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Biomedical subjects

T Brown

Publications and source records attributed to T Brown.

At least 217 records · Page 12Linked to original sources
PubMed1994

Fluoxetine effects on cerebral glucose metabolism.

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Adult↗
PubMed1994

Crystal structure of a DNA duplex containing 8-hydroxydeoxyguanine-adenine base pairs.

The crystal structure of the oligonucleotide d(CGCAAATTO8GGCG), containing the chemically modified base 8-hydroxydeoxyguanine (O8G), has been determined at 2.5-A resolution and refined to a crystallographic R-factor of 16.8%. The B-type DNA helix contains standard Watson-Crick base pairs except at the mismatch sites, where O8G adopts a syn conformation and forms hydrogen bonds to adenine in the anti conformation. The thermodynamic stability of the duplex was found by UV melting techniques to be intermediate between the native oligonucleotide d(CGCAAATTTGCG) and an oligonucleotide containing A.G mispairs d(CGCAAATTGGCG). Comparison of the structure of the O8G(syn).A(anti) base pair with those of Watson-Crick base pairs has given a reason why O8G.A base pairs are not well repaired by DNA proofreading enzymes.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Crystal and molecular structure of r(CGCGAAUUAGCG): an RNA duplex containing two G(anti).A(anti) base pairs.

BACKGROUND: Non-Watson-Crick base pair associations contribute significantly to the stabilization of RNA tertiary structure. The conformation adopted by such pairs appears to be a function of both the sequence and the secondary structure of the RNA molecule. G.A mispairs adopt G(anti).A(anti) configurations in some circumstances, such as the ends of helical regions of rRNAs, but in other circumstances probably adopt an unusual configuration in which the inter-base hydrogen bonds involve functional groups from other bases. We investigated the structure of G.A pairs in a synthetic RNA dodecamer, r(CGCGAAUUAGCG), which forms a duplex containing two such mismatches. RESULTS: The structure of the RNA duplex was determined by single crystal X-ray diffraction techniques to a resolution in the range 7.0-1.8A, and found to be an A-type helical structure with 10 Watson-Crick pairs and two G.A mispairs. The mispairs adopt the G(anti).A(anti) conformation, held together by two obvious hydrogen bonds. Unlike analogous base pairs seen in a DNA duplex, they do not exhibit a high propeller twist and may therefore be further stabilized by weak, reverse, three-center hydrogen bonds. CONCLUSIONS: G(anti).A(anti) mispairs are held together by two hydrogen of guanine and the N6 and N1 of adenine. If the mispairs do not exhibit high propeller twist they may be further stabilized by inter-base reverse three-centre hydrogen bonds. These interactions, and other hydrogen bonds seen in our study, may be important in modelling the structure of RNA molecules and their interactions with other molecules.

Animals↗
PubMed1994

Guanine-1,N6-ethenoadenine base pairs in the crystal structure of d(CGCGAATT(epsilon dA)GCG).

A single-crystal X-ray analysis of the synthetic oligomer d(CGCGAATT(epsilon dA)GCG) (epsilon dA = 1,N6-ethenoadenosine) has been carried out. The B-form duplex crystallizes in the orthorhombic space group P2(1)2(1)2(1) with unit cell dimensions a = 24.31 A, b = 39.65 A, and c = 63.05 A. Refinement has converged with R = 0.182 for 2837 reflections in the resolution range 7.0-2.25 A for a model consisting of the duplex, one Mg2+ ion, and 127 water molecules. The structure contains two G.epsilon dA base pairings which adopt a G(anti).epsilon dA(syn) conformation. The geometry of the two mispairs suggests that the G.epsilon dA pairing are held together by three interbase hydrogen bonds. These are N2(G)-H...N1(epsilon dA), N1(G)...N9(epsilon dA), and O6(G)...H-C8(epsilon dA). The last interaction serves to alleviate the destabilizing effect that would occur due to the presence of an unfulfilled hydrogen bond acceptor. A superposition of the G(4).epsilon dA-(21) base pair found in this structure and the Watson-Crick G(4).C(21) base pair observed in the native dodecamer d(CGCGAATTCGCG) indicates a significant difference in the sugar/phosphate backbone. However, the overall conformations of the two duplexes remain similar, suggesting that the modified base pairs are accommodated into the double helix mainly by alterations of the backbone conformation. Such structural rearrangement of the backbone, upon incorporation of epsilon dA, may provide a signal to the 3-methyladenine-DNA glycosylase that repairs such lesions.

