OBJECTIVE: To compare the short- and long-term prognosis following a first Q-wave or non-Q-wave myocardial infarction. DESIGN: Cohort study with a mean follow-up period of 5.1 +/- 4.9 years. SETTING: Population-based. PARTICIPANTS: Framingham (Mass) Heart Study subjects with an initial recognized myocardial infarction during a 17-year period were studied, including 227 men and 136 women with a mean age of 67.2 years. Seventy-seven percent of first infarctions were Q-wave infarctions and 23% were non-Q-wave infarctions. MAIN OUTCOME MEASURES: Reinfarction and death from coronary heart disease. RESULTS: During the follow-up period, subjects with non-Q-wave infarctions had a significantly higher rate of reinfarction than subjects in the Q-wave group (P = .02 for the entire follow-up). The 10-year reinfarction rates were 44.8% vs 27.4%. When analyzed separately by age and sex, differences in reinfarction rates were only noted in men and in those under the age of 65 years. There were no differences in coronary heart disease death rates based on Q-wave status, even when examined separately by age and sex. Multivariate analysis revealed a 1.8-fold higher risk of reinfarction in the non-Q-wave group (95% confidence interval, 1.1 to 3.1), and also demonstrated that baseline hypertension was an independent risk factor for predicting reinfarction (relative risk, 1.8; 95% confidence interval, 1.1 to 3.2). There were no differences in the rates of sudden death or all-cause mortality following the two types of myocardial infarction. Additionally, subjects with a first Q-wave infarction had a higher rate of subsequent congestive heart failure, while those with non-Q-wave infarctions had a significantly higher rate of coronary insufficiency (unstable angina with transient ST-T wave abnormalities). CONCLUSIONS: These results confirm and extend findings from prior studies that have identified patients with first non-Q-wave myocardial infarctions as potentially unstable, with greater subsequent morbidity and similar mortality to their counterparts with Q-wave infarctions.

Adult↗

PubMedDate not supplied

Cholesterol and carotid atherosclerosis in older persons: the Framingham Study.

We studied the relationship between extracranial carotid atherosclerosis as measured by high-resolution carotid sonography and serum total cholesterol and high-density-lipoprotein cholesterol (HDL-C) levels which were determined at the time of carotid sonography and 8 years previously in 1189 members of the Framingham cohort, aged 66 to 93 years. Among participants, no carotid disease was found in 30%; 1 to 49% stenosis, in 62%; 50 to 74% stenosis, in 5%; 75 to 99% stenosis, in 2%; and 100% stenosis, in 1%. Total cholesterol measured 8 years prior to the carotid examination showed a strong positive association with the occurrence of stenosis in both men and women. There was no association between concurrently measured cholesterol levels and stenosis for either men or women. For women there was a strong association between both the 8-year HDL-C level and the concurrently measured HDL-C level and the degree of carotid stenosis. For men, neither concurrent nor 8-year HDL-C measurements were significantly related to carotid stenosis. These results suggest that there is a time lag between the observation of an elevated cholesterol level and its expression as an increased degree of carotid atherosclerosis.

Age Factors↗

PubMedDate not supplied

An interaction between type 1 and type 2 programmed cell death and clonogenic survival.

UNLABELLED: We suggest two additional reasons why current, non-surgical therapies for most solid, epithelial-derived cancers can lack effectiveness. Studies with panc-1 human pancreatic cancer cells cultured with actinomycin D and/or MK 886 indicate firstly, that type 2 (intrinsic, autophagic, mitochondrial-dependent, MK 886-induced) programmed cell death is less effective than the type 1 (apoptotic, extrinsic, ligand-dependent, actinomycin D-induced) form in reducing the number of residual clonogenic cells, and secondly, that activation of cellular suicide during their combined culture results in a greater number of residual clonogenic cells compared with either agent alone. HYPOTHESIS: Based on results from the culture of panc-1 cells with MK 886 and/or actinomycin D, we suggest that in this system, and possibly in others: (a) type 2 programmed cell death is a less effective inhibitor of residual cells with clonogenic potential, and (b) activation together of both forms of PCD increases the number of residual clonogenic cells.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Concomitant T- and Tk-activation associated with acquired-B antigens.

Three patients with acquired-B antigens are reported whose red blood cells also manifested T- and Tk-activation. The results of tests using purified Arachis hypogaea and Bandeiraea simplicifolia (BS II) lectins, and red blood cells either T, Tk or both T and Tk-activated by bacterial enzymes in vitro, suggest that the acquired-B phenomenon, T-activation and Tk-activation result from the action of different bacterial enzymes.

ABO Blood-Group System↗

PubMedDate not supplied

BMP-2 gene expression and effects on human vascular smooth muscle cells.

