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Biomedical subjects

M A Flynn

Publications and source records attributed to M A Flynn.

At least 19 recordsLinked to original sources
PubMed2002

Longitudinal study of effects of alcohol use and/or personal exercise on high density lipoprotein cholesterol in aging humans.

Self-controlled alcohol use and/or personal physical exercise is generally believed to be advantageous in extending good health in aging humans. We investigated whether data collected over 31 years in the same subjects (369 men, 75 women) in our Longitudinal Aging Study of humans (1969-2000) showed strong relationship between alcohol and/or physical exercise with High Density Lipoprotein Cholesterol (HDLC). Women s HDLC interactions among age, diet, alcohol use and/or exercise were not found to be statistically significant in our study. Men, however, showed a strong positive statistical significance (p<or= 0.0001) among alcohol, personal physical exercise and HDLC.

Adult↗
PubMed2001

Facile entry to the tetracyclic 5-7-6-3 tigliane ring system.

[figure: see text] A tandem anionic 5-exo-dig cyclization/Claisen rearrangement sequence was used to effect a facile, "one-pot" conversion of an appropriately substituted 4-alkyn-1-ol to the tetracyclic carbon core structure of phorbol. The synthesis was conducted using readily available nonracemic starting materials to provide the target structure as a single enantiomer in high chemical yield.

Alkynes↗
PubMed2001

Cardiovascular complications of weight reduction diets.

Weight reduction diets may reduce the severity of risk factors for coronary heart disease such as diabetes mellitus, hypertension, and dyslipidemia. Several case reports and small studies of patients receiving starvation diets have reported hypotension and sudden cardiac death. Myofibrillar damage was documented in 1 case. Very-low-calorie diets are generally safe and well-tolerated. However, low QRS voltage, QT interval prolongation, and both nonsustained ventricular arrhythmias and sudden cardiac death have been described in subjects treated with such diets. Orthostatic hypotension may complicate very-low-calorie protein diets because of sodium depletion and depressed sympathetic nervous system activity. Bariatric surgery is associated with disproportionately high mortality rates in both the perioperative and postoperative periods.

Adult↗
PubMed2000

Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy. Results in normal and ischemic porcine models.

OBJECTIVES: To test the feasibility of myocardial angiogenic gene expression using a novel catheter-based transendocardial injection system. BACKGROUND: Angiogenesis has been induced by direct injection of growth factors into ischemic myocardium during open-heart surgery. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without need of surgery. METHODS: A new guidance system for intramyocardial therapy utilizes magnetic fields and catheter-tip sensors to locate a position in space and reconstruct three-dimensional left ventricular (LV) electromechanical maps without using fluoroscopy. A retractable 27G needle was coupled with the guidance system for LV transendocardial injection. In 12 pigs, the catheter was used to inject 0.1 ml of methylene-blue (MB) dye and 8 pigs had myocardial injections of adenoviral vector (1 x 10(10) particles per site) containing the LacZ transgene. Ten pigs underwent catheter-based transendocardial injection and six pigs were injected using transepicardial approach with the gene encoding adenovirus vascular endothelial growth factor-121 (Ad.VEGF121; 1 x 10(10) viral particles x 6 sites) and sacrificed at 24 h. Injection sites were identified with ultraviolet light by coinjection of fluorescent beads. RESULTS: Overall, 138 of 152 attempted injection MB tracks (91%) were found after sacrifice. Tissue staining was 7.1+/-2.1 mm in depth and 2.3+/-1.8 mm in width. No animal had pericardial effusion or tamponade. In Ad.LacZ injected animals, gross pathology showed positive staining in injected zones, and histology confirmed positive myocyte staining. Adenovirus vascular endothelial growth factor-121 injected sites showed high levels of VEGF121 production that was of similar magnitude whether injected using the transendocardial (880.4+/-412.2 pg VEGF121/mg protein) or transepicardial (838.3+/-270 pg VEGF121/mg protein) delivery approach (p = 0.62). CONCLUSIONS: Using this magnetic guidance catheter-based navigational system, transgenes can effectively be transfected into designated myocardial sites. Thus, if it is determined that direct intramyocardial injection of angiogenic factors enhances collateral function in patients, this less invasive catheter-based system offers a similar gene delivery efficiency and, thus, may have clear advantages compared with the surgically-based transepicardial injection approach.

