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Biomedical subjects

M Simons

Publications and source records attributed to M Simons.

At least 127 records · Page 7Linked to original sources
PubMed1996

Myocardial perfusion scintigraphy: effect on diagnostic and clinical management algorithms.

UNLABELLED: Research has demonstrated that myocardial perfusion imaging increases the sensitivity and specificity of stress electrocardiography. However, the additional effect of the perfusion component of a stress study on clinical management algorithms remains poorly defined. METHODS: We prospectively assessed the decision-making process in 518 patients, from 191 clinicians, undergoing stress myocardial perfusion imaging in our departments. Each clinician was asked, by telephone interview, to define the probability of reversible myocardial ischemia and their management plan (i.e., no antianginal treatment, medical therapy or an invasive intervention) in three stages: pretest, after the stress data was made available and after completion of the perfusion study. RESULTS: The results of the stress data alone influenced the estimate of the probability of reversible ischemia in 149 of 518 patients, and management strategy in 50 of 518 patients. The data from the perfusion component in isolation changed probability of reversible disease in 219 of 518 patients and altered clinical management in 77 of 518 patients. Of 103 patients in whom an invasive procedure was planned after the stress data, the availability of the perfusion data led to deferral of catheterization in 48 cases (46.6%). Conversely, of the 415 patients triaged to a noninvasive plan after stress data, only 29 (7.0%) were changed to an invasive strategy. Of note, only 2.3% of women changed from a conservative strategy as a consequence of the perfusion data, compared to 9.1% of men. CONCLUSION: The perfusion component of a stress study has a significant effect on both estimation of clinical probability and the definition of patient management strategy. Myocardial perfusion imaging reduced the number of catheterizations in patients initially triaged to an invasive management strategy. Conversely, the effect of stress and perfusion data in patients triaged to conservative management on clinical grounds, especially women, remains less well defined.

Algorithms↗
PubMed1995

Production of intracellular amyloid-containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence.

A distinguishing feature of Alzheimer's disease (AD) is the deposition of amyloid plaques in brain parenchyma. These plaques arise by the abnormal accumulation of beta A4, a proteolytic fragment of amyloid precursor protein (APP). Despite the fact that neurons are dramatically affected in the course of the disease, little is known about the neuronal processing of APP. To address this question we have expressed in fully mature, synaptically active rat hippocampal neurons, the neuronal form of human APP (APP695), two mutant forms of human APP associated with AD, and the mouse form of APP (a species known not to develop amyloid plaques). Protein expression was achieved via the Semliki Forest Virus system. Expression of wild type human APP695 resulted in the secretion of beta A4-amyloid peptide and the intracellular accumulation of potential amyloidogenic and non-amyloidogenic fragments. The relative amount of amyloid-containing fragments increased dramatically during expression of the clinical mutants, while it decreased strongly when the mouse form of APP was expressed. 'Humanizing' the rodent APP sequence by introducing three mutations in the beta A4-region also led to increased production of amyloid peptide to levels similar to those obtained with human APP. The single Gly601 to Arg substitution alone was sufficient to triple the ratio of beta A4-peptide to non-amyloidogenic p3-peptide. Due to the capacity of these cells to secrete and accumulate intracellular amyloid fragments, we hypothesize that in the pathogenesis of AD there is a positive feed-back loop where neurons are both producers and victims of amyloid, leading to neuronal degeneration and dementia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed1995

Two-dimensional gel mapping of the processing of the human amyloid precursor protein in rat hippocampal neurons.

The proteolytic fragments derived from the amyloid precursor protein (APP) in primary cultures of rat hippocampal neurons were analyzed by two-dimensional gel electrophoresis. The Semliki Forest Virus expression vector was used to express human APP695 and a mutant form associated with familial Alzheimer's disease (APP-FAD670/671). Hippocampal neurons expressing wtAPP695 or APP-FAD670/671 secrete at least six APP fragments of 100-110 kDa with isoelectric focusing points ranging from 4.5 to 4.0. The heterogeneity of the secreted APP forms is shown to be in part due to differences in glycosylation. In contrast to wtAPP695, neurons producing the APP-FAD670/671 variant did not secrete detectable amounts of secretory APP derived from cleavage within the amyloid beta A4 domain. This result suggests that there is little alpha-secretase cleavage in neurons expressing the APP-FAD670/671 mutant.

