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Biomedical subjects

R H Brown

Publications and source records attributed to R H Brown.

At least 55 records · Page 3Linked to original sources
PubMed2000

Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.

CONTEXT: Occasionally, 2 or more major neurodegenerative diseases arise simultaneously. An understanding of the genetic bases of combined disorders, such as amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), will likely provide insight into mechanisms of these and related neurodegenerative diseases. OBJECTIVE: To identify loci that contain genes whose defects cause ALS. DESIGN: A genome-wide linkage analysis of 2 data sets from an ongoing study begun in the mid-1980s at 4 university research centers. SUBJECTS: An initial subset of 16 families (549 people) potentially informative for genetic analysis, in which 2 or more individuals were diagnosed as having ALS, identified from a Boston data set of 400 families and 4 families potentially informative (244 people) subsequently identified from a Chicago data set of more than 300 families to test a hypothesis based on findings from the Boston families. MAIN OUTCOME MEASURES: Linkage calculations assuming autosomal dominant inheritance with age-dependent penetrance (a parametric logarithm-of-odds [lod] score of 1.0 or greater required for further study of a potential locus); crossover analysis involving the ALS-FTD locus. RESULTS: In a set of families in which persons develop both ALS and FTD or either ALS or FTD alone, a genetic locus that is linked to ALS with FTD located between markers D9S301 and D9S167 was identified on human chromosome 9q21-q22. Families with ALS alone did not show linkage to this locus. Crossover analysis indicates this region covers approximately 17 cM. CONCLUSION: These data suggest that a defective gene located in the chromosome 9q21-q22 region may be linked to ALS with FTD. JAMA. 2000;284:1664-1669.

Aged↗
PubMed2000

Increased oxidative damage to DNA in ALS patients.

Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, substantial evidence indicates that oxidative toxicity is associated with neuronal death in this disease. We examined levels of a well-established marker of oxidative damage to DNA, 8-hydroxy-2'-deoxyguanosine (8OH2'dG) in plasma, urine, and cerebrospinal fluid (CSF) at a single time point from subjects with ALS, other neurological diseases, or no known disorders. We also measured the rate of change of 8OH2'dG levels in plasma and urine from ALS and in urine from control subjects over 9 months and examined the relationship to disease severity. In each fluid, 8OH2'dG levels were significantly elevated in the ALS group as compared to control subjects. In all subjects, the plasma and CSF 8OH2'dG levels increased with age, providing further evidence for a role of oxidative damage in normal aging. Plasma and urine 8OH2'dG levels increased significantly with time in the ALS group only. The rate of increase in urine 8OH2'dG levels with time was significantly correlated with disease severity. These findings are consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS and suggest that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Glaucoma laser treatment parameters and practices of ASCRS members--1999 survey. American Society of Cataract and Refractive Surgery.

A survey of glaucoma laser parameters and practices was mailed to all United States members of the American Society of Cataract and Refractive Surgery (ASCRS) in March 1999. Approximately 19% (947) of the 5100 surveys were returned. The survey assessed parameters used for laser trabeculoplasty, laser iridotomy, and gonioplasty. Respondents also answered questions about the application of these laser therapies in a wide variety of clinical situations. The results were cross-tabulated by age, number of laser trabeculoplasties performed per month, fellowship training in glaucoma, and geographic location.

Glaucoma↗
PubMed2000

HRCT imaging of airway responsiveness: effects of anesthetics.

The noninvasive imaging method, high resolution computed tomography (HRCT), has been developed in animal models and applied to humans with obstructive lung disease for assessing regional and individual airway responsiveness. The ability to directly view airway responses during provocations such as tracheal intubation in an asthmatic could greatly enhance our understanding and treatment of airway hyperresponsiveness. HRCT uses increased kilovoltage peak (kVp) and milliamperage (mAs) settings, thin slices, high spacial frequency reconstruction algorithms, and small fields of view to resolve structures as small as 200 microm. Therefore, airways as small as 1-2 mm in diameter can be viewed and measured. HRCT is a more sensitive technique for resolving airway caliber changes than clinical or research methods of pulmonary function tests. HRCT allows direct in vivo measurement of airway responsiveness to pharmacological and physiological stress that induces bronchoconstriction or bronchodilation. Using HRCT, we are able to measure airway dilation at baseline airway tone with inhalation anesthetics, differentiate the bronchodilating properties of inhalational agents in airways with tone, assess bronchodilating agents commonly used as premedications prior to anesthesia, and measure airway heterogeneity at baseline tone and their response to a variety of stimuli. This ability of HRCT to measure airway caliber and response heterogeneity in vivo noninvasively will dramatically improve our understanding of pulmonary physiology in general and the effects of anesthetics on the airways specifically.

