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J C Martin

Publications and source records attributed to J C Martin.

At least 19 recordsLinked to original sources
PubMed1992

Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase.

Peroxynitrite (ONOO-), the reaction product of superoxide (O2-) and nitric oxide (NO), may be a major cytotoxic agent produced during inflammation, sepsis, and ischemia/reperfusion. Bovine Cu,Zn superoxide dismutase reacted with peroxynitrite to form a stable yellow protein-bound adduct identified as nitrotyrosine. The uv-visible spectrum of the peroxynitrite-modified superoxide dismutase was highly pH dependent, exhibiting a peak at 438 nm at alkaline pH that shifts to 356 nm at acidic pH. An equivalent uv-visible spectrum was obtained by Cu,Zn superoxide dismutase treated with tetranitromethane. The Raman spectrum of authentic nitrotyrosine was contained in the spectrum of peroxynitrite-modified Cu,Zn superoxide dismutase. The reaction was specific for peroxynitrite because no significant amounts of nitrotyrosine were formed with nitric oxide (NO), nitrogen dioxide (NO2), nitrite (NO2-), or nitrate (NO3-). Removal of the copper from the Cu,Zn superoxide dismutase prevented formation of nitrotyrosine by peroxynitrite. The mechanism appears to involve peroxynitrite initially reacting with the active site copper to form an intermediate with the reactivity of nitronium ion (NO2+), which then nitrates tyrosine on a second molecule of superoxide dismutase. In the absence of exogenous phenolics, the rate of nitration of tyrosine followed second-order kinetics with respect to Cu,Zn superoxide dismutase concentration, proceeding at a rate of 1.0 +/- 0.1 M-1.s-1. Peroxynitrite-mediated nitration of tyrosine was also observed with the Mn and Fe superoxide dismutases as well as other copper-containing proteins.

Animals↗
PubMed1992

Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite.

Superoxide dismutase and Fe3+EDTA catalyzed the nitration by peroxynitrite (ONOO-) of a wide range of phenolics including tyrosine in proteins. Nitration was not mediated by a free radical mechanism because hydroxyl radical scavengers did not reduce either superoxide dismutase or Fe3+EDTA-catalyzed nitration and nitrogen dioxide was not a significant product from either catalyst. Rather, metal ions appear to catalyze the heterolytic cleavage of peroxynitrite to form a nitronium-like species (NO2+). The calculated energy for separating peroxynitrous acid into hydroxide ion and nitronium ion is 13 kcal.mol-1 at pH 7.0. Fe3+EDTA catalyzed nitration with an activation energy of 12 kcal.mol-1 at a rate of 5700 M-1.s-1 at 37 degrees C and pH 7.5. The reaction rate of peroxynitrite with bovine Cu,Zn superoxide dismutase was 10(5) M-1.s-1 at low superoxide dismutase concentrations, but the rate of nitration became independent of superoxide dismutase concentration above 10 microM with only 9% of added peroxynitrite yielding nitrophenol. We propose that peroxynitrite anion is more stable in the cis conformation, whereas only a higher energy species in the trans conformation can fit in the active site of Cu,Zn superoxide dismutase. At high superoxide dismutase concentrations, phenolic nitration may be limited by the rate of isomerization from the cis to trans conformations of peroxynitrite as well as by competing pathways for peroxynitrite decomposition. In contrast, Fe3+EDTA appears to react directly with the cis anion, resulting in greater nitration yields.

Animals↗
PubMed1992

Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine.

A number of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and tested in vitro for anti-herpes and anti-human immunodeficiency virus (HIV) activity. Among these analogues, (R)-2'-methyl-PMEG [(R)-3] and 2',2'-dimethyl-PMEG (7) demonstrated potent anti-HIV activity in the XTT assay with EC50 values of 1.0 and 2.6 microM, respectively. The corresponding (S)-2'-methyl-PMEG [(S)-3] was found to be less potent against HIV. In addition, the (R) and (S) enantiomers of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine (HPMPG, 8) were prepared for comparison of biological activity, and shown to be active and equipotent against herpesviruses, but inactive against HIV.

Antiviral Agents↗
PubMed1992

Hageman factor and risk of myocardial infarction in middle-aged men.

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.

Aged↗
PubMed1992

Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.

