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M Simons

Publications and source records attributed to M Simons.

At least 145 records · Page 8Linked to original sources
PubMed1995

c-myc in vasculoproliferative disease.

Antisense oligonucleotides to genes central to cellular proliferation have suppressed smooth muscle cell growth in vitro and in vivo. We now report that although the response of cultured smooth muscle cells to antisense oligonucleotides to c-myc and c-myb is identical, the response of the injured arterial wall to these oligomers depends on the kinetics of gene expression and oligonucleotide delivery. Two different antisense oligonucleotides to each oncogene were administered to the perivascular aspect of injured rat carotid arteries via polymer-based delivery systems. The acute release of antisense oligonucleotides from the Pluronic gels reduced in vitro cell growth 54.8% with c-myc and 56.9% with c-myb. The more sustained release from ethylene vinyl acetate copolymer (EVAc) matrices was slightly less efficient, inhibiting proliferation 47.3% and 43.3%, respectively. However, although both EVAc and Pluronic release of c-myb antisense oligonucleotide sequences inhibited intimal hyperplasia 2 weeks after injury, only the more prolonged EVAc matrix release of antisense oligonucleotide to c-myc was effective. The failure of the short course of c-myc oligomer release from Pluronic gels stemmed from early successful suppression with late loss of regulation and not from inactivation of the antisense oligonucleotide within the polymeric gel. Within 24 hours of injury, Pluronic-based release of c-myc antisense oligomers reduced mRNA levels in the tunica media 2.5-fold and immunocytochemical identification of c-myc expression by 98.8%. As a result, the number of proliferating cells was decreased 6.5-fold 3 days after injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Thallium-201 accumulation in myositis ossificans and in juxta-articular ossification.

We present the findings on 201Tl and 99mTc-MDP scintigraphy in three patients suffering from heterotopic ossification (two patients presenting with myositis ossificans and one patient presenting with juxta-articular ossification in combination with myositis ossificans). Since resection of the lesions has to be delayed until stabilization, 99mTc-MDP is often used as a parameter of lesional activity, although it is not optimal. For this clinical problem, we evaluated 201Tl scintigraphy as a marker of metabolic activity. In addition to the well-documented uptake of 99mTc-MDP, marked accumulation of 201Tl was observed in all heterotopic ossification sites. Hence, our results support the use of 201Tl scintigraphy in the therapeutic management and monitoring of conditions associated with ectopic ossification. On the other hand, although myositis ossificans is sometimes clinically, radiographically and even histologically confused with extraosseous osteogenic sarcoma, 201Tl accumulation may not be a helpful factor in the differential diagnosis due to the presence of tracer accumulation in both disorders.

Adult↗
PubMed1995

beta-Adrenergic receptors contribute to hypoxaemia induced vasodilation in man.

1. It was the aim of the present study to investigate the role of the beta-adrenergic receptor in hypoxaemia induced vasodilatation in the human forearm. 2. The study was performed in 12 non-smoking male volunteers. In six subjects the local vascular effects of intra-arterially (i.a.) infused propranolol (0.1 mu kg-1 min-1) was determined during normoxaemia and hypoxaemia (peripheral oxygen saturation; SpO2 80%), and compared with the contra-lateral (control) arm. beta-adrenergic receptor blockade by propranolol was confirmed by i.a. infusions of adrenaline. In six other subjects the effects of incremental hypoxaemia (SpO2 90, 85, 80%) on forearm- and finger blood flow was investigated. A difference between these vascular beds is the absence of vascular beta-adrenergic receptors in the finger. Forearm- and finger blood flow were measured by venous occlusion plethysmography. Plasma levels of (nor-)adrenaline were determined in both arterial and venous blood samples. Hypoxaemia was attained by gradual decompression of a hypobaric chamber and individually adjusted. 3. During normoxaemia the single infusion of propranolol did not influence forearm vascular resistance. In contrast, during hypoxaemia a net vasoconstriction was observed in the arm treated with propranolol, which was significantly different (P = 0.009) from the vasodilatation in the control arm (mean difference in response 40%; 95% confidence interval 13.2-66.8). The net arterio-venous spillover of noradrenaline from the forearm increased after the first 15 min of hypoxaemia (P < 0.05) and returned to baseline in the next 15 min. Arterial and venous plasma levels of adrenaline during hypoxaemia remained unchanged compared with normoxaemia. In the second set of experiments incremental levels of hypoxaemia induced a vasoconstriction in the finger, which was significantly different (P = 0.025) from the vasodilatation in the forearm (mean difference in response 300%; 95% confidence interval 63-537). 4. The data indicate that beta-adrenergic receptors contribute to hypoxaemia induced vasodilatation, despite unaltered adrenaline plasma concentrations.