Alzheimer Disease↗
PubMed1995

Intracellular routing of human amyloid protein precursor: axonal delivery followed by transport to the dendrites.

A characteristic neuropathological feature of Alzheimer's disease is the cerebral deposition of amyloid plaques. These deposits contain beta A4 amyloid peptide, a cleavage product of the transmembrane protein amyloid protein precursor (APP). Despite numerous studies on the processing of the different APP isoforms in non-neuronal cells, little is known about its sorting and transport in neurons of the central nervous system (CNS). To analyze this question we expressed in cultured rat hippocampal neurons the human APP 695, tagged at its N-terminus with the myc epitope, using the Semliki forest virus (SFV) expression system. APP was first delivered from the cell body to the axon and later appeared also in the dendrites. Inhibition of protein synthesis at the time of axonal expression did not block the late appearance of the protein in the dendrites. An antibody directed against the myc tag, bound to the cell surface at 4 degrees C at the time of axonal APP expression, could be chased to the dendritic domain after subsequent incubation at 37 degrees C. These results suggest that the newly synthesized APP, after initial axonal delivery, may be transported to the dendrites by a transcytotic mechanism. The routing of APP in polarized neurons is different from that of polarized epithelial cells, in which the protein is delivered basolaterally, arguing for neuronal specific sorting and processing mechanisms.

Amino Acid Sequence↗
PubMed1995

Beta-adrenergic modulation of the collateral-dependent coronary microcirculation.

The effect of chronic, collateral-dependent perfusion on beta-adrenergic coronary microvascular responses was examined. Ameroid constrictors were placed on the proximal left circumflex (LCx) coronary artery in 16 pigs. In 8 pigs, heparinized saline containing vascular endothelial growth factor (VEGF) was administered into the perivascular space of the proximal LCx artery using an implanted osmotic pump. After 5-7 weeks, coronary arterial microvessels (70-150 microns) were studied in a pressurized (40 mm Hg) no-flow state with video-microscopy. beta-Adrenoceptor-mediated relaxations of isolated microvessels from the collateral-dependent LCx region to isoproterenol (P < 0.01) were markedly reduced, as were those to the adenylate cyclase activator forskolin (P < 0.01), compared to the respective response of vessels from the normally perfused left anterior descending artery region. Responses to the Gs-protein activator NaF showed a similar trend, but the differences were not significant. Chronic treatment with VEGF normalized responses to isoproterenol, NaF, and forskolin in the collateral-dependent LCx region. Blood flow in the LCx region increased in both control (P < 0.01) and VEGF-treated (P < 0.05) groups during rapid atrial pacing. The absolute increase in LCx blood flow was greater in the VEGF group than in the control group at rest (P < 0.05), but not during rapid pacing. Thus, beta-adrenergic microvascular relaxation is impaired in the collateral-dependent coronary microcirculation. The periadventitial delivery of VEGF improves myocardial perfusion to the collateral-dependent area and preserves beta-adrenergic-mediated relaxation of microvessels in the collateral-dependent myocardium.

Animals↗
PubMed1995

Statistical properties of DNA sequences.

We review evidence supporting the idea that the DNA sequence in genes containing non-coding regions is correlated, and that the correlation is remarkably long range--indeed, nucleotides thousands of base pairs distant are correlated. We do not find such a long-range correlation in the coding regions of the gene. We resolve the problem of the "non-stationarity" feature of the sequence of base pairs by applying a new algorithm called detrended fluctuation analysis (DFA). We address the claim of Voss that there is no difference in the statistical properties of coding and non-coding regions of DNA by systematically applying the DFA algorithm, as well as standard FFT analysis, to every DNA sequence (33301 coding and 29453 non-coding) in the entire GenBank database. Finally, we describe briefly some recent work showing that the non-coding sequences have certain statistical features in common with natural and artificial languages. Specifically, we adapt to DNA the Zipf approach to analyzing linguistic texts. These statistical properties of non-coding sequences support the possibility that non-coding regions of DNA may carry biological information.

