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Biomedical subjects

M A Davis

Publications and source records attributed to M A Davis.

At least 145 records · Page 8Linked to original sources
PubMed1990

Delayed treatment with a t-PA analogue and streptokinase in a rabbit embolic stroke model.

Fibrinolytic therapy may be effective in the treatment of ischemic stroke, and clinical trials are under way. We evaluated two fibrinolytic agents, an analogue of tissue plasminogen activator (Fb-Fb-CF, the catalytic fragment of the tissue plasminogen activator molecule with a prolonged serum half-life, n = 10) and streptokinase (n = 7), in a rabbit model of embolic stroke. Both agents were given 3 hours after stroke onset, a time relevant to the clinical setting. Fb-Fb-CF was significantly better (p less than 0.04) than saline (n = 7) in restoring blood flow to previously occluded intracranial arteries, but streptokinase was ineffective. Neither fibrinolytic agent was associated with a substantial risk for intracerebral hemorrhagic side effects. Our study demonstrates that Fb-Fb-CF can safely and effectively reperfuse rabbit intracranial arteries 3 hours after occlusion, while streptokinase does not.

Animals↗
PubMed1990

Living arrangements and dietary quality of older U.S. adults.

The association between living arrangement and dietary quality of older U.S. adults was investigated in 4,402 adults aged 55 years or older who participated in the Nationwide Food Consumption Survey, 1977 to 1978. Dietary quality was based on percent of Recommended Dietary Allowances for 3-day intakes of nine nutrients. More men living alone consumed a poor-quality diet than did men living with a spouse, particularly those 75 years or older; for women, this effect was seen only in the 55- to 64-year-old group. In general, more women than men had poor-quality diets. A number of factors (economic, employment, health status, energy intake, body mass index, and nutrient supplement use) were examined for their importance in accounting for differences in dietary quality of older men and women living alone compared with those living with a spouse. Energy intake was the most important variable accounting for the association of living arrangement with dietary quality. Evidence indicated that older adults living alone did not make poorer food choices than those living with a spouse, but rather that they consumed fewer calories.

Age Factors↗
PubMed1990

The effect of single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization and DNA strand breakage in human tumor cells.

To better understand the mechanism underlying halogenated pyrimidine-mediated cytotoxicity and radiosensitization in human tumor cells, a study was undertaken to determine the influence of unifilar (one DNA strand) versus bifilar (both DNA strands) substitution of thymidine by the halogenated bases 5-iodo-2'-deoxyuridine (IdUrd) and 5-bromo-2'-deoxyuridine (BrdUrd) in HT29 human colon cancer cells. Unifilar labeling was obtained by incubating cells with IdUrd or BrdUrd for one doubling time. Cells were incubated for at least three doublings to approximate bifilar substitution. Only IdUrd caused significant cytotoxicity, which correlated with incorporation into DNA. Both BrdUrd and IdUrd were potent radiosensitizers. Radiosensitization was linearly correlated with incorporation of both bases regardless of the number of strands in which thymidine was substituted. In contrast, the relationship between radiosensitization and DNA double-strand breakage was critically dependent in the case of IdUrd, but not for BrdUrd, on whether substitution was unifilar or bifilar. These findings suggest that incorporation is the best predictor of radiation sensitivity, and that the induction of DNA double-strand breaks alone does not account for radiosensitization mediated by halogenated pyrimidines in these human tumor cells.

Bromodeoxyuridine↗
PubMed1989

Dependence of etoposide-induced cytotoxicity and topoisomerase II-mediated DNA strand breakage on the intracellular ionic environment.

