomoses with the pulmonary circulation, we studied sheep lungs in situ serial sectioned with high-resolution computed tomography (CT). Differences in radiodensities of blood, air, and nonionic contrast medium were used to differentiate and localize airways and vessels and to identify the effluent from the bronchial circulation. After an initial series of scans to identify the pulmonary arteries and veins adjacent to airways 2-12 mm in diameter, contrast material was infused into the bronchial artery. In three sheep, the major accumulation of contrast medium was found in pulmonary veins. In one of the sheep, a comparable number of pulmonary arteries and veins contained contrast medium. Serial histologic sections were able to identify small bronchial venules lying within subepithelial bronchial folds that drain directly into pulmonary veins. These results using serial CT and histologic images suggest that drainage from the intraparenchymal bronchial vasculature is predominantly into postcapillary pulmonary vessels.

Animals↗
PubMed1999

SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter.

The mechanism by which Cu2+/Zn2+ superoxide dismutase (SOD1) mutants lead to motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS) is unknown. We show that oxidative reactions triggered by hydrogen peroxide and catalyzed by A4V and I113T mutant but not wild-type SOD1 inactivated the glutamate transporter human GLT1. Chelation of the copper ion of the prosthetic group of A4V prevented GLT1 inhibition. GLT1 was a selective target of oxidation mediated by SOD1 mutants, and its reactivity was confined to the intracellular carboxyl-terminal domain. The antioxidant Mn(III)TBAP rescued GLT1 from inhibition. Because inactivation of GLT1 results in neuronal degeneration, we propose that toxic properties of SOD1 mutants lead to neuronal death via an excitotoxic mechanism in SOD1-linked FALS.

ATP-Binding Cassette Transporters↗
PubMed1999

Mechanisms of bronchoprotection by anesthetic induction agents: propofol versus ketamine.

BACKGROUND: Propofol and ketamine have been purported to decrease bronchoconstriction during induction of anesthesia and intubation. Whether they act on airway smooth muscle or through neural reflexes has not been determined. We compared propofol and ketamine to attenuate the direct activation of airway smooth muscle by methacholine and limit neurally mediated bronchoconstriction (vagal nerve stimulation). METHODS: After approval from the institutional review board, eight sheep were anesthetized with pentobarbital, paralyzed, and ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, 5 mg/ml concentrations of propofol, ketamine, and thiopental were infused into the bronchial artery at rates of 0.06, 0.20, and 0.60 ml/min. After 10 min, airway resistance was measured before and after vagal nerve stimulation and methacholine given via the bronchial artery. Data were expressed as a percent of baseline response before infusion of drug and analyzed by analysis of variance with significance set at P< or =0.05. RESULTS: Systemic blood pressure was not affected by any of the drugs (P>0.46). Baseline airway resistance was not different among the three agents (P = 0.56) or by dose (P = 0.96). Infusion of propofol and ketamine into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction to 26+/-11% and 8+/-2% of maximum, respectively (P<0.0001). In addition, propofol caused a significant decrease in the methacholine-induced bronchoconstriction to 43+/-27% of maximum at the highest concentration (P = 0.05) CONCLUSIONS: The local bronchoprotective effects of ketamine and propofol on airways is through neurally mediated mechanisms. Although the direct effects on airway smooth muscle occur at high concentrations, these are unlikely to be of primary clinical relevance.

Anesthetics, Dissociative↗
PubMed1999

A method of endotracheal intubation and pulmonary functional assessment for repeated studies in mice.

The ability to successfully intubate the trachea of mice and control their ventilation is important for longitudinal studies requiring recovery from anesthesia and repeated pulmonary function measurements or other evaluations, such as the use of radiological imaging (e.g., computed tomography or magnetic resonance imaging). We describe a method for rapid and repeated intubation of mice, with subsequent pulmonary function measurements at baseline and after an agonist challenge. We describe a simply constructed metal blade used as a laryngoscope to facilitate oropharyngeal exposure, transillumination of the neck to facilitate visualization of the trachea through the oropharynx, readily available polyethylene tubing to intubate the trachea, and a simple solenoid ventilator to maintain physiological ventilation and assess respiratory resistance and compliance. Brief infusions of acetylcholine through a needle into the jugular vein are used to assess the responsiveness of the airway smooth muscle.

Animals↗
PubMed1999

Confirmation of linkage of type 1 hereditary sensory neuropathy to human chromosome 9q22.

