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Biomedical subjects

B A Martin

Publications and source records attributed to B A Martin.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group.

A previous study (M.J. Robinson, B.A. Martin, T.D. Gootz, P.R. McGuirk, M. Moynihan, J.A. Sutcliffe, and N. Osheroff, J. Biol. Chem. 266:14585-14592, 1991) demonstrated that novel 6,8-difluoroquinolones were potent effectors of eukaryotic topoisomerase II. To determine the contribution of the C-8 fluorine to drug potency, we compared the effects of CP-115,955 [6-fluoro-7-(4-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid] on the enzymatic activities of Drosophila melanogaster topoisomerase II with those of CP-115,953 (the 6,8-difluoro parent compound of CP-115,955). Removal of the C-8 fluoro group decreased the ability of the quinolone to enhance enzyme-mediated DNA cleavage approximately 2.5-fold. Like its difluorinated counterpart, CP-115,955 increased the levels of cleavage intermediates without impairing the DNA religation reaction of the enzyme. Removal of the C-8 fluorine reduced the ability of the quinolone to inhibit topoisomerase II-catalyzed DNA relaxation. In addition, the cytotoxicity of CP-115,955 towards Chinese hamster ovary cells was decreased compared with that of CP-115,953. These results demonstrate that the C-8 fluorine increases the potency of quinolone derivatives against eukaryotic topoisomerase II and mammalian cells. Further comparisons of CP-115,955 with CP-115,953 and CP-67,804 (the N-1 ethyl-substituted derivative of the difluoro parent compound) indicate that the two intrinsic activities of quinolone-based drugs towards topoisomerase II (i.e., enhancement of DNA cleavage and inhibition of catalytic strand passage) can be differentially influenced by alteration of ring substituents. Finally, correlations between the biochemical and cytological activities of these drugs suggest that the ability to inhibit catalytic strand passage enhances the cytotoxic potential of quinolones towards eukaryotic cells.

Animals↗
PubMed1991

Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage.

The effects of two novel quinolone derivatives, CP-67,804 and CP-115,953 (the 1-ethyl and 1-cyclopropyl derivatives of 6,8-difluoro-7-(4-hydroxyphenyl)-4-quinolone-3-carboxylic acid, respectively), on the enzymatic activities of Drosophila melanogaster topoisomerase II were examined. Both drugs enhanced the enzyme's pre- and post-strand passage DNA cleavage activities. CP-67,804 was nearly as potent an enhancer as etoposide, while CP-115,953 was approximately 2 times more potent than this topoisomerase II-targeted antineoplastic drug. In contrast to etoposide, which stabilizes enzyme-DNA cleavage complexes primarily by inhibiting topoisomerase II-mediated DNA religation, neither quinolone impaired the enzyme's ability to religate cleaved DNA. To further assess the characteristics of these unusual quinolone derivatives, the cytotoxic effects of CP-67,804 and CP-115,953 toward wild-type Chinese hamster ovary cells and VpmR-5 cells (an epipodophyllotoxin-resistant Chinese hamster ovary line) were examined. Both quinolones were cytotoxic to the wild-type cells. CP-115,953 was the more potent agent and displayed a level of cytotoxicity similar to that of etoposide. Finally, the VpmR-5 line showed cross-resistance to CP-67,804 (approximately 3.7-fold) and CP-115,953 (approximately 1.3-fold). Although quinolone cross-resistance was less pronounced than observed for etoposide (approximately 12-fold), it indicates that topoisomerase II is a physiological target for CP-67,804 and CP-115,953 in mammalian cells. These findings strongly suggest that these quinolone derivatives represent a novel class of topoisomerase II-targeted drugs which have potential as antineoplastic agents.

Animals↗
PubMed1991

Characterization of high-level quinolone resistance in Campylobacter jejuni.