We have found that blockade of the Na+,K+-pump by the cardiac glycoside ouabain protects human A549 and hamster V79 cells from the cytotoxic effects of the topoisomerase II poison etoposide. One thousand-fold higher concentrations of ouabain were required to protect V79 cells compared to A549 cells. Since this difference parallels previously measured differences in pump sensitivity, it suggests that protection is mediated directly through pump blockade. Ouabain affected neither the cellular influx nor efflux of etoposide. However, pump blockade did decrease the formation of etoposide-induced DNA-topoisomerase, II-cleavable complexes, assessed as single and double strand DNA breaks using alkaline and neutral elution. To determine if this decrease were a direct effect of change in ionic environment produced by pump blockade, experiments with isolated nuclei and partially purified topoisomerase II were performed. Etoposide-induced cleavable complex formation and topoisomerase-mediated decatenation were assessed in buffers which mimicked either normal intracellular ionic conditions or those produced by ouabain. Compared to the buffer which resembled the normal intracellular ionic conditions, the buffer that mimicked the conditions produced by pump blockade produced fewer etoposide-mediated cleavable complexes in isolated nuclei and less decatenating activity of partially purified topoisomerase II. These findings demonstrate that inhibition of the Na+,K+-pump causes an alteration in the intracellular ionic environment which decreases the activity of topoisomerase II, thus producing a decrease in etoposide-induced cleavable complex formation and cytotoxicity. Since ionic changes occur inside normal cells during progression through the cell cycle as well as in cells that have undergone transformation, these data suggest that the intracellular ionic environment plays a role in determining the sensitivity of normal and malignant cells to this group of chemotherapeutic agents.

Animals↗
PubMed1989

A controlled trial of leuprolide with and without flutamide in prostatic carcinoma.

To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.

Aged↗
PubMed1989

The effects of a new tissue plasminogen activator analogue, Fb-Fb-CF, on cerebral reperfusion in a rabbit embolic stroke model.

Early fibrinolytic therapy with full molecular tissue plasminogen activator (t-PA) has been observed to be both angiographically and clinically effective when employed in animal stroke models. Preliminary clinical trials with t-PA are in progress. It is possible to refine t-PA by developing fragments or analogues of the drug. Using recombinant DNA technology in the Escherichia coli system, a t-PA analogue consisting of the catalytic fragment of t-PA and a dimer of the B fragment of staphylococcal protein A (Fb-Fb-CF) has been produced. Because this analogue has a long serum half-life of 90 minutes, we employed Fb-Fb-CF in a rabbit cerebral embolic stroke model to assess its efficacy as a reperfusion agent. When given as a bolus to 10 animals 15 minutes after embolization, Fb-Fb-CF produced angiographic cerebral reperfusion in 48 +/- 21 minutes (+/- SD), while in 8 saline-treated controls, reperfusion was not observed at 180 minutes in any animal (p less than 0.01). In another experiment reperfusion was demonstrated at 66 +/- 32 minutes in 11 animals treated with Fb-Fb-CF 90 minutes after embolization as compared with 100 +/- 25 minutes in 12 saline-treated controls (p less than 0.01). A small macroscopic hemorrhage within an infarct was seen in 1 Fb-Fb-CF-treated animal in the 15-minute experiment and in none of the controls. In the 90-minute experiment, macroscopic hemorrhagic infarction was seen in 4 Fb-Fb-CF-treated animals and in 3 controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Regulatory genes in Aspergillus nidulans.

A major area for the study of gene regulation in lower eukaryotes has been the coordinated control of catabolic enzyme synthesis. Studies of catabolic gene regulation aim to define how interactions between input signals and regulatory proteins are transmitted to the transcription machinery to bring about changes in gene expression. In the past, mutants altered in the utilization of a wide variety of substrates have been characterized in Aspergillus nidulans. Recently, the development of a transformation system for A. nidulans has meant that molecular techniques can now be combined with the traditional genetic approach.

Aspergillus nidulans↗
PubMed1989

Selective radiosensitization and cytotoxicity of human melanoma cells using halogenated deoxycytidines and tetrahydrouridine.