Adenine↗
PubMed1992

Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is an antiviral phosphonate nucleotide analogue that displays activity against a range of herpesviruses. Anion exchange high performance liquid chromatography analysis of the 60% methanol extract from [14C]HPMPC-treated cells reveals the formation of three major metabolites. Two of these were identified as phosphorylated forms of HPMPC, HPMPC phosphate, and HPMPC diphosphate, by liberation of HPMPC upon acid digestion and coelution with synthetic standards on high performance liquid chromatography. The third metabolite, which is resistant to alkaline phosphatase cleavage but sensitive to phosphodiesterase, is proposed to be an HPMPC phosphate adduct. In herpes simplex virus-1-infected cells the same three metabolites are detected, at concentrations comparable to those in uninfected cells. When HPMPC is removed from the medium, the concentrations of the metabolites in cells decrease slowly, with half-lives of approximately 6, 17, and 48 hr for HPMPC phosphate, HPMPC diphosphate, and the HPMPC phosphate adduct, respectively. HPMPC diphosphate inhibits herpes simplex virus-1 and -2 DNA polymerases with a lower Ki than that for DNA polymerase alpha, and enzyme inhibition is competitive in each case. The formation and the persistence of HPMPC phosphates in cells and the selective inhibition of viral DNA polymerases by HPMPC diphosphate can explain why cells pretreated with HPMPC remain refractory to viral infection even long after HPMPC is removed from the medium.

Animals↗
PubMed1991

Immunofluorescence-digital image processing system for the quantitation of secreted immunoglobulin by single cells.

To quantitate the amount of secreted immunoglobulin (Ig) by a single cell, the immunofluorescence digital image processing (IDIP) system was adapted to the modified enzyme-linked immunospot (ELI-SPOT) assay. In this assay, an immunofluorescence (tetramethylrhodamine isothiocyanate) conjugated antibody was used for the detection of spots instead of the usual method of enzyme coupling. We have named this the immunofluorescence-linked immunospot (ILISPOT) assay. In addition to the quantitation of secreted Ig by single cells, this method allowed us to objectively determine the exact number of Ig producing spot forming cells (SFC). 96 well culture plates were pre-coated with goat anti-mouse Ig. The mouse IgM producing hybridoma (E-3-4) was incubated in the plates for 4 h at 37 degrees C. Cells were removed prior to the addition of biotinylated goat anti-mouse mu antibody. After overnight incubation, immunofluorescence conjugated avidin was added for the visualization of spots by the IDIP system. The IDIP system consists of a fluorescent microscope equipped with a video camera and computer. The gray scale of secreted IgM was initially established as a standard by the known amount of purified IgM. By using digital image processing, the number of spots and the gray scale of individual spots were computed. The shape and pattern of gray scale data were used to distinguish between the real spots and pseudo spots. This IDIP system could detect as little as 0.19 pg of secreted IgM (1.2 x 10(5) molecules) and an average of approximately 1.33 pg (8.3 x 10(5) molecules) produced by a single cell. Adaptation of the digital image processing system to the ILISPOT assay allowed the measurement of both the amount of Ig produced at the single cell level and also the exact numbers of SFC present in a totally objective fashion.

Animals↗
PubMed1991

Structural studies of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (D4T).

An x-ray crystallographic analysis of the potent anti-HIV agent D4T revealed two independent conformations (conformers a and b) with different glycosyl bonds and furanose geometries. Conformer a exhibits the unusual O4' exo configuration and chi (C2, N1, C1', O4') of -118 degrees. Conformer b exhibits a nearly planar furanose geometry and chi of -174 degrees. The reduced form of D4T, ddT, is poorly active against HIV and also exists in two independent conformations. Chi of forms a and b (-129 and -170.9 degrees) are similar to that found with D4T. However, the furanoses exhibit the classical C2' endo and C3' endo geometries, respectively. These observed differences are not sufficient to account for the differing potencies of D4T versus ddT.

Antiviral Agents↗
PubMed1991

Cocaine and the use of alcohol and other drugs during pregnancy.

Recent reports of adverse pregnancy outcomes associated with prenatal cocaine exposure have raised questions about the actual numbers of infants who are exposed to cocaine in utero. Whereas toxicologic urine screens obtained at delivery can detect cocaine use in the preceding few days, they fail to yield a comprehensive picture of use during and immediately before pregnancy. According to postpartum self-report, 15% of a teaching hospital sample and 3% of a private hospital sample of mothers had used cocaine during pregnancy or in the previous month (total = 876). Rates at the teaching hospital reflect a fifteenfold increase over the past 12-year period, when compared with previously obtained data. Cocaine users were significantly more likely to report that they drank alcohol, smoked cigarettes, and took other illicit drugs during pregnancy than women who denied using cocaine. Mothers at highest risk for cocaine use were those who were black (20%), were single-separated-divorced (24% to 33%), and had less than a high school education (21%).

Adolescent↗
PubMed1991

Plasma factor VII is activated by postprandial triglyceridaemia, irrespective of dietary fat composition.