Adult↗
PubMed1994

Linguistic features of noncoding DNA sequences.

We extend the Zipf approach to analyzing linguistic texts to the statistical study of DNA base pair sequences and find that the noncoding regions are more similar to natural languages than the coding regions. We also adapt the Shannon approach to quantifying the "redundancy" of a linguistic text in terms of a measurable entropy function, and demonstrate that noncoding regions in eukaryotes display a smaller entropy and larger redundancy than coding regions, supporting the possibility that noncoding regions of DNA may carry biological information.

Algorithms↗
PubMed1994

Statistical mechanics in biology: how ubiquitous are long-range correlations?

The purpose of this opening talk is to describe examples of recent progress in applying statistical mechanics to biological systems. We first briefly review several biological systems, and then focus on the fractal features characterized by the long-range correlations found recently in DNA sequences containing non-coding material. We discuss the evidence supporting the finding that for sequences containing only coding regions, there are no long-range correlations. We also discuss the recent finding that the exponent alpha characterizing the long-range correlations increases with evolution, and we discuss two related models, the insertion model and the insertion-deletion model, that may account for the presence of long-range correlations. Finally, we summarize the analysis of long-term data on human heartbeats (up to 10(4) heart beats) that supports the possibility that the successive increments in the cardiac beat-to-beat intervals of healthy subjects display scale-invariant, long-range "anti-correlations" (a tendency to beat faster is balanced by a tendency to beat slower later on). In contrast, for a group of subjects with severe heart disease, long-range correlations vanish. This finding suggests that the classical theory of homeostasis, according to which stable physiological processes seek to maintain "constancy," should be extended to account for this type of dynamical, far from equilibrium, behavior.

Base Sequence↗
PubMed1994

Correlation approach to identify coding regions in DNA sequences.

Recently, it was observed that noncoding regions of DNA sequences possess long-range power-law correlations, whereas coding regions typically display only short-range correlations. We develop an algorithm based on this finding that enables investigators to perform a statistical analysis on long DNA sequences to locate possible coding regions. The algorithm is particularly successful in predicting the location of lengthy coding regions. For example, for the complete genome of yeast chromosome III (315,344 nucleotides), at least 82% of the predictions correspond to putative coding regions; the algorithm correctly identified all coding regions larger than 3000 nucleotides, 92% of coding regions between 2000 and 3000 nucleotides long, and 79% of coding regions between 1000 and 2000 nucleotides. The predictive ability of this new algorithm supports the claim that there is a fundamental difference in the correlation property between coding and noncoding sequences. This algorithm, which is not species-dependent, can be implemented with other techniques for rapidly and accurately locating relatively long coding regions in genomic sequences.

Algorithms↗
PubMed1994

Mosaic organization of DNA nucleotides.

Long-range power-law correlations have been reported recently for DNA sequences containing noncoding regions. We address the question of whether such correlations may be a trivial consequence of the known mosaic structure ("patchiness") of DNA. We analyze two classes of controls consisting of patchy nucleotide sequences generated by different algorithms--one without and one with long-range power-law correlations. Although both types of sequences are highly heterogenous, they are quantitatively distinguishable by an alternative fluctuation analysis method that differentiates local patchiness from long-range correlations. Application of this analysis to selected DNA sequences demonstrates that patchiness is not sufficient to account for long-range correlation properties.

Bacteriophage lambda↗
PubMed1994

Basic FGF enhances endothelium-dependent relaxation of the collateral-perfused coronary microcirculation.

The effect of chronic, periadventitial administration of basic (b) fibroblast growth factor (FGF) on endothelial dysfunction in the collateral-dependent and normally perfused coronary microcirculation was examined. Ameroid constrictors were placed on the proximal left circumflex coronary artery (LCX) in 23 pigs. In 11 pigs, bFGF was released from calcium alginate microcapsules into the perivascular space of the proximal left anterior descending coronary artery (LAD) and LCX. After 5-8 wk, coronary arterial microvessels (80-170 microns) were studied in a pressurized (40 mmHg) no-flow state with video microscopy. Receptor-mediated endothelium-dependent relaxations to ADP and serotonin were reduced while contraction to acetylcholine was enhanced in the collateral-dependent LCX microvessels of non-bFGF-treated control hearts. Relaxation of vessels to the non-receptor-mediated, endothelium-dependent agent A-23187; endothelium-independent relaxation to nitroprusside; and contraction to KCl were similar in all groups. Chronic treatment with bFGF normalized responses to ADP, serotonin, and acetylcholine in the collateral-dependent LCX region but had no effect on the responses of vessels in the normally perfused LAD region. Arteriolar density in the collateral-perfused LCX region of bFGF-treated hearts was markedly increased (4-fold compared with that in untreated hearts, suggesting a link between the angiogenic effect of bFGF and its action on endothelial preservation. Thus the periadventitial, sustained delivery of bFGF preserves receptor-mediated, endothelium-dependent responses in the collateral-dependent LCX region but has no effect on responses of microvessels in the normally perfused LAD region or on non-receptor-mediated endothelium-dependent relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Antisense proliferating cell nuclear antigen oligonucleotides inhibit intimal hyperplasia in a rat carotid artery injury model.