Adenine↗
PubMed1994

Thermodynamic stability and solution conformation of tandem G.A mismatches in RNA and RNA.DNA hybrid duplexes.

G.A mismatches form a variety of hydrogen-bonded structures in DNA, most of which destabilise the duplex. Tandem G.A mismatches in the context YGAR (Y = pyrimidine, R = purine), however, form base pairs using the amino group of the guanine residue [Li, Y., Zon. G. & Wilson, W.D. (1991) Proc. Natl Acad. Sci. USA 88, 26-30], which permits extensive base-base stacking, leading to a slight stabilisation of the helix [Ebel, S., Lane, A. N. & Brown, T. (1992) Biochemistry 31, 12083-12086]. We have measured the thermodynamic stability of several RNA and RNA.DNA hybrid duplexes containing tandem G.A mismatches. The RNA duplexes are intrinsically much more stable than the corresponding DNA duplexes and the mutations are destabilising in all cases. NOE and coupling-constant data show that all of the sugars are in the C3'-endo range of conformations, and glycosidic torsion angles are in the range -160 degrees to -180 degrees in [sequence: see text]. Both sequential NOE intensities and circular-dichroism measurements indicate that the global conformation of the mismatched RNA is A-like. The N1H group of the mismatched guanine residue is not involved in hydrogen bonding with the adenine residue, indicating the presence of the amino-pairing scheme. Determination of the structure using 'loose' NMR-derived constraints shows that the potential energies of the imino-paired and amino-paired forms are similar, but substantially higher than energy-minimised RNA. Using tighter constraints derived from more extensive analysis of one-dimensional and two-dimensional NOE data showed that the amino-paired structure agrees with the constraint data better than the imino-paired structure, and also accounts for unusual chemical shifts and the lack of hydrogen bonding of the guanine N1H group. Resulting molecular models show that the amino-paired mismatches are not as extensively stacked on the neighbouring part of the duplex as in the B-DNA analogues, largely accounting for the lower thermodynamic stability in the RNA duplexes.

Base Sequence↗
PubMed1994

Properties of multiple G.A mismatches in stable oligonucleotide duplexes.

The solution structure of the deoxydecanucleotide [sequence: see text] has been determined by NMR methods. This duplex, which contains six G.A mismatches and four Watson-Crick base pairs, is thermodynamically more stable than a decamer where T.A base pairs are substituted for the G.A mismatches, and is less stable than the duplex that contains G.C base pairs. Circular-dichroism spectroscopy indicates an overall B-like conformation for the decamer, but stronger than usual base stacking. 1H-NMR spectroscopy revealed that the N1H groups of the mismatched guanine residues are not hydrogen bonded, and 31P-NMR showed the presence of BII phosphate conformations for the GpA steps. Detailed analysis of the NMR data showed that all nucleotides have anti glycosidic torsion angles and S type sugar puckers. The G.A mismatches pair in the amino form as originally proposed by Li et al. [Li, Y., Zon, G. & Wilson, W. D. (1991) Proc. Natl Acad. Sci. USA 88, 26-30], which results in extensive base-base stacking between the tandem G.A base pairs and their nearest neighbours. The terminal G.A base pairs are less stable than the central base pairs and show evidence of an equilibrium between two conformations, one involving BII phosphate.

Base Sequence↗
PubMed1994

Small bowel explosion: a complication of strictureplasty.

Explosion injury to the intestinal tract resulting from electrocautery is a rare occurrence. Only two small bowel explosions have been described previously. Here we describe an explosion of small bowel during strictureplasty in a patient with chronic obstructing Crohn's disease. Recommendations to avoid this disastrous complication include proximal decompression prior to incision and, in some cases, it may be wise to avoid electrocautery altogether.

