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Biomedical subjects

M Borgers

Publications and source records attributed to M Borgers.

At least 55 records · Page 3Linked to original sources
PubMed1999

Repeated stunning precedes myocardial hibernation in progressive multiple coronary artery obstruction.

OBJECTIVE: The aim of this study was to characterize a regional myocardial flow-function relationship in collateral dependent myocardium produced by multiple coronary artery obstruction. METHODS: Ameroid constrictors were placed around the proximal right (RC) and circumflex (CX) coronary arteries and a silicon tubing cuff around the proximal LAD (left anterior descending artery) (luminal stenosis +/- 77%) in 18 dogs. Weekly two-dimensional echocardiography was performed for regional function (anterior [A], inferoposterior [IP], wall thickening [WT]), and fractional shortening (FS). Colored microspheres injected at baseline and before sacrifice, before and after dipyridamole (0.5 mg/kg) injection, determined resting flow (RF) and coronary reserve (CR), respectively. RESULTS: Coronary angiography performed at four weeks after surgery confirmed occlusion of RC and CX with collateralization and a tight stenosis of LAD. Initially, an episodic reduction in A and IP WT was observed which became persistent later (AWT: 16 +/- 3%; IPWT: 16 +/- 4%, FS: 20 +/- 4%, p < 0.005 vs. baseline [BS]). With dobutamine a biphasic response (improvement in A and IP WT between 5-15 and dysfunction between 20-30 microg/kg/min) was observed. Seven dogs were sacrificed at eight weeks and showed normal RF but reduced transmural CR (A: 75 +/- 18%; IP: 46 +/- 22% of control). Seven dogs underwent PTCA of the LAD at eight weeks and showed gradual improvement in AWT with normalization at 12 weeks (AWT: 30 +/- 5%, p < 0.001 vs. eight weeks). At sacrifice RF and CR in the A wall were normal but there was reduced subendocardial RF in the IP region (64% of BS). Further, biopsy samples showed normal histological findings and high energy phosphate content in all dogs. Radioligand binding assays using 125I-iodocyanopindolol showed downregulation of beta-adrenergic receptor density in the dysfunctional regions compared with control. CONCLUSIONS: In this canine model of viable, collateral dependent and reversibly dysfunctional myocardium, there was early episodic dysfunction followed by persistent dysfunction which was initially associated with normal RF and later with subendocardial hypoperfusion.

Animals↗
PubMed1999

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

Animals↗
PubMed1999

Accumulation of 3-ketosteroids induced by itraconazole in azole-resistant clinical Candida albicans isolates.

The effects of itraconazole on ergosterol biosynthesis were investigated in a series of 16 matched clinical Candida albicans isolates which had been previously analyzed for mechanisms of resistance to azoles (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother., 39:2378-2386, 1995). Under control conditions, all isolates contained ergosterol as the predominant sterol, except two strains (C48 and C56). In isolates C48 and C56, both less susceptible to azoles than their parent, C43, substantial concentrations (20 to 30%) of 14alpha-methyl-ergosta-8,24(28)-diene-3beta,6alpha-dio l (3, 6-diol) were found. Itraconazole treatment of C43 resulted in a dose-dependent inhibition of ergosterol biosynthesis (50% inhibitory concentration, 2 nM) and accumulation of 3,6-diol (up to 60% of the total sterols) together with eburicol, lanosterol, obtusifoliol, 14alpha-methyl-ergosta-5,7,22,24(28)-tetraene-3betaol, and 14alpha-methyl-fecosterol. In strains C48 and C56, no further increase of 3,6-diol was observed after exposure to itraconazole. Ergosterol synthesis was less sensitive to itraconazole inhibition, as was expected for these azole-resistant isolates which overexpress ATP-binding cassette transporter genes CDR1 and CDR2. In addition to 3,6-diol, substantial amounts of obtusifolione were found after exposure to itraconazole. This toxic 3-ketosteroid was demonstrated previously to accumulate after itraconazole treatment in Cryptococcus neoformans and Histoplasma capsulatum but has not been reported in Candida isolates. Accumulation of obtusifolione correlated with nearly complete growth inhibition in these azole-resistant strains compared to that found in the susceptible parent strain, although the onset of growth inhibition only occurred at higher concentrations of itraconazole. ERG25 and ERG26 are the only genes assigned to the 4-demethylation process, of which the 3-ketoreductase is part. To verify whether mutations in these ERG25 genes contributed to obtusifolione accumulation, their nucleotide sequences were determined in all three related isolates. No mutations in ERG25 alleles of isolates C48 and C56 were found, suggesting that this gene is not involved in obtusifolione accumulation. The molecular basis for the accumulation of this sterol in these two strains remains to be established.

