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Biomedical subjects

C Matthews

Publications and source records attributed to C Matthews.

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

Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients.

To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 7 1/3 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma (Cmax) and the time to reach Cmax were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally (P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC(0-8)) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases in Cmax and the concentration at 8 h postdosing (C8) were not as great as the decrease in AUC(0-8). Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically (P > 0.5) or clinically significant effect on the Cmax and C8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.

Adolescent↗
PubMed1998

NO decreases phosphorylation of focal adhesion proteins via reduction of Ca in rat aortic smooth muscle cells.

Our laboratory has previously reported that the antimitogenic effect of nitric oxide (NO) in primary cultures of rat aortic smooth muscle cells may be attributed to activation of protein tyrosine phosphatase and dephosphorylation of protein phosphotyrosine [G.S. Dhaunsi, C. Matthews, K. Kaur, and A. Hassid, Am, J. Physiol. 272 (Heart Circ. Physiol. 41): H1342-H1349, 1997]. The goal of the current study was to investigate the role of cytoplasmic Ca in this process and to identify protein substrates that are dephosphorylated by treatment with NO. Treatment of primary rat aortic smooth muscle cell cultures with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) decreased cytoplasmic Ca levels and elicited phosphotyrosine dephosphorylation. Both effects were mimicked by the extracellular and intracellular Ca chelators ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), respectively, and by the Ca channel blocker nifedipine. Conversely, elevation of cytoplasmic Ca via the use of the Ca ionophore A-23187 or high extracellular K+ prevented or attenuated SNAP-induced dephosphorylation. Both BAPTA and nifedipine also decreased DNA synthesis, providing further evidence to link dephosphorylation to antimitogenesis. Two of the proteins dephosphorylated by treatment of cells with NO or EGTA were identified as the focal adhesion proteins, cortactin and paxillin. These results indicate that NO-induced dephosphorylation of protein phosphotyrosine is mediated by reduction of cytoplasmic Ca and suggest that dephosphorylation of focal adhesion proteins may be of relevance to the antimitogenic effect of NO.

Animals↗
PubMed1998

Follitropin (FSH) deficiency in an infertile male due to FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations.

We studied a man who sought medical attention at age 28 years because of infertility in both his first and second marriages. His sexual development appeared to have been normal, with normal puberty and virilization, and normal libido and sexual potency. At examination, his testicles were small and soft; otherwise he had a normal physical appearance. Evaluations revealed azoospermia, undetectable in serum before and after 100 microg of intravenously administered gonadotrophin releasing hormone, but moderately elevated lutropin concentration with a brisk rise after gonadotrophin releasing hormone. The alpha subunit concentration was normal before and after gonadotrophin releasing hormone; that of inhibin B was very low. Analysis of the follitropin beta gene, exon 3, revealed a Cys82 --> Arg mutation (TGT --> CGT). Judging from studies of the biosynthesis of the chorionic gonadotrophin beta subunit one may conclude that inability to form the first intramolecular disulphide bond in the follitropin beta subunit results in an abnormal tertiary structure during follitropin beta biosynthesis with extensive intracellular degradation of the products, inability to associate with the alpha subunit and defective glycosylation, as well as inability to form a biologically active hormone. This first male case of follitropin deficiency thus defines a new syndrome of male infertility.

Adult↗
PubMed1997

A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators.

The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone beta receptor (TR beta) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo- and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic alpha-helix at the carboxyl terminus of TR beta and the position of the homologous residue in the crystal structure of TR alpha indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroid-stimulating hormone alpha promoter by this mutant, suggests that the amphipathic alpha-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Reduced pregnancy rates following the transfer of human embryos frozen or thawed in culture media supplemented with normal serum albumin.

Over a 26 month period 17% of couples having treatment in our clinical programmes selected a commercially available protein (normal serum albumin, NSA) prepared from pooled human sera instead of using their own serum as a supplement for their embryo culture media. In a retrospective analysis of >2000 gonadotrophin-stimulated cycles and 1000 cycles where frozen/thawed embryos were transferred, fertilization, embryo quality and pregnancy rates following in-vitro fertilization (IVF), gamete intra-Fallopian transfer (GIFT) or intracytoplasmic sperm injection (ICSI) were unaffected by the type of protein used to supplement the culture medium. When embryos were thawed in medium containing NSA, both pregnancy (PR) and implantation rates (IR) were significantly lower (P <0.05) than if the medium was supplemented with serum (PR 8.3% and 17.5%; IR 4.6% and 10.5%). Inclusion of NSA before freezing reduced the IR of thawed embryos. To further test this observation all cycles where embryos were cultured and frozen in medium containing NSA (173 cycles) were matched to cycles where serum was used and the outcome was compared. At the end of 1995 just over half of the embryos in both groups had been thawed. No statistical difference was noted in the pregnancy rates (NSA, 5.6% versus serum, 11.3%) but the IR per embryo was significantly lower when embryos were cultured and frozen in medium supplemented with NSA (2.2%) than when serum was used as the supplement (6.6%).