High-level resistance to quinolones has previously been shown to occur in Campylobacter spp. both in vitro and in patients treated with quinolones. We have selected isolates that are resistant to quinolones by plating cells from a susceptible C. jejuni strain, UA535, on medium containing nalidixic acid at 32 micrograms/ml. Fluctuation analysis indicated that resistance occurred by mutation at a frequency of 5 x 10(-8) per cell plated. Unlike what is observed with other gram-negative organisms, the nalidixic acid-resistant mutants demonstrated high-level cross-resistance (MIC, greater than or equal to 4 micrograms/ml) to newer quinolones, including ciprofloxacin, norfloxacin, and temafloxacin, yet remained susceptible to coumermycin A1 and several other unrelated antibiotics. Mutants with an identical resistance phenotype could also be selected from UA535 with ciprofloxacin and norfloxacin at a similar frequency. To study the mechanism of quinolone resistance, DNA gyrases were purified from C. jejuni UA535 and two resistant mutants by heparin-agarose and novobiocin-Sepharose chromatography. After the respective enzyme concentrations were adjusted to equivalent units of activity in the DNA supercoiling reaction, the DNA gyrases from the resistant mutants were found to be 100-fold less susceptible than the wild-type enzyme to inhibition by quinolones. Subunit switching experiments with purified A and B subunits from the wild type and one of the quinolone-resistant mutants indicated that an alteration in the A subunit was responsible for resistance. These results show that a single-step mutation can occur in vitro in the gene encoding DNA gyrase in C. jejuni, producing clinically relevant levels of resistance to the newer quinolones.

Anti-Infective Agents↗
PubMed1991

Electroconvulsive therapy: electric stimulus variables and the convulsive response.

The ability of an electrical stimulus to induce a grand mal convulsion during electroconvulsive therapy (ECT) was investigated using four clinical treatment protocols during which the stimulus waveform, the electrical energy and/or the electrode placement were varied. The statistically significant results support the view that a pulsatile square wave stimulus is effective in inducing convulsions, provided that the d'Elia and not the Muller unilateral electrode placement is used. Higher stimulus energy may be required for older patients. The results illustrate successive attempts to remedy a previously reported problem with the effectiveness of the pulsatile waveform as a convulsive stimulus. The benefit of maintaining a database of treatment variables in order to monitor the effect of changes in the protocol under conditions of routine clinical practice is also demonstrated.

Adult↗
PubMed1991

Electric stimulus energy and the clinical response to electroconvulsive therapy.

The relationship between electric stimulus energy and clinical response was examined in depressed patients receiving electroconvulsive therapy (ECT) under routine clinical conditions with a protocol which dichotomized the stimulus energy by patient age. There was no significant difference in the number of treatments and cumulative seizure duration between groups. The results support the observation that the stimulus energy may contribute to the therapeutic effect of ECT. Reduction of that energy in order to minimize side-effects may compromise the therapeutic effectiveness. The implications for dosage strategies in routine clinical practice are discussed.

Adult↗
PubMed1990

Pollen germination is impeded by tap water.

Pollen germination in vitro is totally inhibited in tobacco (Nicotiana tabacum) and other species if tap water is used to prepare the germination medium. This effect is already fully present if tap water accounts for only 25% of the medium. Furthermore, the pollen grains deteriorate rapidly and the culture medium turns yellowish-brown. The water toxicity is not caused by one or several compounds regularly monitored by the water authorities but can be removed by ion exchange purification. Although the factor(s) responsible for the inhibition were not identified, the study clearly shows the presence of such a contaminant in three different Orange County (Southern California) water wells. The fact that a fundamental botanical process like pollen germination is inhibited by a factor in drinking water not included in water quality control causes some general health concern. In addition, crop yield might be largely reduced if overhead spray irrigation with this water is utilized. The experiments also suggest that pollen germination in vitro could serve as a sensitive and simple bioassay for water quality.

Journal Article↗
PubMed1990

Macromolecular synthesis in varicella-zoster virus-infected epithelial and fibroblast cells.

Replication of varicella-zoster virus (VZV) was studied in a range of human cells (Chang conjunctival, HEp2 and Vero) and compared with that in HEL cells. Evidence for virus-specific protein and nucleic acid synthesis was obtained from each of these cell lines. In some cell lines, virus proteins were clearly visible by polyacrylamide gel electrophoresis both with and without immunoprecipitation. Multiple passage of infected cells enhanced both virus-specific protein synthesis and shutoff of host protein synthesis. No qualitative differences in the patterns of VZV-specific protein synthesis were detected. Approximately 2000 copies of the VZV genome were detected per infected HEL cell.

Animals↗
PubMed1990

Respiration and Alternative Oxidase in Corn Seedling Tissues during Germination at Different Temperatures.