Antifungal Agents↗
PubMed1998

Altered [Ca2+] homeostasis in PC12 cells after nerve growth factor deprivation.

[Ca2+]i homeostasis in individual PC12 cells after elevated [K+]o was studied by ratiometric microscopy, during nerve growth factor (NGF) deprivation. A significantly lower number of cells responded with an increased [Ca2+]i in the NGF deprived condition. Moreover, the responding cells were more deficient in regulating their [Ca2+]i back to control levels, after the transient peak. This suggests that differentiated neurons do not traverse the apoptotic program homogeneously with regard to their [Ca2+]i regulation and that NGF deprived PC12 cells have more difficulties to reduce their [Ca2+]i after influx of [Ca2+]o.

Animals↗
PubMed1998

Calcium uptake by the sarcoplasmic reticulum, high energy content and histological changes in ischemic cardiomyopathy.

OBJECTIVES: Sarcoplasmic reticulum (SR) Ca2+ uptake, myocardial high energy content and histology were examined in different zones of hearts from patients with ischemic cardiomyopathy. METHODS AND RESULTS: Unfractionated homogenates were prepared from left ventricular samples obtained in three zones of each heart: an infarct-remote zone, an outer peri-infarct zone, and an inner peri-infarct zone. Oxalate-supported 45Ca2+ uptake was measured at 37 degrees C using a filtration method. Maximum rate (Vmax) of uptake in absence or in presence of ryanodine was lower in inner peri-infarct (7.4 +/- 0.7 and 9.5 +/- 0.8 nmol min-1 mg-1 of protein, respectively; mean +/- SEM) and outer peri-infarct tissues (8.8 +/- 0.8 and 12.0 +/- 0.8 nmol min-1 mg-1) than in infarct-remote myocardium (12.7 +/- 2.1 and 15.8 +/- 2.2 nmol min-1 mg-1). The apparent affinity constants for Ca2+ (KCa) as well as the Hill coefficients were not different. Homogenate DNA (1.6 +/- 0.1, 1.6 +/- 0.1 and 1.7 +/- 0.1 mg/g of remote, inner peri-infarct and outer peri-infarct myocardium, respectively) and adenine nucleotides contents (ATP: 15 +/- 1.3, 14 +/- 0.8 and 15 +/- 1.0 mumol/g dry weight, respectively) were similar in all tissues. Fibrosis was increased in inner peri-infarct tissue (37 +/- 6%; vs. 13 +/- 2% and 12 +/- 2% in both remote and outer peri-infarct tissues, respectively), but the number of abnormal cells was not significantly different. CONCLUSION: The decrease of Ca2+ uptake in ischemic cardiomyopathy is not homogeneous in the ventricular wall, and reflects a decreased number/activity of SR Ca(2+)-ATPase, without altered Ca(2+)-affinity or increased Ca2+ leakage through ryanodine receptors.

Adult↗
PubMed1998

The effect of brain death on cardiovascular function in rats. Part I. Is the heart damaged?

