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Biomedical subjects

J A Stafford

Publications and source records attributed to J A Stafford.

10 recordsLinked to original sources
PubMed2001

Post-myocardial infarction risk stratification in elderly patients.

BACKGROUND: The purpose of this study was to examine the use of post-myocardial infarction (MI) risk stratification in the elderly. Although expert panels have recommended risk stratification after MI, limited data are available on whether patients actually undergo suggested testing. In particular, concern has been raised that the elderly, who are at high risk for recurrent ischemia and short-term death, are not referred as often as younger patients for post-MI testing. METHODS: We studied the records of 192,311 Medicare patients (age > or = 65 years) admitted with MI between January 1992 and November 1992. By combining Medicare part A and part B data, we created a longitudinal record of patient care within 60 days of an MI admission. We describe the pattern of post-MI testing for ischemia and left ventricular function and outcomes as a function of patient age. RESULTS: Patients > or = 75 years of age were significantly less likely than patients 65 to 74 years of age to have either cardiac catheterization (17% vs 43%) or any test for coronary artery disease severity (24% vs 53%). They were also less likely to have a test of left ventricular function (61% vs 76%). Even after adjustment for baseline characteristics, older patients remained less likely than younger patients to have an assessment of coronary artery disease severity (odds ratio, 0.44) or left ventricular function (odds ratio, 0.65). CONCLUSIONS: Post-MI risk stratification declines with age and falls short of recommendations in our nation's elderly. This lack of testing may result in lost opportunities for therapeutic interventions in this high-risk group.

Aged↗
PubMed1998

Dual inhibition of human type 4 phosphodiesterase isostates by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3- methyl-1-pyrrolidinecarboxylate.

Purified recombinant human type 4 phosphodiesterase B2B (HSPDE4B2B) exists in both a low- and a high-affinity state that bind (R)-rolipram with Kd's of ca. 500 and 1 nM, respectively [Rocque, W. J., Tian, G., Wiseman, J. S., Holmes, W. D., Thompson, I. Z., Willard, D. H., Patel, I. R., Wisely, G. B., Clay, W. C., Kadwell, S. H., Hoffman, C. R., and Luther, M. A. (1997) Biochemistry 36, 14250-14261]. Since the tissue distribution of the two isostates may be significantly different, development of inhibitors that effectively inhibit both forms may be advantageous pharmacologically. In this study, enzyme inhibition and binding of HSPDE4B2B by (R, R)-(+/-)-methyl 3-acetyl-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidin ecarboxylate (1), a novel inhibitor of phosphodiesterase 4 (PDE 4), were investigated. Binding experiments demonstrated high-affinity binding of 1 to HSPDE4B2B with a stoichiometry of 1:1. Inhibition of PDE activity showed only a single transition with an observed Ki similar to the apparent Kd determined by the binding experiments. Deletional mutants of HSPDE4B2B, which have been shown to bind (R)-rolipram with low affinity, were shown to interact with 1 with high affinity, indistinguishable from the results obtained with the full-length enzyme. Bound 1 was completely displaced by (R)-rolipram, and the displacement showed a biphasic transition that resembles the biphasic inhibition of HSPDE4B2B by (R)-rolipram. Theoretical analysis of the two transitions exemplified in the interaction of (R)-rolipram with HSPDE4B2B indicated that the two isostates were nonexchangeable. Phosphorylation at serines 487 and 489 on HSPDE4B2B had no effect on the stoichiometry of binding, the affinity for binding, or the inhibition of the enzyme by 1. These data further illustrate the presence of two isostates in PDE 4 as shown previously for (R)-rolipram binding and inhibition. In contrast to (R)-rolipram, where only one of the two isostates of PDE 4 binds with high affinity, 1 is a potent, dual inhibitor of both of the isostates of PDE 4. Kinetic and thermodynamic models describing the interactions between the nonexchangeable isostates of PDE 4 and its ligands are discussed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Relationship between physician and hospital coronary angioplasty volume and outcome in elderly patients.

BACKGROUND: With the expectation that physicians who perform larger numbers of coronary angioplasty procedures will have better outcomes, the American College of Cardiology/ American Heart Association guidelines recommend minimum physician volumes of 75 procedures per year. However, there is little empirical data to support this recommendation. METHODS AND RESULTS: We examined in-hospital bypass surgery and death after angioplasty according to 1992 physician and hospital Medicare procedure volume. In 1992, 6115 physicians performed angioplasty on 97,478 Medicare patients at 984 hospitals. The median numbers of procedures performed per physician and per hospital were 13 (interquartile range, 5 to 25) and 98 (interquartile range, 40 to 181), respectively. With the assumption that Medicare patients composed one half to one third of all patients undergoing angioplasty, these median values are consistent with an overall physician volume of 26 to 39 cases per year and an overall hospital volume of 196 to 294 cases per year. After adjusting for age, sex, race, acute myocardial infarction, and comorbidity, low-volume physicians were associated with higher rates of bypass surgery (P < .001) and low-volume hospitals were associated with higher rates of bypass surgery and death (P < .001). Improving outcomes were seen up to threshold values of 75 Medicare cases per physician and 200 Medicare cases per hospital. CONCLUSIONS: More than 50% of physicians and 25% of hospitals performing coronary angioplasty in 1992 were unlikely to have met the minimum volume guidelines first published in 1988, and these patients had worse outcomes. While more recent data are required to determine whether the same relationships persist after the introduction of newer technologies, this study suggests that adherence to minimum volume standards by physicians and hospitals will lead to better outcomes for elderly patients undergoing coronary angioplasty.