Respiration rates of Zea mays L. seedling tissues grown at 30 and 14 degrees C were measured at 25 degrees C at different stages of seedling growth. Accumulation of heat units was used to define the developmental stages to compare respiration between the two temperatures. At both temperatures, respiration rates of most tissues were highest at the youngest stages, then declined with age. Respiration rates of mesocotyl tissue were the most responsive to temperature, being nearly twofold higher when grown at 14 compared to 30 degrees C. Alternative pathway respiration increased concomitantly with respiration and was higher in mesocotyls grown in the cold. When seedlings were started at 30 then transferred to 14 degrees C, the increase in alternative pathway respiration due to cold was not observed unless the seedlings were transferred before 2 days of growth. Seedlings transferred to 14 degrees C after growth at 30 degrees C for 2 days had the same alternative oxidase capacity as seedlings grown at 30 degrees C. Seedlings grown at 14 degrees C for 10 to 12 days, then transferred to 30 degrees C, lost alternative pathway respiratory capacity over a period of 2 to 3 days. Western blots of mitochondrial proteins indicated that this loss of capacity was due to a loss of the alternative oxidase protein. Some in vitro characteristics of mitochondria were determined. The temperature optimum for measurement of alternative oxidase capacity was 15 to 20 degrees C. At 41 degrees C, very little alternative oxidase was measured, i.e., the mitochondrial oxygen uptake was almost completely sensitive to cyanide. This inactivation at 41 degrees C was reversible. After incubation at 41 degrees C, the alternative oxidase capacity measured at 25 degrees C was the similar to when it was measured at that temperature directly. Isolated mitochondria lost alternative oxidase capacity at the same rate when incubated at 41 degrees C as they did when incubated at 25 degrees C. Increasing the supply of electrons to isolated mitochondria increased the degree of engagement of the alternative pathway, whereas lower temperature decreased the degree of engagement. Lower temperatures did not increase the degree of engagement of the pathway in intact tissues. We interpret these observations to indicate that the greater capacity of alternative oxidase in cold-grown seedlings is a consequence of development at these low temperatures which results in elevated respiration rates. Low temperature itself does not cause greater capacity or engagement of the alternative oxidase in mitochondria that have developed under warm temperatures. Our hypothesis would be that the low growth temperatures require the seedlings to have a higher respiration rate for some reason, e.g., to prevent the accumulation of a toxic metabolite, and that the alternative pathway functions in that respiration.

Journal Article↗
PubMed1990

Seedling growth, mitochondrial characteristics, and alternative respiratory capacity of corn genotypes differing in cold tolerance.

Four maize (Zea mays L.) inbreds representing genetic differences in seedling cold tolerance were used to determine the effect of growth temperatures on dry weight accumulation and mitochondrial properties, especially the alternative oxidase capacity. Seedlings were grown in darkness at 30 degrees C (constant), 14 degrees C (constant), and 15 degrees C for 16 hours and 8 degrees C for 8 hours. Inbreds B73 and B49 were characterized as cold tolerant while G50 and G84 were cold sensitive. Shoot growth rate of cold-sensitive inbreds in the lower temperatures was slower relative to the tolerant inbreds. Mesocotyl tissue was particularly sensitive to low temperatures during growth after germination. There were no significant differences in relative rates of mitochondrial respiration in the cold-tolerant compared to cold-sensitive inbreds measured at 25 degrees C. Mitochondria from all seedlings grown at all temperatures had the ability to phosphorylate as indicated by the observation of respiratory control. This result indicated that differences in low temperature growth were probably not related to mitochondrial function at low temperatures. Alternative oxidase capacity was higher in mitochondria from seedlings of all inbreds grown at 14 degrees C compared to 30 degrees C. Capacities in seedlings of 14 degrees C-grown B73 and G50 were higher than in B49 and G84. Capacities in seedlings grown for 16 hours at 15 degrees C and 8 hours at 8 degrees C were similar to those from 14 degrees C-grown except in G50 which was lower and similar to those grown at 30 degrees C. Mesocotyl tissue was the most responsive tissue to low growth temperature. Coleoptile plus leaf tissue responded similarly but contained lower capacities. Antibody probing of western blots of mitochondrial proteins confirmed that differences in alternative oxidase capacities were due to differences in levels of the alternative oxidase protein. Male sterile lines of B73 were also grown under the three different temperature regimes. These lines grew equally as well as the normal B73 at all temperatures and the response of alternative oxidase capacity and protein to low growth temperature was similar to normal B73.

