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Biomedical subjects

R R Brown

Publications and source records attributed to R R Brown.

At least 37 records · Page 2Linked to original sources
PubMed1998

Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease.

AIMS: To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease. METHODS: The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg(-1) [13C-3-methyl] caffeine orally and had breath and urine samples collected. RESULTS: Tacrine oral clearance (CL F(-1) kg(-1)), which varied 15-fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the 'paraxanthine/caffeine ratio' (1,7X + 1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the 'caffeine metabolic ratio' (AFMU + 1X + 1U)/1, 7U)(r=0.76, P=0.0001). CONCLUSIONS: These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not sufficient to be clinically useful in individualizing tacrine therapy.

Administration, Oral↗
PubMed1998

Evaluation of the triangular fibrocartilage and the scapholunate and lunotriquetral ligaments in cadavers with low-field-strength extremity-only magnet. Comparison of available imaging sequences and macroscopic findings.

RATIONALE AND OBJECTIVES: The authors assessed the ability of a low-field-strength extremity-only magnet to provide visualization of the triangular fibrocartilage and the scapholunate and lunotriquetral ligaments. METHODS: Twelve human wrists were examined with a 0.2 T extremity-only magnet. T1-weighted spin echo, proton density-weighted, and T2-weighted turbo spin echo, short-tau inversion recovery, and three-dimensional gradient recalled echo images were acquired, and sections of the specimens were then made that corresponded to the magnetic resonance images. Masked imaging analyses were correlated with macroscopic and limited histopathologic findings. RESULTS: Low-field-strength extremity-only magnet allowed consistent visualization of the triangular fibrocartilage and accurate assessment of a small number of complete tears of the triangular fibrocartilage. The scapholunate ligaments in all cases were identified using a combination of imaging sequences. Consistent visualization of the lunotriquetral ligament with a low-field-strength extremity magnet was difficult. CONCLUSIONS: Magnetic resonance imaging with a low-field-strength extremity-only magnet can be used to visualize the triangular fibrocartilage and the scapholunate ligament, but not the lunotriquetral ligament.

Aged↗
PubMed1998

4-Hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats.

The mechanisms that underlie cholinergic neuronal degeneration in Alzheimer disease (AD) are unclear, but recent data suggest that oxidative stress plays a role. We report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, damages and kills basal forebrain cholinergic neurons when administered intraparenchymally. Examination of Nissl-stained brain sections following unilateral HNE infusion revealed widespread neuronal loss in basal forebrain ipsilateral to the injection, but not on the contralateral side. Levels of choline acetyltransferase activity and immunoreactivity in the ipsilateral basal forebrain and hippocampus were significantly reduced by 60-80% seven days following HNE administration. Performance in Morris water maze tasks of visuospatial memory was severely impaired in a dose-dependent manner seven days following bilateral administration of HNE. Bilateral infusion of FeCl2 (an inducer of membrane lipid peroxidation) into the basal forebrain caused neuron loss and decreased choline acetyltransferease immunoreactivity and deficits in visuospatial memory. Additionally, FeCl2 infusion increased HNE immunoreactivity, implicating HNE in iron-induced oxidative damage. Because recent studies have demonstrated HNE adducts in degenerating neurons in AD brain, the present findings suggest a role for HNE in damage to cholinergic neurons in AD.

Aldehydes↗
PubMed1998

Glenohumeral joint: comparison of shoulder positions at MR arthrography.