Bone morphogenetic proteins (BMPs) and their serine/threonine kinase receptors have been identified in atherosclerotic arteries and vascular smooth muscle cells, respectively. Thus, BMPs (the largest subfamily of the TGF-beta superfamily) have been implicated in the pathogenesis of atherosclerosis. However, the origins of BMP biosynthesis and the functional roles of BMP in blood vessels are unclear. The present study explored BMP-2 gene expression in various human blood vessels and vascular cell types. Functional in vitro studies were also performed to determine the effects of recombinant human BMP-2 on migration (transwell assay) and proliferation ([3H]-thymidine incorporation) of human aortic vascular smooth muscle cells (HASMC). RT-PCR experiments revealed BMP-2 gene expression in normal and atherosclerotic human arteries as well as cultured human aortic and coronary vascular smooth muscle cells, human umbilical vein endothelial cells (HUVECs) and human macrophages. In cellular migration studies, incubation with BMP-2 produced efficacious (</=610-fold), concentration- and time-dependent chemotaxis of HASMCs (EC50 = 0.8 microM) with little or no effect on HUVEC chemotaxis. The increased HASMC motility induced by BMP-2 was inhibited by coincubation with an anti-BMP-2 mAb. In addition, subthreshold concentrations of BMP-2 produced a dramatic synergistic effect upon platelet-derived growth factor (PDGF)-induced chemotaxis. In contrast to PDGF, BMP-2 had no significant effet on [3H]-thymidine incorporation in HASMC at chemotaxic concentrations (</=6.0 microM) nor did it synergize with the mitogenic effects of PDGF. In conclusion, the expression of BMP-2 by numerous cell types in the blood vessel wall may play a chemotactic or cochemotactic role in the smooth muscle cell response to vascular injury.

Aorta↗

PubMedDate not supplied

Receptor binding and internalization of a unique biologically active angiotensin II-colloidal gold conjugate: morphological analysis of angiotensin II processing in isolated vascular strips.

It is well recognized that following binding of ligand, many receptors undergo a process of agonist-induced receptor-mediated endocytosis (RME) or internalization. We recently characterized the intracellular pathway and kinetics of angiotensin II (AII)-RME in cultured explant-derived rat aortic vascular smooth muscle cells (VSMCs). To definitively study vascular internalization of AII, however, it is critical to examine AII binding and uptake in intact, differentiated VSM. For the present study, we used a unique, biologically active AII-colloidal gold conjugate to qualitatively examine, by transmission electron microscopy, the ultrastructural details of AII binding and internalization in intact VSM. Strips of isolated, cleaned, and denuded rat aortic smooth muscle were incubated with AII-gold probe for 2 h at 4 degrees C to allow binding of the complex without simultaneous internalization. After rinsing to remove unbound AII-gold, the strips were incubated at 37 degrees C (5-90 min) to initiate internalization. These studies show that AII initially binds over the entire surface of medial VSMCs. Following binding, the AII is internalized via small receptosomes which likely represent clathrin-coated vesicles. By 20 min after internalization, gold particles are evident within large lysosome-like vesicles deep within the VSM. There was no evidence of association of gold particles with the Golgi network at any of the time periods examined. Gold particles were occasionally observed in perinuclear regions after 90 min at 37 degrees C, although this did not appear to represent a typical pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMedDate not supplied

Altered oncogene, tumor suppressor and cell-cycle gene expression in PANC-1 cells cultured with the pleiotrophic 5-lipoxygenase inhibitor, MK886, assessed with a gene chip.

We describe a genomic response of mRNAs associated with a subset of oncogenes, tumor suppressor and cell cycle-related genes in proliferating human Panc-1 pancreatic cancer cells after 24 hours of culture with MK886, a pleotrophic 5-lipoxygenase inhibitor. Ninety-eight of these cDNAs are represented in one of the sub-arrays included in the Clontech Human cDNA Expression Array. In this initial analysis, control cells exhibited apparent widespread low levels of disparate mRNA synthesis. In cells cultured with 40 microM MK886 for 24 hr, while most expressed genes, including a number of specific proliferation-enhancing genes such as c-myc were inhibited, 19 other ones including some countervailing genes including tyrosine SRC protein kinase, cyclins B1 and D1, CDC25B phosphatase and 40s ribosomal S19, amounting to 19 percent of the cDNAs resident on the chip were up-regulated at > 1.10 experimental/control values. Therapy-induced activation of compensatory proliferative genomic responses provides an additional explanation why malignant cells can fail therapy. Among their many future uses, gene chips clearly will be an extremely powerful tool for identifying relationships between the hierarchical linear and non-linear control and implementation-related cellular events and for identifying potential molecular targets tor cancer therapy.

Blotting, Western↗

PubMedDate not supplied

A genomic response of H-358 bronchiolar carcinoma cells to MK 886, an inhibitor of 5-lipoxygenase, assessed with a cDNA array.