We have used antisense phosphorothioate oligonucleotides to define the role played by proliferating cell nuclear antigen (PCNA) in neointimal accumulation of smooth muscle cells in a rat carotid artery injury model. The short-term extraluminal delivery of 250 nmol of antisense oligonucleotides, but not control oligonucleotides, immediately after arterial injury produces a 77% suppression of PCNA mRNA after 24 h and a 52% decrease in the frequency of medial smooth muscle cells expressing PCNA after 72 h. This reduction in PCNA expression is accompanied by a 59% decrease in the frequency of proliferating medial smooth muscle cells at 3 d as measured by BudR staining and an 80% decrease in neointimal accumulation assessed morphometrically at 2 wk. Thus, the expression of PCNA is required for medial smooth muscle cell growth in vivo and for neointimal formation after arterial injury.

Animals↗
PubMed1994

Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts.

The effect of basic fibroblast growth factor (bFGF) administration on regional myocardial function and blood flow in chronically ischemic hearts was studied in 26 pigs instrumented with proximal circumflex coronary artery (LCX) ameroid constrictors. In 13 animals bFGF was administered extraluminally to the proximal left anterior descending (LAD) and LCX arteries with heparin-alginate beads and 13 other animal served as controls. bFGF-treated pigs showed a fourfold reduction in left ventricular infarct size compared to untreated controls (infarct size: 1.2 +/- 0.4% vs. 5.1 +/- 1.3% of LV mass, mean +/- SEM, P < 0.05). Percent fractional shortening (% FS) in the LCX area at rest was reduced compared with the LAD region in both bFGF and control pigs. However, there was better recovery in the LCX area after rapid pacing in bFGF-treated pigs (% FSLCX/% FSLAD, 22.9 +/- 7.3%-->30.5 +/- 8.5%, P < 0.05 vs. prepacing) than in controls (16.0 +/- 7.8%-->14.3 +/- 7.0%, P = NS). Furthermore, LV end-diastolic pressure rise with rapid pacing was less in bFGF-treated than control pigs (pre-pacing; pacing; post-pacing, 10 +/- 1; 17 +/- 3; 11 +/- 1* mmHg vs 10 +/- 1; 24 +/- 4; 15 +/- 1 mmHg, *P < 0.05 vs. control). Coronary blood flow in the LCX territory (normalized for LAD flow) was also better during pacing in bFGF-treated pigs than in controls. Thus, periadventitial administration of bFGF in a gradual coronary occlusion model in pigs results in improvement of coronary flow and reduction in infarct size in the compromised territory as well as in prevention of pacing-induced hemodynamic deterioration.

Animals↗
PubMed1993

Relation between activated smooth-muscle cells in coronary-artery lesions and restenosis after atherectomy.

BACKGROUND: Neointimal proliferation leading to restenosis frequently develops after coronary angioplasty. This process is associated with a change in vascular smooth-muscle cells from a contractile (quiescent) phenotype to a synthetic or proliferating (activated) one. We investigated whether the presence of activated smooth-muscle cells in coronary lesions at the time of coronary atherectomy predisposes patients to subsequent restenosis. METHODS: We used in situ hybridization to study the expression of messenger RNA in coronary-atherectomy specimens from 20 patients. Plaque material was hybridized with a probe for the B isoform of human nonmuscle myosin heavy chain, a major nonmuscle myosin isoform in activated, but not quiescent, smooth-muscle cells. Angiographic follow-up data were obtained a mean (+/- SD) of 174 +/- 54 days after atherectomy in 16 of the 20 patients, and the extent of recurrent luminal narrowing was analyzed quantitatively. The presence of restenosis was assessed by exercise thallium scintigraphy in the other four patients. RESULTS: Atherectomy specimens from 10 of the 20 patients showed hybridization with the probe, defined as the clustering of more than 20 silver grains per cell nucleus in more than 10 nuclei in five high-power fields (x250); specimens from the other 10 patients showed no such hybridization. At follow-up, restenosis had developed in 8 of the 10 patients with positive hybridization results, but was absent in 9 of the 10 patients with negative results (P = 0.007). The degree of late loss in luminal diameter was significantly higher in patients with positive hybridization results than in those with negative results (ratio of late loss to immediate gain after atherectomy, 0.76 +/- 0.3 vs. 0.36 +/- 0.3; P < 0.001). CONCLUSIONS: We conclude that the expression of the B isoform of nonmuscle myosin heavy chain is increased in some coronary atherosclerotic plaques and that this increase in expression identifies a group of lesions at high risk for restenosis after atherectomy.