PURPOSE: To compare neutral, external rotation, and abduction external rotation positions of the glenohumeral joint during magnetic resonance (MR) arthrography in the assessment of the joint capsule, biceps-labral complex, and glenohumeral ligaments. MATERIALS AND METHODS: MR imaging with intraarticular administration of gadopentetate dimeglumine was performed in 10 adult cadaveric glenohumeral joints. Fat-suppressed oblique coronal, oblique sagittal, and axial. T1-weighted spin-echo imaging and axial three-dimensional spoiled gradient-recalled imaging were performed with each shoulder in the neutral, external rotation, and abduction external rotation positions. Shoulders were sectioned in the planes that yielded optimal MR images. Anatomic and MR imaging findings were correlated. RESULTS: The biceps-labral complex was best visualized on oblique coronal and axial images obtained in external rotation. Oblique axial abduction external rotation imaging best delineated the inferior glenohumeral ligament but did not improve assessment of the superior and middle glenohumeral ligaments in comparison with findings in neutral and external rotation. CONCLUSION: Although MR arthrography of the glenohumeral joint clearly delineates the biceps-labral complex and glenohumeral ligaments, external rotation of the shoulder optimizes visualization of the former structures. Abduction external rotation is the best position for evaluation of the inferior glenohumeral ligament and anterior capsular attachment.

Adult↗
PubMed1997

Extensive intraosseous gas associated with lymphangiomatosis of bone: report of three cases.

Asymptomatic pneumatosis may be found in patients with lymphangiomatosis of bone. The authors report three cases from three institutions in which development of intraosseous gas in association with lymphangiomatosis of bone was found incidentally at imaging. Soft-tissue emphysema also developed in two cases. In all three cases, intraosseous gas developed after biopsy or surgery in the areas involved with lymphangiomatosis.

Adolescent↗
PubMed1996

Nitric oxide mediates early dysfunction of rat and mouse islets after transplantation.

Evidence presented in this paper indicates that nitric oxide (NO), generated by a nonspecific "wound"-type of inflammation, is an important mediator of the early dysfunction of transplanted islets in rodents. Although allogeneic islets stimulate NO production to a greater degree than syngeneic islets, the amounts of NO produced after either are significantly elevated above baseline. Inhibition of NO production by N(G)-monomethyl-L-arginine (NMA), markedly decreases the time needed to restore euglycemia after intraportal transplantation of syngeneic islets in diabetic rats. The dose of NMA used was not observably toxic, with no significant changes in blood pressure, hepatic artery blood flow, serum hepatic enzyme levels, or in weight compared with control animals. In rat recipients of intraportal syngeneic transplants, evidence that NO is produced at the site of implantation includes (1) an early and transient increase in posttransplant hepatic vein nitrate levels (pretransplant, 90 microM; 24 hr, 230 microM; 48 hr, 250 microM; 72 hr, 170 microM; and 96 hr, 140 microM), (2) concurrent appearance of inducible NO synthase mRNA in liver extracts, and (3) immunohistochemical localization of inducible NO synthase within the transplanted islets. Suppression of NO production or inhibition of NO activity is a potential strategy to increase the early function and engraftment transplanted islets in the clinical setting.

Animals↗
PubMed1996

Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA.

Restoration of the impaired balance between pro- and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-1ra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-1ra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-1ra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-1ra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-1ra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.

Animals↗
PubMed1996

Control of extracellular matrix degradation by interferon-gamma. The tryptophan connection.

Interleukin-1 beta (IL-1 beta) is a potent signal for the induction of the matrix-degrading enzymes collagenase and stromelysin. These metalloproteinases (MMP) play a critical role in physiologic and pathologic connective tissue remodeling, and are potential targets for therapeutic manipulation. Treatment of human dermal fibroblasts with interferon-gamma inhibited. Type I collagen gene expression, and abrogated the effect of IL-1 beta on MMP expression. Interferon-gamma also caused a dramatic dose-dependent increase in indoleamine 2,3-dioxygenase mRNA, with consequent depletion of tryptophan and accumulation of kynurenine in the culture media. To examine the role of tryptophan metabolism in the effects of interferon-gamma on matrix-degrading enzymes, exogenous tryptophan was added to tryptophan-depleted media, followed by stimulation of the cultures with IL-1 beta. Supplementation with tryptophan completely overcame the inhibitory effects of interferon-gamma on MMP mRNA expression and metalloproteinase secretion into the media. In contrast mRNA levels for Type I collagen remained profoundly depressed in interferon-gamma-treated cultures in spite of addition of exogenous tryptophan. These results indicate that oxidative tryptophan metabolism mediates the effects of interferon-gamma on MMP gene expression in human fibroblasts.