Airway Resistance↗
PubMed2000

Enhancement of diphtheria toxin potency by replacement of the receptor binding domain with tetanus toxin C-fragment: a potential vector for delivering heterologous proteins to neurons.

This study describes the expression, purification, and characterization of a recombinant fusion toxin, DAB(389)TTC, composed of the catalytic and membrane translocation domains of diphtheria toxin (DAB(389)) linked to the receptor binding fragment of tetanus toxin (C-fragment). As determined by its ability to inhibit cellular protein synthesis in primary neuron cultures, DAB(389)TTC was approximately 1,000-fold more cytotoxic than native diphtheria toxin or the previously described fusion toxin, DAB(389)MSH. The cytotoxic effect of DAB(389)TTC on cultured cells was specific toward neuronal-type cells and was blocked by coincubation of the chimeric toxin with tetanus antitoxin. The toxicity of DAB(389)TTC, like that of diphtheria toxin, was dependent on passage through an acidic compartment and ADP-ribosyltransferase activity of the DAB(389) catalytic fragment. These results suggest that a catalytically inactive form of DAB(389)TTC may be useful as a nonviral vehicle to deliver exogenous proteins to the cytosolic compartment of neurons.

3T3 Cells↗
PubMed2000

New European legislation and its relation to methods performance criteria and standardization.

In the European context, two new directives, in particular, are under development, namely a Chemical Agents Directive and an Ambient Air Directive. The first concerns the workplace and the second outdoor air, but both require an assessment of air quality and imply a requirement for actual measurement. If measurement results are to be comparable across Europe, there is also a requirement for standardization of such measurements, either as defined reference methods or as method performance requirements. The task of standardization in the field of measurement is ultimately the responsibility of the European Commission, but it usually devolves this responsibility to Scientific Expert Groups, reporting to the Commission, or to Technical Committees of CEN, the Comité Européen de Normalisation. The development of standard measurement procedures, ideally meeting the CEN performance criteria, is also the responsibility of ISO, the International Organisation for Standardisation. In practice, CEN TC 137 has developed method performance requirements for measuring workplace air quality and CEN TC 264 has developed reference methods for measuring ambient air quality. However, these approaches are not entirely incompatible, because in most cases a reference method can only be established if it meets certain performance criteria and equivalent procedures are allowed. Most methods actually adopted by CEN as reference methods have previously been standardized by ISO, but a few are being developed within CEN.

Air Pollutants, Occupational↗
PubMed2000

Airway closure with high PEEP in vivo.

When airway smooth muscle is contracted in vitro, the airway lumen continues to narrow with increasing concentrations of agonist until complete airway closure occurs. Although there remains some controversy regarding whether airways can close in vivo, recent work has clearly demonstrated that, if the airway is sufficiently stimulated with contractile agonists, complete closure of even large cartilaginous conducting airways can readily occur with the lung at functional residual capacity (Brown RH and Mitzner W. J Appl Physiol 85: 2012-2017, 1998). This result suggests that the tethering of airways in situ by parenchymal attachments is small at functional residual capacity. However, at lung volumes above functional residual capacity, the outward tethering of airways should increase, because both the parenchymal shear modulus and tethering forces increase in proportion to the transpulmonary pressure. In the present study, we tested whether we could prevent airway closure in vivo by increasing lung volume with positive end-expiratory pressure (PEEP). Airway smooth muscle was stimulated with increasing methacholine doses delivered directly to airway smooth muscle at three levels of PEEP (0, 6, and 10 cmH(2)O). Our results show that increased lung volume shifted the airway methacholine dose-response curve to the right, but, in many airways in most animals, airway closure still occurred even at the highest levels of PEEP.

Animals↗
PubMed2000

Bronchial reactivity of healthy subjects: 18-20 h postexposure to ozone.

