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M Simons

Publications and source records attributed to M Simons.

At least 109 records · Page 6Linked to original sources
PubMed1996

Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons.

The aim of this study was to investigate the proteolytic processing of the amyloid precursor protein (APP) in polarized primary cultures of hippocampal neurons. We have used the Semliki Forest virus (SFV) vector to express human APP695 in hippocampal neurons, sympathetic ganglia, and glial cells. The latter two cells secrete little or no APP, whereas hippocampal neurons secrete two forms of APP695, which differ in sialic acid content and in their kinetic appearance in the culture medium. In addition, rat hippocampal neurons expressing human APP produced significant amounts of the 4 kDa peptide beta A4. After 3 hr of metabolic labeling, the relative amount of beta A4 peptide to total cellular APP was 5.3%. Fibroblasts expressing APP695 using the same SFV vector mainly produced a related 3 kDa p3 peptide, a nonamyloidogenic fragment. Remarkably, the hippocampal neurons also produced significant amounts of beta A4-containing C-terminal fragments (10-12 kDa) intracellularly. Radiosequencing showed that these fragments were created at a previously described beta-secretase cleavage site and at a cleavage site 12 residues from the N terminus of the beta A4 domain (Thr584 of APP695), which we named delta-cleavage. Based on the observation that mature hippocampal neurons produce two potentially amyloidogenic fragments and secrete substantial amounts of beta A4 when expressing human APP, our results strengthen the hypothesis that neurons play a central role in the process of beta A4 deposition in cases of Alzheimer's disease and in aged primates.

Amino Acid Sequence↗
PubMed1996

Air travel and adults with cyanotic congenital heart disease.

BACKGROUND: Concern has been expressed that a reduction of partial oxygen pressure during flight in commercial aircraft may induce dangerous hypoxemia in patients with cyanotic congenital heart disease. METHODS AND RESULTS: To evaluate the validity of this concern, the transcutaneous SaO2 was measured in 12 adults with this type of heart disease and 27 control subjects during simulated commercial flights of 1.5 and 7 hours in a hypobaric chamber. Ten of those patients and 6 control subjects also were evaluated during two actual flights of approximately 2.5 hours in a DC-10 and an A-310, respectively. During the prolonged simulated and actual flights, the capillary blood pH, gases, and lactic acid were analyzed in the patients and during one of the actual flights also in the control subjects. During the simulated flights the SaO2 was at all times lower in the patients than in the control subjects. However, the maximal mean actual percentage decrease, as compared with sea level values, did not exceed 8.8% in either patients or control subjects. During the actual flights, this maximal decrease in the patients was 6%. In-flight reduction of the capillary PO2 was considerable in the control subjects but not in the patients. It is our hypothesis that the lack of a significant decrease of the PO2 in the patients might possibly be due to a high concentration of 2.3 diphosphoglycerate in the red cells. The flights had no influence on the capillary blood pH, PCO2, bicarbonate, or lactic acid levels in either patients or control subjects. CONCLUSIONS: Atmospheric pressure changes during commercial air travel do not appear to be detrimental to patients with cyanotic congenital heart disease.

2,3-Diphosphoglycerate↗
PubMed1996

Angiogenesis induced by acidic fibroblast growth factor as an alternative method of revascularization for chronic myocardial ischemia.