Adult↗
PubMed1995

Inhibition of type I collagen mRNA expression independent of tryptophan depletion in interferon-gamma-treated human dermal fibroblasts.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates type I collagen synthesis. In addition, IFN-gamma also exerts potent effects on cellular tryptophan levels by inducing the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase. Because recent evidence indicates that IDO-mediated oxidative tryptophan catabolism is important in cellular responses to IFN-gamma, we investigated the role of IDO in the IFN-gamma-induced modulation of type I collagen gene expression. IFN-gamma ( > or = 50 U/ml) stimulated IDO expression in human dermal fibroblasts in vitro, resulting in a > 90% depletion of tryptophan in the culture media following incubation for 48 h. Higher concentrations of IFN-gamma ( > or = 500 U/ml) caused a marked decrease in type I collagen mRNA levels. Time-course studies indicated that maximal induction of IDO mRNA expression in IFN-gamma-treated fibroblast cultures (24 h) preceded the maximal decrease in collagen mRNA (96 h). Type I collagen mRNA levels were also markedly and selectively decreased in fibroblasts maintained in tryptophan-depleted cultures. Addition of exogenous tryptophan (up to 2500 microM) to IFN-gamma-treated fibroblasts restored "normal" concentrations of tryptophan in the culture media, but did not abrogate the IFN-gamma-induced decrease in collagen mRNA. Addition of the tryptophan metabolite kynurenine, in concentrations similar to those generated in fibroblast cultures following IFN-gamma treatment for 48 h, had no significant effect on type I collagen mRNA levels. These results indicate that although IFN-gamma causes activation of IDO and enhanced tryptophan catabolism in fibroblast cultures, neither the ensuing tryptophan starvation nor the accumulation of kynurenine in the culture media can fully account for the inhibitory effects of IFN-gamma on type I collagen mRNA expression.

Cells, Cultured↗
PubMed1995

Inhibition of collagenase and stromelysin gene expression by interferon-gamma in human dermal fibroblasts is mediated in part via induction of tryptophan degradation.

The expression of the matrix-degrading enzymes collagenase and stromelysin is modulated by a variety of biologic and pharmacologic agents. IFN-gamma has potent effects on metalloproteinase production and therefore may play an important role in preventing excessive connective tissue degradation during inflammation and repair. We investigated the mechanisms of collagenase and stromelysin regulation by IFN-gamma in human dermal fibroblasts. IFN-gamma (300 U/ml) prevented the stimulation of metalloproteinase gene expression by IL-1 beta. In addition, incubation of fibroblasts with IFN-gamma resulted in a marked increase in cellular indoleamine 2,3-dioxygenase (IDO) mRNA, a > 90% depletion of tryptophan, and a corresponding > 30-fold increase in the tryptophan metabolite kynurenine in the culture media. Reducing the concentration of tryptophan from 25 microM to 0 markedly diminished the ability of fibroblasts to increase collagenase and stromelysin mRNA and collagenase production in response to IL-1 beta. Addition of exogenous tryptophan (25-50 micrograms/ml) to cultures that had been tryptophan depleted by pretreatment with IFN-gamma for 48 h restored the fibroblast response to IL-1 beta or PMA, but had no effect on IFN-gamma-induced HLA-DR alpha chain mRNA expression. These results indicate that inhibition of collagenase and stromelysin gene expression by IFN-gamma in fibroblasts is associated with activation of IDO and enhanced cellular tryptophan metabolism. Tryptophan degradation and ensuing tryptophan depletion may account, at least in part, for the inhibitory effect of IFN-gamma on metalloproteinase production in dermal fibroblasts.

Adult↗
PubMed1995

Tryptophan metabolism in chronic inflammatory lung disease.