Exposure of humans to ambient levels of ozone (O(3)) causes inflammatory changes within lung tissues. These changes have been reported for the "initial" (1- to 3-h) and "late" (18- to 20-h) postexposure periods. We hypothesized that at the late period, when protein and cellular markers of inflammation at the airway surface remain abnormal and the integrity of the epithelial barrier is compromised, bronchial reactivity would be increased. To test this, we measured airway responsiveness to cumulative doses of methacholine (MCh) aerosol in healthy subjects 19+/-1 h after a single exposure to O(3) (130 min at ambient levels between 120 and 240 parts/billion and alternate periods of rest and moderate exercise) or filtered air. Exposures were conducted at two temperatures: mild (22 degrees C) and moderate (30 degrees C). At the late period, bronchial reactivity to MCh increased, i.e., interpolated dose of MCh leading to a 50% fall in specific airway conductance (PC(50)) was less after O(3) than after filtered air. PC(50) for O(3) at 22 degrees C was 27 mg/ml (20% less than the PC(50) after filtered air), and for O(3) at 30 degrees C it was 19 mg/ml (70% less than the PC(50) after filtered air). The forced expiratory volume in 1 s (FEV(1)) at the late time point after O(3) was slightly but significantly reduced (2.3%) from the preexposure level. There was no relationship found between the functional changes observed early after exposure to O(3) and subsequent changes in bronchial reactivity or FEV(1) at the late time point. These results suggest that bronchial reactivity is significantly altered approximately 1 day after O(3); this injury may contribute to the respiratory morbidity that is observed 1-2 days after an episode of ambient air pollution.

Adult↗
PubMed2000

Airway narrowing in healthy humans inhaling methacholine without deep inspirations demonstrated by HRCT.

Normal subjects prevented from taking a deep breath show changes in airflow similar to those of asthmatics when challenged with methacholine (MCh). To confirm airway narrowing by MCh in this setting and to determine its location, we concurrently measured changes in airway lumenal area using high resolution computed tomography (HRCT) and airflow using partial spirometry in five normal subjects challenged with increasing doses of MCh under prohibition of deep breaths. In an attempt to improve imaging accuracy, we corrected for the changes in lung volume during bronchoprovocation. At every step of the provocation, scanning was performed at approximately the same lung volume. On the HRCT images, airway area decreased in response to the increasing doses of MCh to 91 +/- 2%, 88 +/- 2%, and 80 +/- 2% of baseline at the doses of MCh 0.25, 0.75, and 2.5 mg/ml, respectively (p < 0.001). Airway narrowing showed no predilection for particular airway sizes and occurred in a heterogeneous pattern. The changes in the mean airway lumenal area as measured by HRCT and the mean partial spirometric outcomes were highly correlated: FEV(1)p (r(2) = 0.46, p = 0.001), FVCp (r(2) = 0.20, p = 0.05), FEV(1)/FVCp (r(2) = 0.55, p = 0.002), MMEFp (r(2) = 0.31, p = 0.01), and taup (r(2) = 0.51, p = 0.0004). We conclude that in normal subjects who are prevented from taking a deep breath, the spirometric changes occurring with aerosol MCh challenge are associated with conducting airway narrowing.

Adult↗
PubMed2000

Potential mechanism of hyperresponsive airways.

It has been known for many years that the response of asthmatic subjects to a deep inspiration differs from that observed in normal healthy subjects. A deep inspiration causes a decrease in airway resistance in normal subjects, whereas asthmatics demonstrate either no change or a slight increase in airway resistance. It has been suggested by several investigators that the inability to dilate airways during lung inflation may be a primary defect in asthma. One study (Skloot and colleagues, J. Clin. Invest. 1995;96:2393- 2403) showed that in the absence of a deep inspiration during methacholine (MCh) challenge, normal subjects had a greatly exaggerated and sustained response to this agonist. It was suggested that asthmatic airways could be modeled by this condition in normal, subjects. Other investigators, however, suggest that there are more intrinsic differences between the responses to lung inflation in airways from asthmatic and normal subjects (Brusasco and colleagues, J. Appl. Physiol. 1999;87:567-573). Resolution of this controversy requires the ability to assess the responses of airways directly, but unfortunately conventional pulmonary function tests in human subjects are not specific enough to allow this evaluation. In the present study, we have performed experiments using a direct imaging approach that allows us to obtain measurements of airway and parenchymal dimensions that can be used to test the responses of individual airways to deep inspiration in vivo. Our results show that the presence of normal tidal stresses allows airway smooth muscle to respond normally to deep inspirations. Removing tidal stresses at FRC after MCh challenge is sufficient to change the normal dilatory response to deep inspiration into an abnormal one of contraction. Altered sensitivity of airway smooth muscle to normal tidal stresses thus may be operative in the development of the asthmatic pathology.