The halogenated pyrimidines 5-chloro-2'-deoxycytidine (CldCyd) and 5-bromo-2'-deoxycytidine (BrdCyd) can act as radiosensitizers and cytotoxic agents. It was hypothesized that tumor cells and normal cells might use different metabolic pathways to incorporate these halogenated deoxycytidines into DNA. This difference could potentially be exploited to produce selective radiosensitization and cytotoxicity of human tumor cells compared to normal human fibroblasts. This hypothesis was tested using two human melanoma cell lines and two normal fibroblast cell lines. Either CldCyd or BrdCyd alone caused both cytotoxicity and radiosensitization of tumor and normal cells. The addition of the cytidine deaminase inhibitor tetrahydrouridine (H4U) significantly protected the normal cells but had relatively little effect on the tumor cells. These data indicate that it may be possible to exploit differences between the pyrimidine metabolism of normal cells and melanoma cells to improve the therapeutic index of halogenated pyrimidines both as radiosensitizers and as cytotoxic agents.

Antineoplastic Agents↗
PubMed1989

The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee.

The strength of the associations of knee injury and obesity with osteoarthritis of the knee was studied for 3,885 adults aged 45-74 years who received knee x-rays in the First National Health and Nutrition Examination Survey, 1971-1975. Bilateral osteoarthritis was more prevalent (5%) than unilateral osteoarthritis (2%). Bilateral osteoarthritis was twice as prevalent in women as in men; however, there was no sex difference in the prevalence of unilateral osteoarthritis. Odds ratios calculated by means of polychotomous logistic regression indicated that obesity, knee injury, and age were significantly associated with both unilateral and bilateral knee osteoarthritis. Obesity was a stronger predictor of bilateral osteoarthritis than was knee injury (odds ratio (OR) = 6.6 for obesity, 3.5 for right knee injury, and 3.0 for left knee injury; 95% confidence interval (CI) 4.71-9.18, 1.80-6.83, and 1.51-6.11, respectively). Knee injury was a stronger predictor of unilateral osteoarthritis than was obesity (OR = 3.4 and 2.4 for obesity in the right and left knee, respectively (95% CI 1.55-7.29 and 0.96-5.75) and OR = 16.3 and 10.9 for injury in the right and left knee, respectively (95% CI 6.50-40.89 and 3.72-31.93]. These findings suggest that different pathogenetic processes may exist for unilateral and bilateral knee osteoarthritis.

Age Factors↗
PubMed1989

Acute effects of ranitidine, famotidine and omeprazole on plasma gastrin in the rat.

In the rat, treatment with gastric inhibitory drugs may result in hypergastrinemia, an effect thought to be in response to increased gastric pH caused by inhibition of acid secretion. This study compared 24-hr profiles of plasma gastrin levels associated with three different compounds at equivalent, highly effective antisecretory doses. Ranitidine, famotidine and omeprazole at 60, 20 and 40 mg/kg p.o., respectively, inhibited basal acid secretion of chronic gastric fistula rats by greater than 95% and raised intraluminal pH to above 7.0 for 5 hr. The peak plasma gastrin levels associated with each agent were observed 5 hr after dosing. Ranitidine, famotidine and omeprazole induced statistically significant and distinct peak hypergastrinemic responses of 312 +/- 20, 483 +/- 28 and 616 +/- 27 pg/ml, respectively. After 8 hr ranitidine and famotidine associated gastrin values returned to control levels, whereas those of omeprazole remained substantially above control values until the 12th hr. Differences in peak gastrin levels between compounds disappeared at increased dose levels of 500 mg/kg for ranitidine, 200 or 2000 mg/kg for famotidine and 140 mg/kg for omeprazole. Unlike high dose famotidine, omeprazole (140 mg/kg) maintained peak plasma gastrin levels at 8, 12, and 16 hr after dosing. These studies demonstrate clearly hypergastrinemic responses to single dose administration of ranitidine, famotidine and omeprazole. The differences observed in peak plasma gastrin levels at equivalent antisecretory doses of these agents suggests the presence of luminal acid independent components that effect gastrin release. Moreover, these studies indicate that, in the rat, the most unique aspect of omeprazole-associated hypergastrinemia is the magnitude of its prolonged response.