Induction of indoleamine 2,3-dioxygenase (IDO), an enzyme expressed by mononuclear phagocytes and some fibroblast cell lines in response to interferon-gamma, leads to enhanced degradation of tryptophan to kynurenine. Because inflammatory lung diseases are generally associated with activation of pulmonary macrophages, we investigated tryptophan metabolism in patients with interstitial lung disease by measuring circulating levels of tryptophan and kynurenine in peripheral blood and by measuring the IDO activity of bronchoalveolar cells. IDO activities were increased for bronchoalveolar lavage (BAL) cells obtained from patients with interstitial lung disease (115.4 +/- 30.4, n = 37) when compared with BAL cells from normal subjects (15.2 +/- 7.4, n = 14; p < 0.05), and messenger RNA for IDO was present in BAL cells from patients with interstitial disease but was not present in BAL cells from normal volunteer subjects. Patients with inflammatory lung disease also had decreased tryptophan and increased kynurenine concentrations in serum. The ratio of serum tryptophan levels to serum kynurenine levels was significantly depressed for patients with idiopathic pulmonary fibrosis (18.4 +/- 1.7, n = 29; p < 0.0001), patients with fibrosing alveolitis associated with collagen vascular disease (13.1 +/- 1.6, n = 18; p < 0.0001), or patients with sarcoidosis (21.0 +/- 1.1, n = 50; p < 0.0001), as compared with the ratio for normal subjects (31.8 +/- 2.3, n = 18). Patients with fibrotic disease had the highest levels of BAL cell IDO activity, and patients with collagen vascular disease associated fibrosing alveolitis had the most depressed levels of serum tryptophan and the greatest elevations in serum kynurenine. Measurement of tryptophan and kynurenine concentrations in serum may provide a useful measure of disease activity in chronic inflammatory parenchymal lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis.

Actins↗
PubMed1995

Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats.

Gene therapy may provide an effective alternative to conventional approaches for treating rheumatoid arthritis. Direct in vivo gene delivery to synovium has a distinct advantage with respect to clinical use. To date, retroviral vectors are the best studied constructs for gene delivery, and almost all approved gene therapy trials in humans rely on retroviral vectors. However, the applicability of retroviral transduction is limited by requirement for cell division, and attempts to transduce normal synovium in situ using retroviral vectors are reported to fail. The present study was undertaken in order to investigate susceptibility of inflamed synovium to retroviral infection in vivo. Using an experimental model of bacterial cell wall (BCW)-induced arthritis in rats, we attempted two approaches for delivery of retroviral vectors to synovium. In the first approach, recombinant retroviral vectors carrying reporter genes lacZ and neo were directly injected into inflamed rat ankle joints. Alternatively, inflamed joints were inoculated with gamma-irradiated murine retroviral vector-producing packaging cells. We found that about 1% of cells in explants from joints inoculated with packaging cells were lacZ-neo-positive. The lacZ+ neo+ cells in joint explants proliferated in culture and were of rat origin as determined using species-specific polymerase chain reaction (PCR) analysis. There was no evidence of transduction in explants from joints directly injected with retroviral vectors or from contralateral, control joints. These findings show that arthritic joints have a population of cells susceptible to retroviral infection in situ and demonstrate the possibility of using retroviral vectors for direct gene delivery to inflamed synovium.

Animals↗
PubMed1994

Simultaneous determination of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma by high-performance liquid chromatography with fluorescence detection.

An analytical method was developed for the simultaneous reversed-phase (cyano) high-performance liquid chromatographic determination with fluorescence detection of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma. Alkalinized human plasma samples were extracted with a mixture of chloroform/l-propanol (90:10, v/v). Extraction recoveries generally ranged from 68% to 83% for all four compounds and did not appear to be concentration dependent over the range examined. Calibration curves were constructed over the following ranges: 0.5-30.0 ng/mL for tacrine (THA) and 4-hydroxytacrine (4-OH-THA), 1.0-30.0 ng/mL for 2-hydroxytacrine (2-OH-THA), and 0.925-46.2 ng/mL for 1-hydroxytacrine (1-OH-THA). The intra- and interassay precision (RSD) for the quality control specimens analyzed during validation were < or = 11.8% and < or = 9.28%, respectively. The intra- and interassay accuracy (RE) for the quality control specimens analyzed during validation ranged from 14.1% to -7.5% and 12.1% to -3.33%, respectively, for all four compounds. The limit of quantitation was estimated as the level of the lowest concentration in the calibration curve for each compound based on acceptable interassay precision and accuracy statistics generated at this concentration. The sensitivity of the method was adequate for the determination of THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA following oral administration of Cognex (40 mg single dose) to normal volunteers.