Nine adults took two 7-day diets of standardised energy and total fat content, but with a dietary polyunsaturated/saturated fat ratio of less than 0.3 and greater than 3.0 respectively, while adhering to their daily routine. Blood was drawn on 6 occasions between 09.00 and 22.45 h on the final day of each dietary period for factor VII activity (VIIc), factor VII antigen (VIIag) and lipoprotein lipid concentrations. Diurnal variation was described for each variable in terms of its deviation from the individual's daily mean value at each time point across the day. Plasma triglyceride remained low until after the midday meal, whereafter a marked rise was sustained into the later evening. Plasma VIIc declined until early afternoon, but showed a marked rise in the late afternoon. Plasma VIIag showed no significant diurnal variation. Changes in plasma triglyceride concentration during the day were related positively to changes in VIIc about 160 min later, but not to VIIc at other time points. This effect of postprandial triglyceridaemia on VIIc persisted after allowance for the effect of VIIag on VIIc. Dietary fat composition did not influence VIIc or VIIag. The results suggested an acute but evanescent effect of triglyceride-rich lipoproteins on the reactivity of factor VII, irrespective of their lipid core composition.

Antigens↗
PubMed1991

Evaluation of infrequent dosing regimens with (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine (S-HPMPC) on simian varicella infection in monkeys.

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (S-HPMPC) was able to prevent simian varicella infection in African green monkeys inoculated intratracheally with virus. A dose of 50 mg/S-HPMPC/kg administered intravenously was shown to prevent the development of rash, reduce viremia and protect the monkeys from death. The 50 mg/kg dose was effective when treatments initiated on day 2 post-infection (p.i.) was given as ten daily doses of 5 mg/kg, as 10 mg/kg administered on five days on an alternate-day schedule, as two 25 mg/kg doses given on day 2 and on day 7 p.i., or as a single injection of 50 mg/kg on day 2. The single 50 mg/kg dose was also effective when treatment was delayed until four days p.i., but was ineffective when treatment was delayed until six days p.i. The 50 mg/kg dose was not effective when given orally by gavage. No evidence of toxicity was noted in daily clinical examinations, or in frequent hematology and clinical chemistry tests performed during the clinical evaluation of the infection.

Administration, Oral↗
PubMed1991

Rapid DNA sequencing based upon single molecule detection.

We are developing a laser-based technique for the rapid sequencing of 40-kb or larger fragments of DNA at a rate of 100 to 1000 bases per second. The approach relies on fluorescent labeling of the bases in a single fragment of DNA, attachment of this labeled DNA fragment to a support, movement of the supported DNA fragment into a flowing sample stream, and detection of individual fluorescently labeled bases as they are cleaved from the DNA fragment by an exonuclease. The ability to sequence large fragments of DNA will significantly reduce the amount of subcloning and the number of overlapping sequences required to assemble megabase segments of sequence information.

Base Sequence↗
PubMed1991

A new class of acyclic phosphonate nucleotide analogues: phosphonate isosteres of acyclovir and ganciclovir monophosphates as antiviral agents.

Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.

Acyclovir↗
PubMed1991

Essential fatty acid composition of human colostrum triglycerides: its relationship with adipose tissue composition.

The relationships between essential fatty acid (EFA) composition of colostrum and white adipose tissue (WAT) were examined on day 5 after delivery in 69 healthy women. Fatty acid composition was assessed by capillary gas chromatography, and 33 fatty acids were detected in colostrum and in WAT. Total polyunsaturated fatty acid (PUFA) content was similar in colostrum and in WAT (15.7 +/- 3.1% and 16.1 +/- 3.8%, respectively), but long-chain PUFA content was higher in colostrum than in WAT (2.9 +/- 0.6% and 1 +/- 0.2%, respectively; P less than 0.001). The concentrations of linoleic acid were significantly correlated between colostrum and WAT (r = 0.77, P less than 0.0001). No correlation was found for alpha-linolenic acid. The relationships between long-chain PUFA composition of colostrum and WAT suggested that individual factors along with tissue specificity of the mammary gland are involved in either the capacity of desaturating and chain-elongating pathways and/or incorporation of long-chain PUFAs into colostrum.

Adipose Tissue↗
PubMed1991

[Malherbe's calcifying epithelioma (pilomatrixoma) of the head and neck].

Calcifying Epitheliomas of Malherbe (Pilomatrixomas) are benign tumors that have their origin in the hair matrix and clinically resemble a hard subcutaneous swelling. Most of these tumors are placed in the head and neck region, in our sample the Pilomatrixomas of this location were 49.6% of the total. The middle age of presentation of this tumor were 32.2 years, with two main peaks of incidence below 20 years and under 50. The most frequent locations were the auricular, cervical, ciliar, frontal, and temporal regions, with one case of multiple location. The middle size of the tumor in our sample was 1.2 cm. In this paper we review the main pathologic, clinic and therapeutic features of this lesion in the head and neck region.

Adolescent↗