Age Factors↗
PubMed1995

Design and synthesis of conformationally constrained analogues of 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724) as potent inhibitors of cAMP-specific phosphodiesterase.

The synthesis and biological evaluation of cAMP-specific phosphodiesterase (PDE IV) inhibitors is described. The PDE IV inhibitor 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724, 2) was used as a template from which to design a set of rigid oxazolidinones, imidazolidinones, and pyrrolizidinones that mimic Ro 20-1724 but differ in the orientation of the carbonyl group. The endo isomer of each of these heterocycles was more potent than the exo isomer in an enzyme inhibition assay and a cellular assay, which measured TNF alpha secretion from activated human peripheral blood monocytes (HPBM). Imidazolidinone 4a inhibited human PDE IV with a Ki of 27 nM and TNF alpha secretion from HPBM with an IC50 of 290 nM. By comparison, Ro 20-1724 is significantly less active in these assays with activities of 1930 and 1800nM, respectively.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Phosphodiesterase type IV inhibition. Structure-activity relationships of 1,3-disubstituted pyrrolidines.

The synthesis of 1,3-disubstituted pyrrolidines 2 and their activities as type IV phosphodiesterase (PDE) inhibitors are described. Various groups were appended to the nitrogen of the pyrrolidine nucleus to enable structure-activity relationships to be assessed. Groups which render the pyrrolidine nitrogen of 2 nonbasic yielded potent PDE-IV inhibitors. Analogs of amides, carbamates, and ureas of 2 were synthesized to determine the effects that substitution on these functional groups had on PDE-IV inhibitor potency. The structural requirements for PDE-IV inhibitor potency differed among the three classes. A representative amide, carbamate, and urea (2c,d,h) were shown to be > 50-fold selective for inhibiting PDE-IV versus representative PDEs from families I-III and V. Furthermore, these same three inhibitors demonstrated potent functional activity (IC50 < 1 microM) by inhibiting tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide (LPS)-activated purified human peripheral blood monocytes and mouse peritoneal macrophages. These compounds were also tested orally in LPS-injected mice and demonstrated dose-dependent inhibition of serum TNF-alpha levels.

Animals↗
PubMed1989

Type II hyperprolinaemia in a pedigree of Irish travellers (nomads).

We describe a study of 312 subjects in 71 families near related to a proband with type II hyperprolinaemia. The subjects were Irish travellers (nomads) among whom consanguineous marriage and high fertility are common. Thirteen additional cases of type II hyperprolinaemia were discovered; all were offspring of consanguineous unions. A further 50 subjects were found to have mild hyperprolinaemia. We found a strong association between type II hyperprolinaemia and seizures during childhood but no significant association with mental handicap. Most adults with type II hyperprolinaemia enjoyed normal health and there was no evidence that maternal hyperprolinaemia compromised fetal development. The documented association between type II hyperprolinaemia and seizures may be related to the neuromodulatory or reducing-oxidising effects of proline and pyrroline-5-carboxylate, respectively, that has been shown in vitro. Alternatively, another genetic defect closely linked to the type II hyperprolinaemia allele could be the explanation.

1-Pyrroline-5-Carboxylate Dehydrogenase↗
PubMed1984

Alzheimer's disease: a study of epidemiological aspects.

A case-control study was performed to determine the possible roles of various environmental factors, prior illnesses, drug use, and personal habits in the development of Alzheimer's disease. Such information was collected from 40 patients with onset of dementia prior to age 70 and from 80 community control subjects matched for age, sex, and race. No significant differences were found between patients and control subjects in toxic environmental exposures, animal contacts, smoking, drinking, or unusual dietary habits. A significantly higher frequency of prior thyroid disease was found in women patients than in women control subjects (25.0% and 7.1%, respectively). A history of severe head injury was also obtained significantly more often among the patients than among the controls (15.0% and 3.8%, respectively). Aside from these differences, which may prove to be important associative factors in this illness, there appeared to be no major premorbid demographic or clinical factors associated with this form of dementia. There was evidence, however, of a genetic factor that was manifested in an excess of dementia and mental retardation (including Down's syndrome) in families of patients with Alzheimer's disease.

Alzheimer Disease↗