Animals↗
PubMed2000

Use of fluorescent microspheres to localize in vivo gene transfer injection sites.

The potential for using gene therapy to treat a variety of disease states is growing rapidly. Many vector types and delivery systems have been developed that allow the optimization of protein production levels and kinetics for a given therapeutic gene product. In cases in which a transient, localized delivery of gene product is desired, any determination of the locale of transfected tissue by non-marker genes is problematic. We describe a technique by which the use of fluorescent microspheres can help in identifying potentially transfected tissue. Adenovirus containing the gene for beta-galactosidase (beta-gal) was mixed with fluorescent microspheres and injected into rat skeletal muscle and porcine myocardium. The injection sites could be visualized under ultraviolet light and correlated with beta-gal enzyme expression. This method is simple, inexpensive and generally useful for in vivo gene transfer experiments.

Adenoviridae↗
PubMed1999

Butenolide endothelin antagonists with improved aqueous solubility.

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.

Animals↗
PubMed1999

Avian osteoclast cells are stimulated to resorb calcified matrices by and possess receptors for leukotriene B4.

Leukotriene B4 (LTB4) is elevated in inflammatory conditions and appears to be a potential mediator of inflammation. We have recently shown that this 5-lipoxygenase metabolite of arachidonic acid stimulates bone resorption in vitro and in vivo. In order to determine the mechanism whereby LTB4 causes bone resorption, avian osteoclasts were examined for the effects of LTB4 and for the presence of LTB4 receptors. Isolated avian osteoclast mononuclear precursor cells, which fuse in culture to form multinucleated cells, were chosen for receptor binding studies because this population is a morphologically similar source of osteoclasts, and large numbers of these cells can be obtained from egg-laying hens. Binding of LTB4 and activation would support the hypothesis of a direct effect of this compound on osteoclasts. LTB4 stimulated isolated avian osteoclasts to form resorption lacunae on calcified matrices and to increase their content of tartrate-resistant acid phosphatase (TRAP), a marker of activated osteoclasts. Receptor binding studies were performed at day 1, when the cells were mononuclear, at day 4, when mononuclear precursors were actively fusing, and at day 7, when fusion has slowed. Scatchard analysis of saturation binding data showed two classes of binding sites, a high- and low-affinity binding site with dissociation constants (KD) of 0.2-0.4 nM and 5. 6-24 nM. Association studies showed rapid binding of LTB4 to the cells within 10 minutes. These data show that LTB4 accelerates fusion and activates highly enriched populations of avian osteoclasts and that LTB4 receptors are present in this cell population.

Acid Phosphatase↗
PubMed1999

An approach to the development of food-based dietary guidelines for Ireland.

The aim of the present study was to analyse the different food and nutrient intakes of the adult Irish population from the lowest and highest quartiles of intake for total fat (%energy) dietary fibre (g/MJ) and fruit and vegetables (g/day). Data on Irish adults (n = 715) from the Irish National Nutrition Survey conducted in 1989 were used for the analyses and showed that the average diet is low in dietary fibre, with fruit and vegetables being only half the recommended level of 400 g. Comparisons of people with low or high intakes (from lowest and highest quartiles) of total fat (%energy), dietary fibre (g/MJ) and fruit and vegetables (g/day) show patterns of food intake differing in both the percentage of consumers and in the mean intakes among consumers only. This analysis provides data which may be useful as a first step towards the development of food-based dietary guidelines for Ireland. In particular, the low intake of fruit and vegetables in the adult Irish population deserves special attention.

Adult↗
PubMed1999

Dehydroepiandrosterone replacement in aging humans.

Because so much medical and media attention has been drawn to the alleged benefits of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS), it is important to evaluate the effects of replacement therapy objectively using double blind, cross-over, randomized research methodology. In this 9-month study, healthy older men (n = 39) received replacement dose DHEA. Lean body mass, blood hematology, chemistry and endocrine values, as well as urological and psychological data were measured. Data showed some mild and temporary, but significant, changes during oral use of 100 mg DHEA for 3 months compared with placebo taken for 3 months. Body composition did not change during the 6 months of treatment, nor did any urological parameters. Concomitant with the endocrine changes, some small but, significant, variations in blood values (blood urea nitrogen, creatinine, uric acid, alanine transaminase, cholesterol, high density lipoprotein, and potassium) were found. After cessation of DHEA and placebo, followed by 3 months of no treatment, all values previously found to be altered returned to entry baseline. Well publicized effects of the drug reported by others, such as a sense of well-being or improved sexual function, were not found in this study.