Journal Article↗
PubMed1989

A simple and sensitive assay for varicella-zoster virus.

A plaque assay procedure has been adapted for VZV which, by obviating the need of a preformed cell monolayer, shortens the assay time, and provides improved sensitivity. The size and clarity of the plaques obtained are comparable to those seen in previously-described plaque assay methods for VZV.

Animals↗
PubMed1989

Regional pulmonary transit times in humans.

We measured the frequency distribution of erythrocyte (RBC) transit times in resected lobes of lungs in eight human subjects undergoing thoracotomy for peripheral lung tumors. RBC transit times were measured by the injection of radiolabeled blood flow and volume markers, which were counted in samples from the resected lung. In five of these subjects, the measurements from the resected lung were compared with preoperative measurements of the transit times of radiolabeled RBCs with a gamma camera-computer system. Time-activity curves from the cardiac chambers and the lung or its regions were obtained from which transit times were calculated by the centroid and deconvolution techniques. The reproducibility of transit times measured by this technique was assessed in another eight normal subjects, after sequential bolus injections of radiolabeled cells. The mean transit time of the upper lung region was longer (5.1 +/- 0.5 s) than that of the lower (4.1 +/- 0.6 s, P less than 0.05) in the preoperative study. Similarly, the mean transit time of the upper lung slice was longer (5.5 +/- 0.3 s) than that of the lower slice (3.8 +/- 0.3 s, P less than 0.05) in the resected lung specimens. We conclude that there was good agreement between these techniques and that there are long transit times in the upper regions of human lungs.

Blood Circulation Time↗
PubMed1989

Components of care for patients with schizophrenia.

To assist in the planning of mental health services for Metropolitan Toronto, the Mental Health Care Committee of the Metropolitan Toronto District Health Council convened a Task Force on Mental Health Epidemiology to help determine the need for services for patients suffering from schizophrenia. As part of its work, the Task Force described components of care which comprise a comprehensive treatment model. Underlying this approach was the recognition that many efficient, effective interventions for the treatment of schizophrenia have been developed and evaluated, but few attempts have been made to apply these various interventions in a systematic, comprehensive manner. This report presents an inventory of state-of-the-art approaches to dealing with schizophrenia which should be of interest both to practicing clinicians and health care planners.

Adult↗
PubMed1989

Electroconvulsive therapy for depression in general psychiatric practice.

This paper identifies areas of consensus about the use of electroconvulsive therapy (ECT) for depression and some of the important points of disagreement which have implications for clinical practice and research. The clinical indications for ECT as a primary treatment of choice, a secondary treatment, and a maintenance or prophylactic treatment for depression are described. The commonly accepted outcome findings that ECT is highly effective are contrasted with more recent data indicating it may be quite ineffective when administered with a low-dose electric stimulus. The constituents of the treatment dosage are presented in the context of controversy surrounding the respective contributions of the electrical energy of the stimulus and the convulsions themselves to the overall therapeutic effectiveness. The points of consensus within the limited knowledge in this area are identified as the basis for the most appropriate approach to the design of clinical dosage protocols. It is concluded that ECT is an effective treatment for some of the severe presentations of depression. Its therapeutic effectiveness should not be compromised by efforts to minimize the side effects through excessive dosage reduction.

Depressive Disorder↗
PubMed1988

Erythrocyte transit and neutrophil concentration in the dog lung.

We subdivided regional erythrocyte (RBC) transit time into the fraction spent in the large (greater than 50 microns), small (20-50 microns), and capillary (less than 20 microns) vessels of canine lungs. Using a combination of physiological and morphological techniques, the number of RBC and granulocytes in each vessel size was obtained by dividing the aggregate volume of the cell by the calculated volume of a single cell. The data show that the average transit time was 0.60 s in large vessels, 0.10 s in small vessels, and 1.37 s in capillary vessels and was longer (P less than 0.05) in the upper lung regions for small vessels and capillaries. RBCs pass through approximately 60 capillary segments at an average velocity of approximately 550 micron/s. Pulmonary hematocrit averaged 0.95 of the systemic hematocrit and was lower in capillaries than small vessels. PMN's were concentrated approximately 10-fold in the small vessels and 100-fold in the capillaries compared with peripheral blood. The multisegmented nature of the capillary bed allows this concentration because RBCs find pathways to stream around the slower moving PMNs.