Adult↗
PubMed1993

The proto-oncogene c-myb mediates an intracellular calcium rise during the late G1 phase of the cell cycle.

The intracellular concentration of ionized calcium is involved in regulating mitosis. However, little is known about intracellular levels of calcium during G1. We have demonstrated in vascular smooth muscle cells a mid-G1 decrease in ionized calcium concentration followed by a 2-fold rise at the G1/S interface (44 nM +/- 0.6 nM versus 98 nM +/- 1.1 nM, p < 0.01). The elevation of intracellular calcium is preceded by an increase in c-myb mRNA levels and is abolished with antisense but not missense c-myb oligonucleotides. Furthermore, cells stably transfected with c-myb show a similar 2-fold augmentation in intracellular calcium concentrations, as compared with untransfected cells, which is also abolished by antisense c-myb oligonucleotides. The c-myb-induced rise in intracellular calcium is dependent upon the presence of extracellular calcium and is not suppressed by L type calcium channel blockers. We conclude that c-myb induces an elevation in intracellular calcium levels of vascular smooth muscle cells at the G1/S interface which provides a novel role for this proto-oncogene as well as a potentially important control point for cell cycle regulation.

Animals↗
PubMed1993

A comparison of iodine-123 meta-iodobenzylguanidine scintigraphy and single bone marrow aspiration biopsy in the diagnosis and follow-up of 26 children with neuroblastoma.

In staging neuroblastomas, the demonstration of tumoural invasion of the bone marrow is an important criterion with regard to the therapeutic prospects and the prognosis. Iliac crest aspiration sampling has been used routinely for the detection of bone marrow metastases in neuroblastoma. However, due to the limited character of the sampling, it sometimes leads to false-negative results. Another procedure which is used to determine the extent of neuroblastoma is metaiodobenzylguanidine (mIBG) scintigraphy. In order to establish the respective merits of both diagnostic techniques retrospectively, 148 iodine-123 mIBG scans of 26 children with neuroblastoma have been re-evaluated and compared with the results of routine bone marrow samples obtained within a 4-week period before or after scanning. Three types of mIBG uptake in the bone/bone marrow could be differentiated: (1) no visualization of the skeleton; (2) diffuse uptake in the skeleton with or without focally increased uptake, which indicates massive, diffuse bone marrow invasion by the tumour; and (3) focal tracer accumulation in one or several bones. No tracer uptake was observed in the skeleton in 91 scans. In 89 of the 91 the bone marrow biopsy was negative. Twenty-four scans showed diffuse skeletal uptake with or without foci. The bone marrow biopsies were negative for eight of those 24 scans. Hyperactive foci in one or more bones without diffuse tracer accumulation in the skeleton were detected in 33 scans. In only 7 of these 33 scans did bone marrow biopsy specimens from the iliac MDP crest contain neuroblastoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Iodobenzylguanidine↗
PubMed1993

Characterization of 4AOHW cell line panel including new data for the 10IHW panel.

There will be a continuing need for well characterized panels of EBV-transformed lymphoblastoid cell lines. Selection of the 4AOH panel was based on prior MHC typing and was intended to ensure representation of ancestral haplotypes from various racial groups. Cells from nonhuman primates, bone marrow donor-recipient pairs, and patients with IDDM were included. Selected cells from the 10IHW were included to enable further characterization. Cells were distributed to participants in the 4AOHW and were typed at multiple loci by a variety of procedures. Non-HLA genes such as TNF were included. Since the cells were distributed "blind" with hidden replicates, it was possible to evaluate the quality of the typing data. An approach to data management is described. The best current estimates of the typing of these cells are presented. The panel will be useful since it provides standards for most alleles at most loci. Since the cells are so well characterized, they represent a useful resource for MHC sequencing and for the evaluation of new typing procedures.

Alleles↗