Adult↗
PubMed1994

Effect of steroids on iopamidol blood-brain transfer constant and plasma volume in brain tumors measured with X-ray computed tomography.

Tumor blood-brain transfer constant of iopamidol (K) and plasma volume (Vp) were measured in 10 patients with primary brain tumors before and after 7 days of dexamethasone treatment (4 x 4 mg per oral per day) using X-ray computed tomography. Both K and Vp decreased significantly after dexamethasone treatment with p < 0.01 and 0.09 respectively according to one-tail paired t-test. The mean percentage decrease in K and Vp was 32% and 10% respectively. Functional images of the two parameters before and after treatment were generated and showed clearly the effect of steroids on the reduction of K in brain tumors. In contrast, when before and after treatment contrast enhanced CT scans were compared, no difference was observed in the enhancement in 8 out of 10 cases. The result obtained support the conclusion that: (1) corticosteroids reduce the blood-brain permeability to small hydrophilic molecules; (2) the X-ray computed tomography method we have developed can be used to measure the K and Vp response of brain tumors to steroid therapy; and, (3) ordinary contrast enhanced CT scans at one fixed time or multiple times after contrast injection are not sensitive in detecting the reduction of K due to steroids.

Blood-Brain Barrier↗
PubMed1994

LCB 2183 inhibits the inflammation associated with oxazolone-induced contact sensitivity.

LCB 2183, an anti-allergic and potential anti-asthma compound, has been investigated for its ability to inhibit contact sensitivity in the mouse. The delayed response to epicutaneous hapten challenge in this model is a classical T-cell-mediated inflammatory reaction which is dependent on an early initiation phase. Both the early and late components of oxazolone-induced contact sensitivity were inhibited by oral administration of LCB 2183 in a dose-dependent manner. The drug appears to act on the efferent limb of the response since administration before hapten challenge was effective, while administration before the initial sensitization was not. LCB 2183 acts early in the cascade of events leading to inflammation, since the initiation phase of the response was inhibited; nonetheless, an effect of the drug on the late acting inflammatory cells cannot be ruled out. In comparison with oral prednisolone, which was also able to inhibit both the early and late components of the response, LCB 2183 was less active. Sodium cromoglycate and nedocromil sodium, which are poorly absorbed from the gastrointestinal tract, were tested by intraperitoneal administration. Neither of these agents significantly altered the delayed response and only nedocromil sodium had a limited inhibitory effect on the early initiation phase. Thus, in this model, LCB 2183 demonstrated more anti-inflammatory potential and resembled prednisolone more closely than either nedocromil sodium or sodium cromoglycate. The possible relevance of these effects in relation to the inflammation which characterizes human asthma is considered.

Animals↗
PubMed1994

Treatment of advanced colorectal carcinoma with 5-fluorouracil, leucovorin and Roferon-A: a Southwest Oncology Study Group Study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, a pilot study was conducted in which patients with advanced colorectal carcinoma were treated with 5-fluorouracil (5-FU), leucovorin (LV) and Roferon-A. Treatment consisted of LV 20 mg/m2 i.v. push followed by 5-FU, 425 mg/m2 i.v. push daily for 5 days every 4 weeks for 2 cycles, then every 5 weeks; Roferon-A 9 million units subcutaneously was given three times weekly every week. Forty-six eligible patients with bidimensionally measurable disease who had received no prior chemotherapy for advanced disease were treated with this regimen. The most frequent toxicity was leukopenia with 80% of patients experiencing some degree of leukopenia and the most severe toxicity was granulocytopenia with 46% of patients experiencing granulocyte counts < 1,000/mm3. Among the 46 eligible patients, the objective response rate was 13% (95% confidence interval, 5-26%). Thirty-five of the 46 patients have died with a median survival of 17 months. This regimen has significant toxicity and insufficient activity against advanced colorectal carcinoma to warrant further trials.

Adult↗
PubMed1994

Sheep linkage mapping: nineteen linkage groups derived from the analysis of paternal half-sib families.