Incomplete programmed cell death is one explanation for the escape of cancer cells from therapy. Inhibitors of the enzyme 5-lipoxygenase reduce proliferation and initiate programmed cell death in many different types of malignantly transformed cells. The 5-lipoxygenase inhibitor, MK 886. induces an atypical form of programmed cell death in H-358 bronchiolar lung cancer cells. A genomic response of H-358 cells after 24 hr of culture at a 40 uM concentration that inhibited proliferation was analyzed with a Clontech human cDNA array containing 588 cDNAs corresponding to identified genes. The data grouped into 3 major categories and initial conclusions regarding countervailing, cellular stress, programmed cell death, DNA damage and repair mRNA-responses as possible reasons for escape from the antiproliferative response are discussed. The use of cDNA arrays to estimate the extent to which malignantly transformed cells respond to therapy or why they do not and so infer prognosis and identify possible therapeutic modifications is indicated.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMedDate not supplied

A response of Panc-1 cells to cis-platinum, assessed with a cDNA array.

BACKGROUND: The problem posed by the lack of response of cells in most solid cancers to current chemotherapy generally remains intractable. MATERIALS AND METHODS: The use of cDNA arrays represents one global approach to identifying reasons for this failure. A messenger RNA response of pancreatic cancer (Panc-1) cells after culture for 24 hours with 12 microM cis-platinum was analyzed with a commercial cDNA array. RESULTS: Major drug-induced events included inhibition of messenger RNAs associated with cell proliferation and up-regulation of generally countervailing DNA repair, cellular stress, heat shock protein, glutathione stress-related and multiple drug resistance enzyme messenger RNAs, accompanied by a limited programmed cell death response. CONCLUSION: Induction of widespread normal stress-induced countervailing mRNAs by comparatively non-selective agents such as cis-platinum strongly biases against a successful therapeutic outcome. This paradoxical result of a therapeutic intent provides a further compelling argument for the use of specifically-targeted therapy such as growth factor receptor, tyrosine kinase and other discretely focused agents, probably employed in combinations based on expression of their targets in an individual patient's cancer, as identified by cDNA or proteonomic arrays.

Antineoplastic Agents↗

PubMedDate not supplied

Acute changes in U937 nuclear Ca2+ preceding type 1 "apoptotic" programmed cell death due to MK 886.

BACKGROUND: MK 886, a 5-lipoxygenase inhibitor, induces a type 1 "apoptotic" form of programmed cell death in Bcl-2-positive U937 monoblastoid cells. In Ca2+-depleted, nonpermeabilized U937 cells studied with MK 886 in a Ca2+-free medium, an acute increase in Ca2+ occured within 10 to 20 seconds, detected with fura-2 measured with a spectrofluorimeter. METHODS AND RESULTS: The increased fluorescence was nuclear in location, as judged by confocal microscopy. The antioxidant, N-acetyl-L-cysteine, three agents that inhibit mitochondrialfunction at identified sites, antimycin A, atractyloside and cyclosporin A, the L/N-channel inhibitor, loperamide and BAPTA, an intracellular Ca+ chelator preloaded into cells each reduced the extent or prevented the acute MK 886-induced rise in Ca2+, as determined by radiometric detection. Rhodamine-2, a more selective mitochondrial Ca2+ probe, provided no evidence for nuclear Ca2+ originating from that extra-nuclear site or from the endoplasmic reticulum. With 2', 7'-dichloro-dihydrofluorescein-labelled cells to detect reactive oxygen species, MK 886 increased the initial fluorescent signal from a number of intracellular, largely extra-nuclear sites, including mitochondria. Two chemicals that inhibit the function of Bcl-2, HA14-1 and 2-methyl-antimycin A3, reduced the Ca2+ response to MK 886, if pre-incubated with the Bcl-2-positive U937 cells at 37 degrees C for several hours. MK 886 was previously shown to induce reactive oxygen species and a fall in mitochondrial membrane potential in both Bcl-2-positive U937 and in Bcl-2-negative PC-3 prostate and panc-1 pancreatic cancer cells. The latter solid tumor cells undergo an atypical "type 2" PCD without an acute rise in nuclear Ca2+. CONCLUSION: These results are consistent with an MK 886-induced increase of reactive oxygen species from intra-cellular sites including mitochondria which release Ca2+ located primarily at or near nuclei. These events may involve Bcl-2 participating in some form of Ca2+ channel and nuclear Ca2+ binding proteins undergoing conformational changes due to reactive oxygen species. Reasons for the different PCD responses in Bcl-2 positive lympho-hematopoietic compared to Bcl-2-negative solid cancer cell lines, respectively with and without the induced nuclear Ca2+ signal, remain to be defined.

Apoptosis↗