Animals↗
PubMed1989

Radiopharmaceuticals for radiation synovectomy: evaluation of two yttrium-90 particulate agents.

Radiation synovectomy, a noninvasive therapeutic alternative to surgical synovectomy, has not gained widespread acceptance in the United States because of the lack of a suitable radiopharmaceutical. Two new radioactive particles, [90Y]Ca oxalate and [90Y]ferric hydroxide macroaggregates (FHMA), were developed in our laboratory and evaluated for size, stability, and joint leakage. More than 90% of the [90Y]Ca oxalate particles were in the optimal size range of 1-10 microns, and the unbound activity in serum and synovial fluid was 3.7% to 5.0%. Following injection in rabbit knees, leakage of [90Y]Ca oxalate was 5 +/- 2%, with localization primarily in the bone and virtually no uptake by the lymph nodes or liver. Yttrium-90 FHMA particles were larger (95% greater than 10 microns), and at least on a microscopic level, appeared to distribute homogeneously over the articular surface. Leakage of [90Y]FHMA was initially less but eventually slightly exceeded that of [90Y]Ca oxalate. Nevertheless, both radiopharmaceuticals can provide a satisfactory therapeutic dose to the knee with less than half the leakage and a marked reduction in absorbed dose to nontarget tissues compared to previously tested agents. Ease of preparation, physical characteristics of the 90Y beta ray, and apparent lack of substantial leakage from the joint make these agents extremely attractive for clinical evaluation in rheumatoid arthritis patients who are unresponsive to medical therapy.

Animals↗
PubMed1988

An amdS-lacZ fusion for studying gene regulation in Aspergillus.

A translational fusion has been constructed between the amdS gene of Aspergillus nidulans and the lacZ gene of Escherichia coli. Sequencing across the fusion junction confirmed the generation of an in-frame fusion at amino acid 34 of amdS and a novel protein has been detected in transformants carrying the fusion plasmid. Transformants of A. nidulans and Aspergillus niger carrying the fusion plasmid were obtained by co-transformation with a second selectable plasmid. These transformants were readily identified on media containing XGal. The intensity of the reaction on XGal media was indicative of the number of copies of the fusion plasmid carried by the transformants. The growth of highly expressing strains of A. nidulans was inhibited on XGal media. The fusion plasmid was used to develop a two-step gene replacement strategy in which the resident amdS gene was replaced with the fusion gene free of vector sequences. Plate tests and in vitro assays of the beta-galactosidase enzyme confirmed that expression of the fusion gene was regulated by amdS flanking sequences and trans-acting regulatory genes.

Amino Acid Sequence↗
PubMed1988

The safety and angiographic efficacy of tissue plasminogen activator in a cerebral embolization model.

Thrombolysis with tissue plasminogen activator (tPA) has been used to treat myocardial infarction and pulmonary embolism in humans. This plasminogen activator may also be useful in treating certain strokes. We infused tPA or saline in rabbits 15 minutes after selective internal carotid artery embolization with 18-hour aged autologous clot. By serial angiography, the tPA-treated group demonstrated rapid angiographic reperfusion of the occluded vascular territory in 7 of 8 animals, whereas none of 6 saline controls did. None of the animals in either group developed macroscopic cerebral hemorrhage. Both groups showed cerebral infarction, predominantly in the territory of the occluded vessel; the extent of infarction did not differ between tPA-treated animals and controls. Early tPA therapy can allow reperfusion of occluded cerebral arteries safely and effectively in a rabbit cerebral embolization model.

Animals↗
PubMed1988

Recognition of the P1 plasmid centromere analog involves binding of the ParB protein and is modified by a specific host factor.