Blood↗
PubMed1997

Paraoxonase (PON1) gene in mice: sequencing, chromosomal localization and developmental expression.

Serum paraoxonase hydrolyses the toxic metabolites of several organophosphorus insecticides, as well as the nerve agents soman and sarin. We have previously shown that elevated serum paraoxonase levels protect mice against organophosphate toxicity. In the present study, we determined the cDNA sequence and chromosomal location of the mouse paraoxonase gene, as well as its developmental expression in mice and rats. The mouse cDNA encodes a protein of 355 amino acids and shows 81% identity with the human sequence. In situ hybridization demonstrated that the mouse paraoxonase gene maps to chromosome 6, a region conserved with the paraoxonase region of chromosome 7q21-22 in humans. Serum paraoxonase activities toward three substrates, paraoxon, chlorpyrifos-oxon and diazoxon, were very low at birth and increased with age reaching adult levels at 20 days in mice and 25 days in rats. The increase of serum paraoxonase activity in developing animals correlates well with the increased resistance to organophosphate poisoning that has been reported in previous studies.

Age Factors↗
PubMed1997

NO increases protein tyrosine phosphatase activity in smooth muscle cells: relationship to antimitogenesis.

We investigated the mechanisms of NO-induced antimitogenesis in primary aortic smooth muscle cells from newborn rats. S-nitroso-N-acetylpenicillamine (SNAP), an NO-releasing agent, decreased basal and growth factor-stimulated DNA synthesis with a threshold effectiveness of 0.3-3 microM. A second NO-releasing agent, 3-morpholinosydnonimine-N-ethylcarbamide, a hydrolysis-resistant cyclic nucleotide, 8-bromo-guanosine 3',5'-cyclic monophosphate (8-BrcGMP), and atrial natriuretic peptides elicited a similar effect, whereas 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP) was ineffective, supporting the view that NO and cGMP, but not cAMP, mediated at least some of SNAP's antimitogenic effect. SNAP and 8-BrcGMP decreased the levels of phosphotyrosine, especially in proteins of 70-85 kDa and approximately 215 kDa molecular mass. SNAP decreased protein phosphotyrosine levels with a threshold effectiveness similar to that of its antimitogenic effect. Moreover, SNAP increased protein tyrosine phosphatase (PTPase) activity in cell homogenates, indicating that phosphotyrosine dephosphorylation was likely to be the result of increased PTPase activity. Peroxovanadate, a selective PTPase inhibitor, blocked the antimitogenic effect of 8-BrcGMP, suggesting that loss of protein phosphotyrosine and antimitogenesis were causally linked. These findings describe a potential mechanism for NO-induced antimitogenesis in aortic smooth muscle cells in primary culture.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Systolic blood pressure response to exercise in black and white preadolescent and early adolescent boys.

OBJECTIVE: To investigate differences in the response of systolic blood pressure (SBP) to exercise in black and white boys while controlling for the possible confounding effects of relative body weight, body surface area, physical work capacity index, preexercise SBP, and average power output. DESIGN: Comparative and correlational. PARTICIPANTS: Eighty-seven black and 52 white boys between the ages of 5 and 16 years. Participants were recruited from day camps, community centers, and summer recreation programs in and near Augusta, Ga. INTERVENTIONS: None. MEASUREMENTS/MAIN OUTCOMES: The slope of the SBP response to exercise was not significantly different between groups. Analysis of covariance revealed race, age, relative body weight, body surface area, preexercise SBP, and average power output to be significant univariate predictors of SBP at each power output. With multiple regression analyses, the effect of race was removed, and only preexercise SBP and average power output were found to be significant predictors of exercise SBP. CONCLUSION: There were no significant differences between black and white boys in the SBP response to exercise after controlling for the effects of preexercise SBP and average power output.

Adolescent↗
PubMed1994

The minimal metabolism of inhaled 1,1,1,2-tetrafluoroethane to trifluoroacetic acid in man as determined by high sensitivity 19F nuclear magnetic resonance spectroscopy of urine samples.

In this work, oxidative metabolism of the new propellant, 1,1,1,2-tetrafluoroethane to trifluoroacetic acid in man is shown to be minimal. Alternative propellants and refrigerants are under development to replace the currently used chlorofluorocarbons which lead to stratospheric ozone depletion. One potentially useful replacement is the hydrofluorocarbon, 1,1,1,2-tetrafluoroethane (HFA-134a). Before it can be used, however, particularly as a propellant in an aerosol pharmaceutical formulation whereby the compound is in effect dosed to people, it is important that the safety of this compound is established. As a part of this safety evaluation it is necessary to understand the metabolism of HFA-134a. In this work the production of the potential oxidative metabolite of HFA-134a, trifluoroacetic acid (TFA) has been studied in human urine following inhalation dosing with HFA-134a. The concentrations of TFA in urine have been measured using a highly sensitive 19F nuclear magnetic resonance procedure with a limit of detection of 10 ng ml-1 based on an acquisition time of only 2.25 h per sample. TFA is the only fluorinated species observed in the urine samples and only at very low levels, indicating that the oxidative route of metabolism can occur in vivo in man, but this metabolism is minimal in terms of percentage of administered dose.

