Biomedical subjects
Publications and source records attributed to R H Brown.
TATA-binding protein (TBP) is a general transcription factor involved in transcriptional initiation. We have used oligonucleotide primers flanking a polymorphic stretch of 38 glutamine codons in the 5' coding region of the TBP gene to genetically map this gene. We report the location of the human TBP gene to be at 6qter.
Several studies have examined the reproducibility over time of standard clinical measurements of pulmonary airways parameters, such as FEV1 and FVC. These studies indicate fairly consistent reproducibility of such measurements over periods of months and years. Although such traditional pulmonary function tests can provide quantitative measures of lung function, they do not provide any insight into the local or regional variation of individual airways. Therefore, in a longitudinal study in dogs, we directly measured the baseline size (cross-sectional area) of the same individual canine airways multiple times over a 1-yr period, using high-resolution computed tomography (HRCT). We compared the variability of individual airway size both within and between subjects to the various sizes of airways and to seasonal differences in size. Five anesthetized, intubated, and ventilated dogs were studied between five and eight times over a 15-mo period. HRCT scans were acquired at end expiration with the dogs at FRC on all occasions. All individual airways showed considerable variability in size over time as measured by the coefficient of variation (CV) (range: 9.2 to 69.3). The sizes of individual airways within a dog were seen to change by as much as twofold over time. Some dogs also showed significantly greater overall variability in airway size than did other dogs (p < 0.01), but this variability was related neither to the size of the airway (p = 0.34) nor to the season. These findings indicate a substantial local and regional variability in airway caliber that would not be detectable with conventional pulmonary function tests.(ABSTRACT TRUNCATED AT 250 WORDS)
Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.
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The oral health of 207 intellectually handicapped and psychiatrically ill people resident in a long-term hospital was examined. Almost three-quarters of the population were mentally retarded, a similar proportion had secondary medical problems in addition to their main reason for admission, and almost all were taking at least one medication. Half of the population was edentulous and one-quarter of the edentulous wore a denture or were considered capable of wearing a denture. The dentate population had a mean of 22.8 (SD, 7.6) teeth, but their condition was poor with a mean of 3.2 (SD, 4.4) decayed teeth. There were fewer filled teeth than in the national population of similar age, and more teeth were decayed and missing. Although root caries was not a significant problem, oral hygiene and periodontal disease were--83.5 percent of subjects required scaling and cleaning and 17.7 percent complex periodontal therapy. Two-thirds of the population were amenable to treatment in the dental surgery, and one-third required a general anaesthetic for most dental treatment. A greater proportion of people who were mentally retarded or had Down's Syndrome required special facilities or an escort nurse to facilitate dental treatment than those who were psychiatrically ill. The findings have implications for those seeking to provide care for these groups of people living in the community.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS). Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported. Two of the new mutations alter amino acids that have never been implicated in FALS. One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme. These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts. Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases.
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Familial amyotrophic lateral sclerosis (FALS) has been linked to mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1). Assay by transient expression in primate cells of six FALS mutant enzymes revealed a continuum of enzymatic activity bounded by the enzyme carrying the mutation Gly-85-->Arg, which was inactive, and mutant enzyme G37R carrying the Gly-37-->Arg change, which retained full specific activity but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocytes from an individual heterozygous for the G37R and wild-type SOD1 genes; heterodimeric enzymes composed of mutant and wild-type subunits were detected, but there was no measurable diminution in the stability and activity of the wild-type subunits. Thus, for mutants such as G37R, either surprisingly modest losses in activity (involving only the mutant subunit) can yield motor neuron death, or alternatively, mutant SOD1 may acquire properties that injure motor neurons by one or more mechanisms unrelated to the metabolism of oxygen radicals.
Amyotrophic lateral sclerosis (ALS: Lou Gehrig's Disease) is a lethal neurodegenerative disease of upper and lower motorneurons in the brain and spinal cord. We previously reported linkage of a gene for familial ALS (FALS) to human chromosome 21 using 4 restriction fragment length polymorphism DNA markers [Siddique et al.: N Engl J Med 324:1381-1384, 1991] and identified disease-associated mutations in the superoxide dismutase (SOD)-1 gene in some ALS families [Rosen et al.: Nature 362:59-62, 1993]. We report here the genetic linkage data that led us to examine the SOD-1 gene for mutations. We also report a new microsatellite DNA marker for D21S63, derived from the cosmid PW517 [VanKeuren et al.: Am J Hum Genet 38:793-804, 1986]. Ten microsatellite DNA markers, including the new marker D21S63, were used to reinvestigate linkage of FALS to chromosome 21. Genetic linkage analysis performed with 13 ALS families for these 10 DNA markers confirmed the presence of a FALS gene on chromosome 21. The highest total 2-point LOD score for all families was 4.33, obtained at a distance of 10 cM from the marker D21S223. For 5 ALS families linked to chromosome 21, a peak 2-point LOD score of 5.94 was obtained at the DNA marker D21S223. A multipoint score of 6.50 was obtained with the markers D21S213, D21S223, D21S167, and FALS for 5 chromosome 21-linked ALS families. The haplotypes of these families for the 10 DNA markers revealed recombination events that further refined the location of the FALS gene to a segment of approximately 5 megabases (Mb) between D21S213 and D21S219.(ABSTRACT TRUNCATED AT 250 WORDS)
Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate transport.