Algorithms↗
PubMed1995

Fractals in biology and medicine.

Our purpose is to describe some recent progress in applying fractal concepts to systems of relevance to biology and medicine. We review several biological systems characterized by fractal geometry, with a particular focus on the long-range power-law correlations found recently in DNA sequences containing noncoding material. Furthermore, we discuss the finding that the exponent alpha quantifying these long-range correlations ("fractal complexity") is smaller for coding than for noncoding sequences. We also discuss the application of fractal scaling analysis to the dynamics of heartbeat regulation, and report the recent finding that the normal heart is characterized by long-range "anticorrelations" which are absent in the diseased heart.

Biological Evolution↗
PubMed1995

Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis.

Coronary occlusive disease is the leading cause of death in industrial nations and affects one in four adults. Although heart attacks are caused by occlusion of a coronary artery, some patients have occlusions without infarction because they have sufficient collateral vessels providing an alternate pathway for blood supply. Vascular endothelial growth factor (VEGF) is an angiogenic peptide that can stimulate collateral vessel development in the ischaemic myocardium. We used magnetic resonance imaging (MRI) and image processing to identify and quantify non-invasively the benefits related to VEGF infusion on collateral development in the heart. This was accomplished as a placebo-controlled study in the porcine model of chronic ischaemia that most closely mimics the human pathophysiology of progressive coronary occlusion. Image series converted to a space-time map demonstrated that with treatment the ischaemic zone was smaller and the contrast arrival delay was less, which resulted in better ejection fraction and regional wall thickening. These findings demonstrate in a manner applicable to humans, that VEGF improves collateral blood supply, resulting in improved cardiac global and regional function after and in spite of coronary artery occlusion.

Angiogenesis Inducing Agents↗
PubMed1995

Long-range correlation properties of coding and noncoding DNA sequences: GenBank analysis.

An open question in computational molecular biology is whether long-range correlations are present in both coding and noncoding DNA or only in the latter. To answer this question, we consider all 33301 coding and all 29453 noncoding eukaryotic sequences--each of length larger than 512 base pairs (bp)--in the present release of the GenBank to dtermine whether there is any statistically significant distinction in their long-range correlation properties. Standard fast Fourier transform (FFT) analysis indicates that coding sequences have practically no correlations in the range from 10 bp to 100 bp (spectral exponent beta=0.00 +/- 0.04, where the uncertainty is two standard deviations). In contrast, for noncoding sequences, the average value of the spectral exponent beta is positive (0.16 +/- 0.05) which unambiguously shows the presence of long-range correlations. We also separately analyze the 874 coding and the 1157 noncoding sequences that have more than 4096 bp and find a larger region of power-law behavior. We calculate the probability that these two data sets (coding and noncoding) were drawn from the same distribution and we find that it is less than 10(-10). We obtain independent confirmation of these findings using the method of detrended fluctuation analysis (DFA), which is designed to treat sequences with statistical heterogeneity, such as DNA's known mosaic structure ("patchiness") arising from the nonstationarity of nucleotide concentration. The near-perfect agreement between the two independent analysis methods, FFT and DFA, increases the confidence in the reliability of our conclusion.

Animals↗
PubMed1995

Systematic analysis of coding and noncoding DNA sequences using methods of statistical linguistics.