Animals↗
PubMed1988

Immunological evidence for the relation between low MR secreted form of human B cell growth factor and an intracellular 60K protein.

Homogeneously purified intracellular high-Mr BCGF (IC-BCGF) has been used as an immunogen for the development of heterotypic anti-IC-BCGF antibodies. Anti-IC-BCGF immunoglobulin has been purified by affinity chromatography and used for constructing an immunoaffinity matrix. This matrix was shown to recognize specifically IC-BCGF and the extracellular low-Mr secreted form of human BCGF (EC-BCGF). In the cytosolic extracts of lectin activated human PBLs two other proteins of 50K and 30K were also recognized by these antibodies. Immuno dot blot and western blot analysis also demonstrated that anti-IC-BCGF antibodies recognized EC-BCGF. These antibodies weakly interacted with human interferons (alpha, gamma). Immunoaffinity-purified IC-BCGF was shown to have a molecular weight of 60K, and it exhibited BCGF activity in long-term BCGF-dependent B cell lines. The Mr of one-step affinity-purified EC-BCGF was found to be 14K by SDS-PAGE analysis. This material demonstrated BCGF activity in both long-term BCGF-dependent B cell lines and anti-IgM-activated GoB cells, yet it did not exhibit IL-1 and IL-2 activities. We conclude that EC-BCGF is immunologically related to IC-BCGF through common structural epitopes.

Antibody Specificity↗
PubMed1987

Tissue-specific gene expression results from a purine- and pyrimidine-free diet and 6-mercaptopurine in the rat small intestine and colon.

Dietary purines and pyrimidines are not considered to have a nutritional role, much less a direct effect on the functioning of the gastrointestinal tract. We found that a dramatic decrease in adult rat small intestinal and colonic total ribonucleic acid (RNA) results from the removal of dietary purines and pyrimidines or the administration of 6-mercaptopurine. Ribonucleic acid hybridization analysis indicated specific decrease of the messenger ribonucleic acid (mRNA) for the purine salvage enzymes hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase in the small intestine and proximal colon but not in the liver of animals fed a diet lacking purines and pyrimidines. Levels of intestinal and hepatic beta-actin mRNA transcripts were generally not depressed by either diet or by the administration of 6-mercaptopurine. Liver hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase mRNAs were unaffected by the change in diet but were lowered by the administration of 6-mercaptopurine. These data indicate that nutrition and 6-mercaptopurine affect both total RNA, and individual mRNA concentrations at specific sites in the gastrointestinal tract. These findings are of potentially great significance because the regulation of intestinal total RNA levels and purine salvage mRNAs by both 6-mercaptopurine and a purine- and pyrimidine-free diet suggests a potential mechanism by which dietary components differentially control specific proteins synthesized in the body. These findings may be related to the efficacy of 6-mercaptopurine as well as so-called elemental diets as therapeutic agents in chronic inflammatory bowel disease (i.e., Crohn's disease).

Adenine Phosphoribosyltransferase↗
PubMed1987

A method for the separation and partial purification of the three forms of nitrate reductase present in wild-type soybean leaves.

A rapid and simple purification method was used to separate and purify nitrate reductases (NR) from Williams soybean leaves. Blue Sepharose columns were sequentially eluted with 50 millimolar NADPH and 50 millimolar NADH, thus separating NAD(P)H:NR from NADH:NRs. Subsequent purification of the collected peaks on a fast protein liquid chromatography-Mono Q column enabled separation of two NADH:NRs. Sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed that the subunit relative molecular mass for all three NR forms (constitutive NAD(P)H:NR [pH 6.5], EC 1.6.6.2; constitutive NADH:NR [pH 6.5], EC not assigned; and inducible NADH:NR [pH 7.5], EC 1.6.6.1) was approximately 107 to 109 kilodaltons. All three NRs showed similar spectra with absorption maxima at 413 and 273 nanometers in the oxidized state, and with the characteristics of a cytochrome b type heme upon reduction with NADH (absorption maxima at 556, 527, and 424 nanometers). The technique developed provides an improved separation of the three NR forms from soybean leaves. The similarity of the NRs with regard to their cytochrome b(556) type heme content and in relative molecular mass indicated that other differences must exist to account for the different kinetic and physical properties previously reported.

Journal Article↗