OBJECTIVE: To assess the history, clinical course, and response to treatment of 14 patients with a bleb infection (blebitis) following glaucoma surgery. DESIGN: Retrospective study. SETTING: A university referral center in Atlanta, Ga. PATIENTS: Fourteen patients developed a bleb infection that ranged from 1 month to 22 years after glaucoma surgery. Infections were characterized by pain, a whitened bleb surrounded by intense conjunctival injection, marked anterior chamber reaction (hypopyon in six eyes), and a clear vitreous. Before infection, most blebs were described as thin. The results of Seidel's test were positive in six patients, and most patients had a low intraocular pressure without the use of any glaucoma medication. INTERVENTION: Treatment consisted of hospitalization, intravenous antibiotic therapy, and hourly topical fortified cefazolin sodium and gentamicin sulfate. RESULTS: The visual acuity in most patients improved to the level before the bleb infection, with only three eyes losing 2 or more lines of vision. CONCLUSIONS: Bleb infection without vitreous involvement (blebitis) may be a precursor of endophthalmitis. With aggressive treatment, bleb infection appears to have a much better prognosis for visual recovery than endophthalmitis.
Using light and electron microscopy, we examined two conjunctival filtering blebs that had been treated with mitomycin just prior to trabeculectomy and were later excised due to ocular hypotony. Light microscopy showed attenuated epithelium, loosely arranged subepithelial connective tissue, and scattered acute and chronic inflammatory cells. Electron microscopy also showed these findings and demonstrated the presence of presumably viable activated fibrocytes in the subepithelial connective tissue. The presence of inflammatory cells in the blebs was attributed to concurrent infections and suggests that mitomycin does not completely suppress, but may attenuate, the inflammatory response. The mechanism of hypotony and bleb failure in the two eyes was most likely a combination of over-filtration and a persistent wound leak due to a lack of postoperative subconjunctival fibrosis secondary to treatment with mitomycin.
The mechanism whereby dystrophin deficiency leads to excessive fibrosis and muscle degeneration is not known. The absence of dystrophin in skeletal muscle is associated with reduced plasma membrane stability as evidenced by elevated serum levels of the cytoplasmic enzyme creatine kinase. Basic fibroblast growth factor, a cytoplasmic polypeptide growth regulator that stimulates connective tissue synthesis, induces satellite cell proliferation, and suppresses myogenic differentiation, is made by skeletal muscle. We hypothesize that dystrophin deficiency leads to the constant release of basic fibroblast growth factor, which in turn contributes to fibrosis and muscle weakness by stimulating connective tissue and suppressing skeletal muscle differentiation. As an initial step in testing this hypothesis, we measured basic fibroblast growth factor in the serum of Duchenne muscular dystrophy patients. We found that whereas basic fibroblast growth factor was undetectable in the serum of normal individuals (n = 200), levels were elevated in 11 of 18 patients with Duchenne muscular dystrophy.
We tested monoclonal IgM anti-GM1 and asialo-GM1 antibodies from 6 patients with chronic motor neuropathies for binding to lipopolysaccharides (LPS) from three stains of Campylobacter jejuni. Four of the 6 patients showed strong reactivity with LPS from at least one of the three C. jejuni strains tested as shown by enzyme-linked immunosorbent assay or western blot. Preabsorption with GM1 or asialo-GM1, or blocking with cholera toxin, prevented antibody binding to LPS. These studies indicate that human anti-GM1 or anti-asialo-GM1 antibodies cross-react with LPS from certain strains of C. jejuni, and that bacterial LPS might provide antigenic stimuli for the activation of B cells expressing anti-GM1 antibodies.
Previous work by K.A. Tryka et al. (Science 261, 751-754, 1993) has shown that the profile of the 2.148-micrometers band of solid nitrogen can be used as a "thermometer" and determined the temperature of nitrogen ice on Triton to be 38(+2)-1 K. Here we reevaluate that data and refine the temperature value to 38 +/- 1 K. Applying the same technique to Pluto we determine that the temperature of the N2 ice on that body is 40 +/- 2 K. Using this result we have created a nonisothermal flux model of the Pluto-Charon system. The model treats Pluto as a body with symmetric N2 polar caps and an equatorial region devoid of N2. Comparison with the infrared and millimeter flux measurements shows that the published fluxes are consistent with models incorporating extensive N2 polar caps (down to +/- 15 degrees or +/- 20 degrees latitude) and an equatorial region with a bolometric albedo < or = 0.2.
Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset, neurodegenerative disorder characterized by the death of large motor neurons from the cerebral cortex, brainstem, and spinal cord. The etiology of ALS remains unknown; however, approximately 10% of the cases are familial in nature. In the majority of these families, the mode of transmission is autosomal dominant. Recently, linkage of an autosomal dominant familial ALS (FALS) gene to the locus ALS1 on chromosome 21q was established. In addition, evidence was provided for genetic heterogeneity, with approximately 55% of families most likely linked to chromosome 21. The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage-21q21 through 21q22.1-has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS. In addition, we have been able to refine the mapping of ALS1, based on recombination events in two of the linked families. Flanking markers for the FALS gene are D21S213 on the centromeric side and D21S219 on the telomeric side. The candidate region is approximately 4 Mb and contains the genes copper/zinc superoxide dismutase (CuZnSOD); the fourth member of the class II cytokine receptor family (CRF2-4); and the interferon-alpha receptor (IFNAR).