BACKGROUND: The effect of periadventitial administration of acidic fibroblast growth factor (FGF) on coronary microvascular reactivity and blood flow was examined in the collateral-dependent and normally perfused myocardium. METHODS: Ameroid constrictors were placed on the proximal left circumflex (LCx) coronary artery in 14 pigs. In seven pigs acidic FGF (10 micrograms) was administered into the perivascular space of the proximal LCx artery by using an ethylene vinyl acetate copolymer slow release device. After 7 to 9 weeks coronary arterial microvessels (70 to 150 microns) were studied in a pressurized (40 mm Hg) no-flow state with video microscopy. RESULTS: Relaxation mediated by beta-adrenoceptors and induced by isoproterenol (p < 0.05), and endothelium-dependent relaxation induced by adenosine 5' diphosphate (ADP) (p < 0.05) of isolated microvessels from the collateral-dependent LCx region were markedly reduced compared with the respective responses of vessels from the normally perfused left anterior descending (LAD) artery region. Relaxation induced by the adenylate cyclase activator forskolin and the guanylate cyclase activator sodium nitroprusside were unaltered. Chronic treatment with acidic FGF normalized responses to isoproterenol (p < 0.001 versus nontreated LCx) and ADP (p < 0.001 versus nontreated LCx) in the collateral-dependent LCx region, whereas responses to forskolin and sodium nitroprusside were not changed. Blood flow in the collateral-dependent LCx region (0.49 +/- 0.24 ml/min/gm) was less than that in the normally perfused LAD region (0.80 +/- 0.24 ml/min/gm, p < 0.05). Treatment with acidic FGF improved perfusion in the LCx region (0.80 +/- 0.06 ml/min/gm, p < 0.05) but did not significantly affect blood flow in the LAD territory (0.89 +/- 0.09 ml/min/gm). CONCLUSIONS: The periadventitial delivery of acidic FGF normalizes vasomotor regulation by beta-adrenergic and endothelium-dependent mechanisms and improves myocardial perfusion to the collateral-dependent myocardium. This may have implications regarding the treatment of patients with severe coronary artery disease who are not ameneable to conventional methods of revascularization.

Adrenergic beta-Agonists↗
PubMed1996

Gnotobiotic system for studying rhizosphere colonization by plant growth-promoting Pseudomonas bacteria.

A gnotobiotic system for studying tomato rhizosphere colonization by Pseudomonas bacteria was developed. The system is based on sterile seedlings that are inoculated with one or two strains and subsequently grown in a sterile glass tube containing quartz sand. After 7 days of growth in a climate-controlled growth chamber, the number of bacteria present on the root tip was analyzed. The system was optimized with respect to root morphology, inoculation of the seedling, and isolation of root tip bacteria. With this system, rhizosphere colonization on tomato, radish, wheat, and potato was analyzed. For detailed analysis of tomato rhizosphere colonization by some representative plant growth-promoting rhizo-bacteria, the colonization of known poor, moderate, and good potato root-colonizing Pseudomonas strains and of four Rhizobium strains was determined. All strains colonized the root tips when inoculated as single strains. When inoculated in competition with the efficient root colonizer P. fluorescens strain WCS365, many strains were outcompeted. Mutants of Pseudomonas biocontrol bacteria lacking flagella or the O-antigen of lipopolysaccharide (LPS), which were isolated in previous studies and shown to be impaired in potato rhizosphere colonization in field soil systems, showed a reduced colonization ability in the gnotobiotic system also. The gnotobiotic system was used to screen a collection of 300 random P. fluorescens WCS365::Tn5 mutants for colonization-impaired mutants. Three novel mutants were found that were outcompeted by the wild-type strain in tomato root tip colonization but were not impaired in known colonization traits such as motility, amino acid auxotrophy, and presence of the O-antigenic side chain of LPS. One strain appeared to be a thiamine auxotroph, suggesting that the root does not secrete a sufficient amount of thiamine to support growth of this strain. The other two mutants had a reduced growth rate in laboratory media, suggesting that growth rate is an important colonization factor. As the system is gnotobiotic and devoid of field-soil variables, it can also be used to study the effects of selected biotic and abiotic factors on colonization.

Escherichia coli↗
PubMed1996

Direct vasomotor effects of isoflurane in subepicardial resistance vessels from collateral-dependent and normal coronary circulation of pigs.