Nineteen linkage groups containing a total of 52 markers have been identified in the sheep genome after typing large paternal half-sib families. The linkage groups range in size from 2 markers showing no recombination to a group containing 6 markers covering approximately 30 cM of the sheep genome. Thirteen of the groups have been assigned to a sheep chromosome. Three groups contain markers from bovine syntenic groups U2, U7 and U29, and one other group contains a marker that has been mapped only in humans. The remaining three groups are unassigned. This information will provide a useful foundation for a genetic linkage map of sheep.

Animals↗
PubMed1994

Cytokine-induced expression of nitric oxide synthase in C2C12 skeletal muscle myocytes.

Nitric oxide (NO) is an important mediator of diverse physiological and pathological responses. To determine whether NO production can be induced in skeletal muscle, we stimulated C2C12 mouse skeletal muscle myocytes with putative inducers of nitric oxide synthase (NOS). Neither lipopolysaccharide (LPS), interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF), nor interferon-gamma (IFN) was able to stimulate nitrite production by C2C12 cells when administered alone. However, combinations of IFN with either TNF or IL-1 resulted in significant nitrite production; simultaneous stimulation of cells with all three cytokines resulted in significantly increased nitrite production compared with any combination of two cytokines. Northern analysis of RNA obtained from stimulated C2C12 cells revealed induction of a single mRNA band that precisely coincided with the mRNA band of mouse macrophage-inducible NOS (iNOS). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis followed by sequencing of the 5' 765 bases of the skeletal muscle iNOS cDNA demonstrated exact homology with mouse macrophage iNOS. These findings indicate that combinations of cytokines stimulate NO production in skeletal muscle cells via induction of the macrophage-type iNOS gene.

Amino Acid Oxidoreductases↗
PubMed1994

Lung epithelial lining fluid T cell subsets defined by distinct patterns of beta 7 and beta 1 integrin expression.

Integrins are heterodimeric cell-surface glycoproteins that mediate cell-cell and cell-matrix adhesion. We previously identified cDNA encoding a novel integrin beta subunit, beta 7, from bronchoalveolar lavage fluid (BALF) leukocytes. The beta 7 subunit protein is now known to associate with at least two integrin alpha subunits on lymphocytes. One beta 7 integrin, alpha 4 beta 7, mediates lymphocyte adhesion to endothelium and to fibronectin. The other known beta 7 integrin, alpha E beta 7, has recently been shown to mediate lymphocyte-epithelial cell adhesion in vitro. We used flow microfluorometry to analyze the expression of alpha 4 beta 7, alpha E beta 7, and other integrins on blood T cells and epithelial lining fluid T cells obtained from five healthy adult volunteers by bronchoalveolar lavage. alpha 4 beta 7 was the predominant beta 7 integrin on blood T cells, whereas alpha E beta 7 was predominant on BALF T cells. BALF T cells could be divided into alpha E beta 7- and alpha E beta 7+ subsets. Between 29 and 61% (mean 42%) of CD3+ T cells were alpha E beta 7+ alpha E beta 7 was more likely to be present on CD8+ T cells (mean 69% alpha E beta 7+) than on CD4+ T cells (mean 29% alpha E beta 7+). The alpha E beta 7- and alpha E beta 7+ BALF T cell subsets were also found to differ in their expression of other integrins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effect of pH on the bioenergetics of perfused porcine lenses.

Extracellular and intracellular pH has been shown to be an important physiological variable in many biological systems. However, studies on the effect of pH on the metabolic status of the mammalian lens have been few. It has been shown previously that a change in perfusate pH has a significant effect on the lens weight, ion transport, opacification and membrane potential. In this study we show that the bioenergetic status of the perfused pig lens, as assessed by 31P-NMR spectroscopy, is critically dependent on the pH of the bathing medium. At pH's of 7.6 and above, these perfused lenses maintained their nucleotide triphosphates concentrations steady for up to 4 days. In contrast, lenses perfused with identical media at pH 7.0, rapidly lost their nucleotide triphosphates. Our findings suggest that the pH of the extracellular pH may be an important parameter in maintaining the functional competence of the lens.

Adenosine Triphosphate↗