Activities of Daily Living↗
PubMed1998

The pursuit of thinness: a study of Dublin schoolgirls aged 15 y.

Despite increasing trends in the prevalence of overweight and obesity, fatness phobia is common during female adolescence. This study has demonstrated a high level of dissatisfaction with body weight in a sample of Dublin schoolgirls aged 15 y. Of 420 subjects, 59% reported that they wanted to be slimmer and 68% had previously tried to lose weight. Contrary to expectations, overweight girls were not found to hold the monopoly on such dissatisfactions. Normal weight and even underweight girls also expressed a desire to be thinner and reported using unhealthy weight control practices including random avoidance of staple foods, fasting, smoking and purging, in their pursuit of the 'perfect' female figure. Obesity prevention programmes which target adolescent girls 'at risk' of overweight and obesity, must take cognizance of their profound fear of fatness, otherwise the use of harmful slimming strategies may be further increased as teenage girls frantically try to lose weight and to avoid the stigma associated with female fatness.

Adolescent↗
PubMed1998

Endothelin B receptors on human endothelial and smooth-muscle cells show equivalent binding pharmacology.

We have described the pharmacologic profiles of endothelin B receptors in human endothelial cells and vascular and nonvascular smooth-muscle cells. First, by amplifying endothelin B receptor numbers through the use of phosphoramidon and intact cell-binding techniques, we demonstrated the presence of these receptors in human umbilical vein endothelial cells (100% endothelin B receptors), human aortic smooth-muscle cells (22% endothelin B, 78% endothelin A receptors), and human bronchial smooth-muscle cells (55% endothelin B, 45% endothelin A receptors) by using [125I]-endothelin-1 radioligand binding. The typical binding profiles of the endothelin B receptors were established through competition binding curve analysis with endothelin-1, endothelin-3, sarafotoxin 6c, and the endothelin A receptor-selective antagonist BQ-123. In the presence of BQ-123, a diverse group of antagonists, including PD 142893, BQ-788, SB 209670, and Ro 47-0203, were used to probe for binding differences indicative of multiple endothelin B-receptor subtypes. The results indicate a rank order of potency for the antagonists of BQ-788 > SB 209670 > PD 142893 > Ro 47-0203 for each cell line, and that between any of these human cell lines, measurements of [125I]-endothelin-1-binding antagonism for each of the four test compounds differed by less than twofold. Although this study cannot discount the possibility of more than one endothelin B-receptor subtype in humans, it does indicate that these tissues express receptors that show equivalent binding pharmacology.

Binding, Competitive↗
PubMed1997

Structure-activity relationships in a series of orally active gamma-hydroxy butenolide endothelin antagonists.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

Administration, Oral↗
PubMed1997

Risk factors for recurrence of hemorrhagic endovasculitis of the placenta.