BACKGROUND: The purpose of the current investigation was to determine and compare the direct effect of isoflurane on normal resistance coronary arteries and similarly sized coronary arteries in collateral-dependent (CD) circulation. A differential vasomotor effect of isoflurane might contribute to flow redistribution, either adverse or favorable, between normal and CD regions. METHODS: The authors used a swine model of chronic coronary occlusion. Six weeks after ameroid occluder placement around the left circumflex artery, the heart was removed. Myocardial blood flow, measured in vivo before the removal, was lower during rapid atrial pacing in the CD region than in the normally perfused region. These in vivo studies established the existence and location of CD circulation. Subepicardial microvessels, measuring approximately 100 microns, were dissected from both the CD region and the normal region. Either with or without preconstriction of the vessels with the thromboxane analogue U46619 1 microM, direct vasomotor effect of isoflurane was examined in vitro by video microscopy. In addition, vasomotor responses to endothelin-1, the endothelium-dependent dilator adenosine 5' diphosphate, and the endothelium-independent dilator sodium nitroprusside were compared between CD and normal resistance vessels. RESULTS: Isoflurane caused greater concentration-dependent constriction of the normal vessels than of the CD vessels (P < 0.05); this constrictive effect was masked by preconstriction of the vessels. Vasodilation of ADP was less in CD vessels than in normal vessels (P < 0.001), but vasodilation to sodium nitroprusside was not significantly different (P = 0.45). Vasoconstriction to endothelin-1 was greater in CD vessels than in normal vessels (P < 0.01). CONCLUSIONS: The vasoconstrictive effect of isoflurane normally observed in coronary resistance vessels is impaired in resistance vessels that supply a CD area. The basis of this may be related to endothelial dysfunction.

Anesthetics, Inhalation↗
PubMed1996

Improvement in oxygenation after large volume paracentesis.

Seventeen patients with biopsy-confirmed hepatic cirrhosis and tense ascites performed reproducible pulmonary functions and had arterial blood gas analysis before and after having a therapeutic large volume paracentesis. Each patient showed significant improvement in the static lung volumes as determined by helium dilution techniques. Dynamic airflow also improved as expressed by the FVC and the FEV1. The FEV1/FVC ratio remained unchanged. Each patient showed a significant improvement in oxygenation 120 minutes after LVP. Alveolar ventilation as expressed by PaCO2 did not change. The pathophysiology that explains the improvement in oxygenation remains speculative. Large volume paracentesis appears to have a salutary effect on oxygenation, as well as on pulmonary function.

Ascites↗
PubMed1996

Pericardial effusion in patients with cancer: outcome with contemporary management strategies.

OBJECTIVE: To investigate the clinical presentation and current management strategies of pericardial effusion in patients with malignancy. DESIGN: Retrospective single centre, consecutive observational study. SETTING: University hospital. PATIENTS: 93 consecutive patients with a past or present diagnosis of cancer and a pericardial effusion, including 50 with a pericardial effusion > 1 cm. RESULTS: Of the 50 patients with pericardial effusions > 1 cm, most had stage 4 cancer (64%), were symptomatic at the time of presentation (74%), and had right atrial collapse (74%). Twenty patients were treated conservatively (without pericardiocentesis) and were less symptomatic (55% v 87%, P = 0.012), had smaller pericardial effusions (1.5 (0.4) v 1.8 (0.5), P = 0.02), and less frequent clinical (10% v 40%, P = 0.02) and echocardiographic evidence of tamponade (40% v 97%, P < 0.001) than the 30 patients treated invasively with initial pericardiocentesis (n = 29) or pericardial window placement (n = 1). Pericardial tamponade requiring repeat pericardiocentesis occurred in 18 (62%) of 29 patients after a median of 7 days. In contrast, only four (20%) of 20 patients in the conservative group progressed to frank clinical tamponade and required pericardiocentesis (P = 0.005 v invasive group). The overall median survival was 2 months with a survival rate at 48 months of 26%. Survival, duration of hospital stay, and hospital charges were similar with both strategies. By multivariable analysis, the absence of symptoms was the only independent predictor of long-term survival (relative hazards ratio = 3.2, P = 0.05). Survival was similar in the 43 patients with cancer and pericardial effusions of < or = 1 cm. CONCLUSION: Asymptomatic patients with cancer and pericardial effusion can be managed conservatively with close follow up. In patients with symptoms or clinical cardiac tamponade, pericardiocentesis provides relief of symptoms but does not improve survival and has a high recurrence rate. Surgical pericardial windows or possibly percutaneous balloon pericardiotomy should be used for recurrences and should be considered for initial treatment.

Cardiac Tamponade↗
PubMed1996

Vascular endothelial growth factor administration in chronic myocardial ischemia.