Cholinesterase Inhibitors↗
PubMed1994

Interferon gamma induced production of indoleamine 2,3 dioxygenase in cultured human synovial cells.

OBJECTIVE: Synovial membrane cells from inflamed joints share morphological and functional properties with malignant mesenchymal cells. Interferon gamma (IFN-gamma) has antitumor cell activity related to stimulation of 2,3 indoleamine dioxygenase (IDO), a widely distributed tryptophan catabolizing enzyme. Our objective was to measure synoviocyte IDO production to determine if the varied clinical and in vitro effects of IFN-gamma on nonmalignant immunocompetent cells might involve a similar mechanism. METHODS: Using an established radioenzymatic assay, we measured IDO activity in suspensions of freshly isolated cells obtained by enzymatic dispersion of human synovial membrane, and in fresh and longterm (> or = 2 months) cultures of these cells in response to varying concentrations of recombinant human interferons alpha 2a, beta ser, or gamma. RESULTS: In fresh and in > or = 2 month-old cultures, IFN-gamma strongly stimulated IDO activity, a corresponding fall in supernatant tryptophan levels, and an elevation in the supernatant concentration of kynurenine, tryptophan's principal metabolite, mRNA for IDO was likewise markedly increased in cells after 4 days' incubation with IFN-gamma. Staining studies indicated that the IDO producing cells in synovium were not typical macrophages. Interferon beta ser had weak IDO stimulatory activity that was in a few cases additive to that of IFN-gamma. In no case did interferon beta ser abrogate IFN-gamma induced IDO activity increases. Interferon alpha 2a also had weak stimulatory activity. CONCLUSIONS: IFN-gamma stimulates IDO production and tryptophan metabolism in cultured human synovial cells, and therefore may contribute to this cytokine's in vitro and clinical effects in arthritis and inflammation.

Cells, Cultured↗
PubMed1993

Superantigen can reactivate bacterial cell wall-induced arthritis.

Intravenous injection of toxic shock syndrome toxin-1 (TSST-1) produced by Staphylococcus aureus, can reactivate arthritis in a rat ankle joint that has been previously inflamed by injection of peptidoglycanpolysaccharide polymers isolated from the cell walls of group A streptococci. The severity and chronicity of this renewed arthritis is dose dependent and at higher doses (125 micrograms/kg) a prolonged joint inflammation with pannus formation and marginal erosion of cartilage and bone is induced after a single injection of TSST-1. Only modest synovial hyperplasia is induced in control ankle joints by systemic injection of TSST-1. Another superantigen, streptococcal pyrogenic exotoxin induces a much weaker, acute reactivation of arthritis that resolves by 2 days. Repeated injections of TSST-1 at 7-day intervals give the same undiminished pattern of joint response, but the joint swelling persists at a higher level with each succeeding injection. Cyclosporin A suppresses all phases of the recurrent arthritis, indicating that TSST-1 could be functioning through its property of a superantigen activating T lymphocytes. II-1 receptor antagonist and anti-TNF-alpha neutralizing antibody, which reduce reactivation of arthritis by peptidoglycan-polysaccharide polymers, have no effect on reactivation by TSST-1. This experimental model provides a means to examine in vivo the possible role of superantigens in rheumatoid arthritis and related diseases, and to analyze the cellular and molecular pathways induced by this family of microbial products.

Animals↗