The P1 plasmid partition system is responsible for segregation of daughter plasmids during division of the Escherichia coli host cell. The P1-encoded elements consist of two essential proteins, ParA and ParB, and the cis-acting incB region. The incB region determines partition-mediated incompatibility and contains the centromere-like site parS. We have isolated and purified the two proteins. ParB binds specifically to the incB region in vitro. DNase I footprinting assays place a strong binding site over the 35-bp parS sequence previously shown to be sufficient for partition when the Par proteins are supplied in trans. A weaker site lies within the incB region in sequences that are important for specifying incompatibility, but are not essential for partition. Gel band retardation assays show that a host factor binds specifically to the incB sequence. The factor strongly stimulates binding of ParB. Cutting the region at a site between the two ParB binding sites yields two fragments that can bind ParB but not host factor. Thus, information for host-factor binding lies in the region determining the specificity of plasmid incompatibility. The roles of parB and the host factor in partition and the specificity of plasmid incompatibility are discussed.

Bacterial Proteins↗
PubMed1988

Living arrangements and eating behaviors of older adults in the United States.

Associations between living arrangements and several eating behaviors were examined for 4,402 adults aged 55 and older using three-day food intake data from the 1977-78 Nationwide Food Consumption Survey (NFCS). Compared to those living with a spouse, persons living alone ate more meals alone and consumed a higher proportion of total calories away from home; a higher proportion of those living alone skipped meals, including breakfast. There was a sex differential in the effect of living alone for some, but not all, of the eating behaviors. Both the probability of eating away from home and of skipping breakfast declined with age, as did the percentage of calories consumed from snacks. These results indicate a need to focus further research not only on the effects these eating behaviors have on the nutritional status of elderly persons, but also on middle-aged cohorts as they age and on food programs targeted at elderly persons living alone.

Aged↗
PubMed1988

Sex differences in osteoarthritis of the knee. The role of obesity.

This study investigated the role of obesity (body mass index, total body weight, triceps skinfold, subscapular skinfold) compared with other anthropometric variables (body fat distribution, muscularity, elbow breadth, bitrochanteric breadth) in order to explain previously noted sex differences in osteoarthritis of the knee. Anthropometric measures, self-reported symptoms, and knee x-ray data were analyzed for 3,905 adults aged 45-74 years with valid x-ray data from the First National Health and Nutrition Examination Survey, 1971-1975. Prevalence of knee osteoarthritis was 4.9% in women and 2.6% in men. The relative risk for women compared with men increased from 1.57 at 45-54 years to 2.14 at 65-74 years. Adjusting for body mass index and subscapular and triceps skinfolds reduced the sex difference, whereas adjusting for total body weight, body fat distribution, muscularity, and skeletal size increased the sex difference. Body mass index was the variable that best reduced the sex difference when the other variables were included in the analysis; it did not, however, eliminate the sex difference. No sex differences were found in the strength of the association between anthropometric variables and osteoarthritis, nor was there evidence to suggest that obesity is a consequence of knee osteoarthritis rather than a risk factor.

Adult↗
PubMed1988

CT of the pancreas with a fat-density oral contrast regimen.

Visualization of the head of the pancreas by CT was prospectively evaluated in two groups of 100 patients who did not have pancreatic disease. Patients were given either a fat-density oral contrast material (12.5% corn-oil emulsion and metoclopramide) or a conventional high-density oral contrast material (barium suspension or iodinated solution). There was no statistically significant difference in the subjects' tolerance to the two regimens. There was, however, a significant improvement in ability to distinguish the head of the pancreas from the duodenal C-loop when the fat-density contrast material was given. When pancreaticoduodenal discrimination was graded, patients given corn-oil emulsion and metoclopramide received an average score of 0.94, whereas those given the high-density agent received an average score of 0.74, with 1.00 being the highest possible score (p less than .005). These data suggest that for routine CT evaluation of the head of the pancreas, a combination of corn-oil emulsion and metoclopramide may be superior to the conventional high-density oral contrast agents given without metoclopramide.

Administration, Oral↗