Vascular endothelial growth factor (VEGF) is a potent mitogen capable of stimulating angiogenesis. We examined the effect of VEGF administration in a model of chronic porcine myocardial ischemia. Nineteen pigs were instrumented with proximal left circumflex coronary artery (LCX) Ameroid constrictors. In eight animals VEGF (2 microgram) with heparin (50 U) was administered extraluminally to the LCX myocardium with an osmotic pump for 4 wk and 11 other animals served as controls. VEGF-treated animals demonstrated higher flow in the LCX territory during both rest and pacing compared with untreated controls (rest: 1.35 +/- 0.1 vs. 0.80 +/- 0.09 ml.min-1.g-1; pacing; 2.01 +/- 0.37 vs. 1.01 +/- 0.07 ml.min-1.g-1, P < 0.05, VEGF vs. controls). The observed improvement in regional coronary flow in VEGF-treated animals resulted in better preservation of endothelium-dependent microvessel relaxation as well as fractional LV shortening in the LCX territory during pacing in the VEGF-treated than in control animals (controls: 7.1 +/ 2.6 vs. 3.6 +/- 2.0%, rest vs. pacing; VEGF: 6.9 +/- 2.9 vs. 6.3 +/- 2.9%, rest vs. pacing). We conclude that VEGF administration in a gradual coronary occlusion model in pigs results in improvement of coronary flow and preservation of regional hemodynamics in the compromised myocardium.

Animals↗
PubMed1996

VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis.

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is thought to function by interacting with two high-affinity receptors, flk-1 and flt-1. In an adult heart, angiogenesis can occur in a number of pathological conditions, including atherosclerosis, hypertrophy, and infarction. To determine the role played by VEGF, flk-1, and flt-1 in this process in vivo, we studied the expression of the growth factor and its receptors in a rat infarct model. After an acute myocardial infarction, we observed an initial rapid (1h) rise in VEGF (275%), flk-1 (375%), and flt-1 (400%) mRNA expression throughout the entire heart. Initial diffuse induction of VEGF, flk-1, and flt-1 expression in the left ventricle was later replaced by an increase predominantly limited to perimyocardial infarction area where angiogenesis was taking place. In situ hybridization showed at 6 h after infarction, viable myocytes adjacent to the infarct zone expressed markedly increased amounts of VEGF. At both 6 and 24 h, microvessels at the infarct edge overexpressed both flk-1 and flt-1 mRNAs; at 3 and 7 days new vessels infiltrating the infarct also overexpressed both receptors and continued for as late as 6 wk. In summary, acute myocardial infarction is accompanied by rapid and prolonged increase in expression of VEGF and its receptors with characteristic spatial and temporal kinetic. These findings suggest that the VEGF/VEGF receptor system plays an important role in the angiogenesis and stromal deposition associated with myocardial infarction.

Animals↗
PubMed1996

Enhanced microvascular relaxations to VEGF and bFGF in chronically ischemic porcine myocardium.

Changes in the vascular responses to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in chronically ischemic myocardium have not been investigated. Ameroid constrictors were placed on the proximal left circumflex (LCX) artery of seven Yorkshire pigs. Seven to nine weeks later, myocardial blood flow in the collateral-dependent LCX region was reduced, compared with that in the normally perfused left anterior descending (LAD) region. Both growth factors elicited significant relaxations of coronary microvessels. Relaxations to both VEGF and bFGF were inhibited in the presence of either NG-nitro-L-arginine or genistein, suggesting that the relaxations are through the tyrosine kinase-mediated release of endothelium-derived nitric oxide. Microvascular relaxations to both VEGF or bFGF were significantly greater in vessels harvested from the collateral-perfused LCX region, compared with those taken from the normally perfused LAD region. However, relaxation to the endothelium-dependent vasodilator ADP, which does not operate through a tyrosine kinase receptor, was reduced in the collateral-perfused region, compared with the normally perfused territory, suggesting a possible link of tyrosine kinase to the enhanced relaxations to VEGF and bFGF in collateral-perfused coronary microvessels. Northern analysis showed increased expression for both VEGF receptors (flk-1, flt-1) as well as the bFGF receptor 1 (FGFR-1) in the collateral-perfused region compared with that in the normally perfused region. This suggests that the increased relaxation responses to VEGF and bFGF in the ischemic myocardium may be related to increased gene expression of the respective tyrosine kinase receptors.

Adenosine Diphosphate↗
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↗