OBJECTIVES: 1) To confirm linkage of hereditary sensory neuropathy type 1 (HSN-I) to human chromosome 9q22 in a large American family of German origin. 2) To construct a yeast artificial chromosome (YAC) contig spanning the HSN-I candidate interval. 3) To investigate the HSN-I contig for potential candidate genes. BACKGROUND: HSN-I is a rare peripheral neuropathy characterized by loss of temperature sensation, ulceration and osteomyelitis of the digits, and subtle distal weakness. A gene for HSN-I has previously been mapped to human chromosome 9q22.1-q22.3 between markers D9S318 and D9S176 in an 8-cM interval in four Australian families. METHODS: In a large German-American family with HSN-I, genome-wide linkage analysis was performed on 68 family members extending over five generations and including 17 affected members. Genotyping was performed with PCR, and the resulting genotypes were analyzed with two-point linkage analysis with Fastlink. A YAC contig was constructed based on the Whitehead Institute YAC contig WC9.3. RESULTS: Two-point linkage analysis resulted in a maximum lod score of 8.2 at theta = 0 for marker D9S1815. Haplotype analysis locates the HSN-I gene between markers D9S1797 and D9S197. Using YAC clones from the Centre d'Etude du Polymorphism Humain YAC Library, we constructed a YAC contig spanning these markers. Based on the radiation hybrid map of the human genome, we estimate that the size of this interval is less than 2,500 kb. CONCLUSIONS: Our study confirms linkage of a putative HSN-I gene to chromosome 9q22, considerably narrows the HSN-I locus, and provides a basis for identification of the HSN-I gene.

Chromosome Mapping↗
PubMed1999

[Positional cloning of the gene for Miyoshi myopathy and limb-girdle muscular dystrophy].

Miyoshi myopathy (MM) is autosomal recessive distal muscular dystrophy that we have mapped to chromosome 2 p13. We constructed a 3 Mb P 1-derived artificial chromosome contig spanning the MM candidate region. Using this and new polymorphic markers within it, we recently identified a novel, full-length 6.9 kb muscle cDNA, whose corresponding protein we designated "dysferlin" (Nature Genet, 1998: 20: 31-36). We described eighteen mutations in the dysferlin gene with MM or limb-girdle muscular dystrophy type 2 B (LGMD 2 B). Most are predicted to block translation of dysferlin protein. In some cases, corresponding Western immunoblotting reveals absence of dysferlin in muscle biopsies. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb-girdle dystrophy, distal myopathy with anterior tibial onset).

Cloning, Molecular↗
PubMed1998

Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase.

The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1beta converting enzyme substrate, pro-interleukin 1beta, and induces apoptosis. This N2a culture system should be an instructive in vitro model for further investigation of the proapoptotic properties of mutant SOD1.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H.

The skeletal muscle L-type Ca channel serves a dual role as a calcium-conducting pore and as the voltage sensor coupling t-tubule depolarization to calcium release from the sarcoplasmic reticulum. Mutations in this channel cause hypokalemic periodic paralysis (HypoPP), a human autosomal dominant disorder characterized by episodic failure of muscle excitability that occurs in association with a decrease in serum potassium. The voltage-dependent gating of L-type Ca channels was characterized by recording whole-cell Ca currents in myotubes cultured from three normal individuals and from a patient carrying the HypoPP mutation R528H. We found two effects of the R528H mutation on the L-type Ca current in HypoPP myotubes: (1) a mild reduction in current density and (2) a significant slowing of the rate of activation. We also measured the voltage dependence of steady-state L-type Ca current inactivation and characterized, for the first time in a mammalian preparation, the kinetics of both entry into and recovery from inactivation over a wide range of voltages. The R528H mutation had no effect on the kinetics or voltage dependence of inactivation.

Biological Transport↗
PubMed1998

Identification of water ice on the Centaur 1997 CU26.

Spectra of the Centaur 1997 CU26 were obtained at the Keck Observatory on 27 October 1997 (universal time). The data show strong absorptions at 1.52 and 2.03 micrometers attributable to water ice on the surface of 1997 CU26. The reflectance spectrum of 1997 CU26 is matched by the spectrum of a mixture of low-temperature, particulate water ice and spectrally featureless but otherwise red-colored material. Water ice dominates the spectrum of 1997 CU26, whereas methane or methane-like hydrocarbons apparently dominate the spectrum of the Kuiper belt object 1993 SC, perhaps indicating different origins, thermal histories, or both for these two objects.

Hydrocarbons↗