OBJECTIVE: To assess the potential for recurrence of placental hemorrhagic endovasculitis and to identify clinical or pathologic cofactors that might influence recurrence of this lesion or subsequent pregnancy outcome. METHODS: Ninety-seven women with a placenta affected by hemorrhagic endovasculitis, who also had at least one placenta referred to the Michigan Placental Tissue Registry from a subsequent pregnancy, were identified from 10,531 referrals between 1978 and 1988. Histologic slides from 209 placentas and clinical data from 211 infants (two sets of twins) from initial (first) and subsequent referrals were analyzed. Placentas were graded for the presence, extent, and severity of hemorrhagic endovasculitis and chronic villitis of unknown etiology; for placental lesions indicative of hypertensive maternal vessel disease; and for intravascular nucleated erythrocytes and chorionic thrombi. Maternal data included age, gravidity, number of previous losses, and history of toxemia or hypertension. All data were analyzed for significance using chi2 and t tests. Outcome assessment was based on recurrence of hemorrhagic endovasculitis and infant viability with the second referral. RESULTS: With first referrals, 80 of 98 infants (81.6%) were stillborn. Among second referrals, 26 of 98 infants (26.5%) were stillborn. Hemorrhagic endovasculitis recurred in 28 second placentas (28.9%); of these, 18 infants (64.3%) were stillborn. Higher rates of recurrence were found with progressively higher first-referral chronic villitis severity scores (P < .02), higher hypertensive placental lesion scores (P < .001), and first referrals with a history of toxemia or hypertension (P < .02). Recurrence of hemorrhagic endovasculitis was higher in patients with two or more of these factors in first referrals (P < .001). Subsequent stillbirth was more frequent with progressively higher first-referral hypertensive placental lesion scores (P < .01) and in first placentas with two or more risk factors (P = .064). Hemorrhagic endovasculitis severity scores, intravascular nucleated erythrocytes, and chorionic thrombi were associated with stillbirth in index pregnancies only. Maternal age, gravidity, or history of prior losses were not predictive. CONCLUSIONS: Placental hemorrhagic endovasculitis is associated with pregnancy loss and can recur in some patients. Interrelations among placental hemorrhagic endovasculitis, chronic villitis, maternal hypertension, and adverse outcomes in subsequent pregnancies are apparent. This information may be useful in patient counseling.

Adolescent↗
PubMed1997

Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analyses?

BACKGROUND: Bioscientists, physicians and nutritionists are newly interested in the homocysteine-folate-cobalamin triad, in part because homocysteine may be important both in atherogenesis and thrombogenesis. Homocysteine imbalance may be an early marker for cobalamin disorders because cobalamin is a cofactor in remethylation of homocysteine to methionine. METHODS: In 139 men and 32 women of similar mean age of 65 years, we measured markers which have been cited as risk for atherosclerosis: serum homocysteine, folate, total cobalamin, holotranscobalamin I and II, (TCI and TCII), total serum cholesterol (SCHOL), high density lipoprotein cholesterol (HDLC), triglycerides (STG) as well as red blood cell (RBC) folate, food records and body composition by whole body counting of potassium-forty (40K). RESULTS: Statistical relationships among the data showed healthy women had lower mean serum homocysteine and their mean RBC folate and TCI and TCII were higher than men. Eighty-three subjects had TCII much lower than 60 pg/ml (subnormal), yet only 11 of these men and two women had total cobalamin < 200 pg/ml (abnormal). Fifty-two subjects with serum homocysteine greater than 17.5 nmol/ml had TCII less than 60 pg/ml, suggesting serum homocysteine may be a marker for early cobalamin negative balance. None of the subjects in the study had serum folate below abnormal values, i.e., less than 1.6 mg/ml. All subjects had RBC folate within normal range. Serum homocysteine showed inverse relationship with RBC folate and serum total cobalamin, TCI and TCII. CONCLUSIONS: 1) importance of using serum holotranscobalamin TCI and TCII as markers of cobalamin deficiency, 2) necessity to use documented quantitative components of dietary intake if strong comparisons are to be made among quantitative values of serum or plasma homocysteine, folate, cobalamin, and nutrients in food intake.

Adult↗
PubMed1996

Endothelin and PDGF enhance arachidonic acid release and DNA synthesis in vascular smooth muscle cells.

Intracellular signaling mechanisms affected by endothelin (ET), a hypertrophic agonist, and platelet-derived growth factor (PDGF)-BB, a proliferative agonist, in vascular smooth muscle cells were examined. PDGF-BB was a potent mitogen compared with untreated cultures, stimulating both [3H]thymidine incorporation and cell number. In contrast, ET was a poor mitogen, enhancing [3H]thymidine incorporation but not cell number. Simultaneous ET and PDGF-BB treatment was significantly more effective than either agonist alone at stimulating both [3H]thymidine uptake and cell number. Although either ET or PDGF-BB alone stimulated arachidonic acid release, phosphoinositide hydrolysis, protein kinase C activation, PDGF receptor phosphorylation, and mitogen-activated protein kinase activity, of these effectors, only arachidonic acid release was further enhanced by simultaneous ET and PDGF-BB treatment. These results link proliferative and hypertrophic signal transduction pathways in these cells and suggest that arachidonic acid or its metabolites mediate the observed effects of ET on PDGF-BB-stimulated vascular smooth muscle cell proliferation.

Animals↗