Adult↗
PubMed1994

Whole body composition and regional bone mass in women with insulin-dependent diabetes mellitus.

OBJECTIVE: Reduced bone mass has been reported in adult patients with insulin-dependent diabetes mellitus but there are few data on bone density in the axial skeleton or on whole body composition in this group. The aim of this study was to determine whether whole body and regional bone mass are normal in middle-aged women with insulin-dependent diabetes mellitus. DESIGN: Total and regional bone mass were measured in 24 post-menopausal women aged 43-69 years (mean 56.3) with insulin-dependent diabetes, recruited during routine clinic attendance. Results were compared with those obtained from 24 age and weight-matched community-based post-menopausal women. MEASUREMENTS: Whole body bone mineral content and bone mass in the lumbar spine and femoral neck were measured by dual energy X-ray absorptiometry on a Lunar DPX. RESULTS: Whole body bone mineral content was significantly lower in the diabetic women than in community-based controls (P = 0.02). There was no significant difference between the two groups in whole body bone density or lumbar spine bone density. Mean bone density in the femur was lower in the patient group at all sites assessed (femoral trochanter P = 0.003, femoral neck, P = 0.057). Values for all regional bone density measurements in the diabetic women were within the Lunar reference range (mean +/- 2 SD) and at all sites the mean value was close to 100% of the sex and age-matched reference value. There was no correlation between duration or control of diabetes and bone mass at any site. CONCLUSIONS: Insulin-dependent diabetes mellitus in middle-aged women is associated with small reductions in total body bone mineral content and in femoral bone density; the clinical significance of these findings in terms of subsequent fracture risk remains to be established. No evidence was found in this study for a reduction in whole body or lumbar spine bone density.

Adult↗
PubMed1994

Nitric oxide selectively amplifies FGF-2-induced mitogenesis in primary rat aortic smooth muscle cells.

Fibroblast growth factor is present in blood vessels and is thought to play an important role in promoting vascular cell proliferation in vivo. In the current study, we show that three agents that activate the guanosine 3',5'-cyclic monophosphate (cGMP) system, including the nitric oxide-generating agents S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) as well as the stable cGMP analogue 8-bromo-cGMP, increased fibroblast growth factor-2 (FGF-2; basic fibroblast growth factor)-induced [3H]thymidine incorporation by severalfold in primary cultures of rat aortic smooth muscle cells. SNAP increased the efficacy, but not the potency, of FGF-2. The stimulatory effect of SNAP was selective for FGF-2-induced mitogenesis as shown by the lack of a significant effect on [3H]thymidine incorporation induced by several other growth factors. Consistent with thymidine incorporation experiments, SNAP amplified the increase of the cellular DNA content induced by FGF-2 as well as the proliferation of cells. A selective inhibitor of cGMP phosphodiesterases, zaprinast, potentiated the comitogenic effect of SNAP and its ability to increase cGMP levels, supporting the involvement of cGMP as second messenger. Consistent with previous results, and opposite to that found in primary and early subculture, SNAP decreased mitogen-induced [3H]thymidine incorporation in cells in later subculture. Because macrophage- and vascular smooth muscle-derived nitric oxide is likely to be present in relatively large concentrations after vascular injury, we speculate that endogenous nitric oxide may amplify the activity of FGF-2 in vivo.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively asymptomatic, suggesting a generalized disorder (GRTH) or associated with thyrotoxic features, indicating possible selective pituitary resistance (PRTH). 20 GRTH and 9 PRTH cases, sporadic or dominantly inherited, were analyzed. Affected individuals were heterozygous for single nucleotide substitutions in the thyroid hormone receptor beta gene, except for a single case of a seven nucleotide insertion. With one exception, the corresponding 13 novel and 7 known codon changes localized to and extended the boundaries of two mutation clusters in the hormone-binding domain of the receptor. 15 kindreds shared 6 different mutations, and haplotype analyses of the mutant allele showed that they occurred independently. The majority (14 out of 19) of the recurrent but a minority (1 out of 10) of unique mutations were transitions of CpG dinucleotides. Mutant receptor binding to ligand was moderately or severely impaired and did not correlate with the magnitude of thyroid dysfunction. There was no association between clinical features and the nature or location of a receptor mutation. These observations suggest that GRTH and PRTH are phenotypic variants of the same genetic disorder, whose clinical expression may be modulated by other non-mutation-related factors.

Adolescent↗
PubMed1993

Hepatic tumors: role of computed tomographic arterial portography in surgical planning.

Various imaging modalities currently used to evaluate liver tumors include magnetic resonance imaging, ultrasonography, contrast-enhanced computed tomography, and computed tomographic arterial portography. In our review of 28 cases, we found CT arterial portography to be very sensitive, and in 5 of these 28 cases CT arterial portography was a key factor in altering the course of therapy.

Adult↗