Animals↗
PubMed2000

Delayed distension of contracted airways with lung inflation in vivo.

A deep inspiratory sigh is one of the most severe dynamic stresses that lungs normally experience. It typically is a very transient phenomenon, normally lasting only about 2 to 3 s. The airway response to a deep inspiration has been shown to be different in asthmatic and normal individuals. When airway smooth muscle (ASM) is contracted in normal subjects, a deep inspiration results in a subsequent dilation of the airways. However, in asthmatic subjects, a deep inspiration often results in little change in airway function, and sometimes results in an even further contraction of ASM. The mechanism underlying this difference depends on the dynamic behavior of both ASM and the lung parenchyma. If the contracted muscle had slower dynamic responses than the lung parenchyma, the timing of the deep inspiratory maneuver could affect the airway response. In the present study, we designed an experiment to determine how well matched the dynamic response is of airways to that of the lung parenchyma. The results clearly demonstrate that airways contracted with methacholine dilate at about a rate four times slower than that of the lung parenchyma during rapid lung inflation and deflation. This effect may play a role in the unique response of asthmatic subjects to deep inspiration. The mechanism of this dynamic slowness of contracted airways probably involves intrinsic properties of the smooth-muscle contractile processes.

Animals↗
PubMed2000

Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds.

Tangier disease (TD) is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of high density lipoprotein (HDL) cholesterol and, in some cases, peripheral neuropathy and premature coronary heart disease (CHD). Homozygotes are further characterized by cholesteryl ester deposition in various tissues throughout the body, most notably in those of the reticuloendothelial system. Several studies have demonstrated that the excess lipid deposition in TD is due to defective apolipoprotein-mediated efflux of cellular cholesterol and phospholipids. Although much progress has been made in our understanding of the metabolic basis of TD, the precise molecular defect had remained elusive until very recently. By positional cloning methods, we: 1) confirm the assignment of TD to chromosome 9q31, 2) provide evidence that human ATP-binding cassette-1 (hABC-1) maps to a 250 kb region on 9q31, and 3) describe novel deletion, insertion, and missense mutations in the gene encoding hABC-1 in four unrelated TD kindreds. These results establish a causal role for mutations in hABC-1 in TD and indicate that this transporter has a critical function in the regulation of intracellular lipid trafficking that dramatically affects plasma HDL cholesterol levels.

ATP-Binding Cassette Transporters↗
PubMed1999

Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

OBJECTIVE: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. BACKGROUND: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. METHODS: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. RESULTS: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. CONCLUSIONS: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.

Action Potentials↗
PubMed1999

Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy.

Recently we reported that mutations in a muscle protein "dysferlin" are present in limb girdle muscular dystrophy-2B and a related, adult-onset, distal dystrophy known as Miyoshi myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.

Dysferlin↗
PubMed1999

Decreased intracellular superoxide levels activate Sindbis virus-induced apoptosis.

Infection of many cultured cell types with Sindbis virus (SV), an alphavirus, triggers apoptosis through a commonly utilized caspase activation pathway. However, the upstream signals by which SV activates downstream apoptotic effectors, including caspases, remain unclear. Here we report that in AT-3 prostate carcinoma cells, SV infection decreases superoxide (O-2) levels within minutes of infection as monitored by an aconitase activity assay. This SV-induced decrease in O-2 levels appears to activate or modulate cell death, as a recombinant SV expressing the O-2 scavenging enzyme, copper/zinc superoxide dismutase (SOD), potentiates SV-induced apoptosis. A recombinant SV expressing a mutant form of SOD, which has reduced SOD activity, has no effect. The potentiation of SV-induced apoptosis by wild type SOD is because of its ability to scavenge intracellular O-2 rather than its ability to promote the generation of hydrogen peroxide. Pyruvate, a peroxide scavenger, does not affect the ability of wild type SOD to potentiate cell death; and increasing the intracellular catalase activity via a recombinant SV vector has no effect on SV-induced apoptosis. Moreover, increasing intracellular O-2 by treatment of 3T3 cells with paraquat protects them from SV-induced death. Altogether, our results suggest that SV may activate apoptosis by reducing intracellular superoxide levels and define a novel redox signaling pathway by which viruses can trigger cell death.

3T3 Cells↗