We compare the statistical properties of coding and noncoding regions in eukaryotic and viral DNA sequences by adapting two tests developed for the analysis of natural languages and symbolic sequences. The data set comprises all 30 sequences of length above 50 000 base pairs in GenBank Release No. 81.0, as well as the recently published sequences of C. elegans chromosome III (2.2 Mbp) and yeast chromosome XI (661 Kbp). We find that for the three chromosomes we studied the statistical properties of noncoding regions appear to be closer to those observed in natural languages than those of coding regions. In particular, (i) a n-tuple Zipf analysis of noncoding regions reveals a regime close to power-law behavior while the coding regions show logarithmic behavior over a wide interval, while (ii) an n-gram entropy measurement shows that the noncoding regions have a lower n-gram entropy (and hence a larger "n-gram redundancy") than the coding regions. In contrast to the three chromosomes, we find that for vertebrates such as primates and rodents and for viral DNA, the difference between the statistical properties of coding and noncoding regions is not pronounced and therefore the results of the analyses of the investigated sequences are less conclusive. After noting the intrinsic limitations of the n-gram redundancy analysis, we also briefly discuss the failure of the zeroth- and first-order Markovian models or simple nucleotide repeats to account fully for these "linguistic" features of DNA. Finally, we emphasize that our results by no means prove the existence of a "language" in noncoding DNA.

Animals↗
PubMed1995

Statistical and linguistic features of DNA sequences.

We present evidence supporting the idea that the DNA sequence in genes containing noncoding regions is correlated, and that the correlation is remarkably long range--indeed, base pairs thousands of base pairs distant are correlated. We do not find such a long-range correlation in the coding regions of the gene. We resolve the problem of the "non-stationary" feature of the sequence of base pairs by applying a new algorithm called Detrended Fluctuation Analysis (DFA). We address the claim of Voss that there is no difference in the statistical properties of coding and noncoding regions of DNA by systematically applying the DFA algorithm, as well as standard FFT analysis, to all eukaryotic DNA sequences (33 301 coding and 29 453 noncoding) in the entire GenBank database. We describe a simple model to account for the presence of long-range power-law correlations which is based upon a generalization of the classic Levy walk. Finally, we describe briefly some recent work showing that the noncoding sequences have certain statistical features in common with natural languages. Specifically, we adapt to DNA the Zipf approach to analyzing linguistic texts, and the Shannon approach to quantifying the "redundancy" of a linguistic text in terms of a measurable entropy function. We suggest that noncoding regions in plants and invertebrates may display a smaller entropy and larger redundancy than coding regions, further supporting the possibility that noncoding regions of DNA may carry biological information.

Algorithms↗
PubMed1995

c-myb affects intracellular calcium handling in vascular smooth muscle cells.

The protooncogene c-myb is responsible for elevating intracellular calcium concentration ([Ca2+]i) at the G1/S interface in vascular smooth muscle cells (VSMC). However, the molecular components of this pathway are undefined, and the biological effects of increased levels of divalent cation are unknown. We have demonstrated that growth-arrested c-myb-transfected VSMC, compared with wild type VSMC, exhibit a fourfold increased number of insulin-like growth factor I (IGF-I) receptors, increased amount of secreted IGF-I activity, and a twofold increased level of [Ca2+]. The c-myb transfected cells, compared with wild type cells, also possess a twofold increased rate of calcium influx and a twofold decreased rate of calcium efflux. The elevated calcium influx rate of transfected cells is decreased to that of wild type cells with IGF-I neutralizing antibody, whereas the decreased calcium efflux rate of transfected cells is increased to that of wild type cells with antisense c-myb oligonucleotides. Proliferating wild type VSMC exhibit an increased calcium influx rate in late G1, which is dependent on production of augmented amounts of IGF-I activity but not increased levels of IGF-I receptors. The wild type VSMC also show a decreased calcium efflux rate at the same point in the cell cycle, which is dependent on expression of c-myb. The treatment of wild type cells with antisense c-myb or IGF-I receptor oligonucleotides induces a late G1 block in cell proliferation, which can be overcome by exposure to the calcium ionophore, 4-bromo-A-27318, in amounts sufficient to raise [Ca2+]i to levels observed at the G1/S interface. We conclude that IGF-I/IGF-I receptors and c-myb are involved in control of [Ca2+]i at the G1/S interface by separately regulating the rates of calcium influx and efflux and that elevated levels of divalent cation are necessary for progression of VSMC into the S phase of the cell cycle.

Animals↗
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↗