OBJECTIVE: Brain death induces important haemodynamic changes in rats, with a drop in arterial blood pressure, left ventricular developed pressure and dP/dtmax to less than 50% of its control value. Myocardial damage was reported to contribute to this paradigm. The role of potential underlying pathogenetic mechanisms, such as a circulating cardiodepressant factor, NO, endogenous opioid peptides, vagal or beta-adrenergic activation, or hypophyseal dysfunction, were explored, but none of them could be demonstrated as the culprit. This study investigated whether functionally important intrinsic myocardial damage was induced by brain death in the rat, and whether coronary endothelial cell dysfunction, possibly causing multifocal ischaemia, contributed to this. METHODS: Brain death was induced in rats by sudden inflation of an intracranial balloon. Extensive haemodynamic measurements, including heart rate, arterial blood pressure central venous pressure, left ventricular pressure, and cardiac output, were performed. Hearts excised 1 and 4 h after brain death were examined histologically. The contractile reserve of these hearts was tested by administration of increasing doses of adrenaline (10(-9) to 10(-6) mol/l) in a Langendorff system. The coronary endothelium was tested with regard to its barrier function for macromolecules by determining the extravasation of injected Evans blue, and with regard to its vasoactive function by testing the effects of serotonin and nitroglycerin in a Langendorff system. RESULTS: The haemodynamic measurements suggested that the cardiovascular collapse consisted mainly in alterations in afterload. Contractile reserve, as tested with increasing adrenaline doses, revealed a normal dose-response curve. No histological myocardial damage was found after brain death in rats. No abnormal extravasation of Evans blue was seen. Coronary vasoreactivity towards nitroglycerin and serotonin was normal. CONCLUSION: Myocardial damage, if present at all, contributes only minimally to the changes in haemodynamic profile seen after brain death in the rat, and the coronary endothelium appears to preserve its barrier and vasoactive function.

Animals↗
PubMed1998

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells.

The clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozole-fumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10(-6) M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (10(-6) M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (10(-6) M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity.

Antineoplastic Agents↗
PubMed1998

All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro.

All-trans-retinoic acid (ATRA) is well known to inhibit the proliferation of human breast cancer cells. Much less is known about the antiproliferative activity of the naturally occurring metabolites and isomers of ATRA. In the present study, we investigated the antiproliferative activity of ATRA, its physiological catabolites 4-oxo-ATRA and 5,6-epoxy-ATRA and isomers 9-cis-RA and 13-cis-RA in MCF-7 human breast cancer cells by bromodeoxyuridine incorporation. MCF-7 cells were grown in steroid- and retinoid-free medium supplemented with growth factors. Under these culture conditions, ATRA and its naturally occurring catabolites and isomers showed significant antiproliferative activity in MCF-7 cells in a concentration-dependent manner (10[-11] M to 10[-6] M). The antiproliferative activity of ATRA catabolites and isomers was equal to that of the parent compound ATRA at concentrations of 10(-8) M and 10(-7) M. Only at 10(-6) M were the catabolites and the stereoisomer 13-cis-RA less potent. The stereoisomer 9-cis-RA was as potent as ATRA at all concentrations tested (10[-11] M to 10[-6] M). In addition, we show that the catabolites and isomers were formed from ATRA to only a limited extent. Together, our findings suggest that in spite of their high antiproliferative activity the catabolites and isomers of ATRA cannot be responsible for the observed growth inhibition induced by ATRA.

Breast Neoplasms↗
PubMed1998

Okadaic acid-induced apoptosis in neuronal cells: evidence for an abortive mitotic attempt.

There is increasing evidence that apoptosis in postmitotic neurons is associated with a frustrated attempt to reenter the mitotic cycle. Okadaic acid, a specific protein phosphatase inhibitor, is currently used in models of Alzheimer's research to increase the degree of phosphorylation of various proteins, such as the microtubule-associated protein tau. Okadaic acid induces programmed cell death in the human neuroblastoma cell lines TR14 and NT2-N, as evidenced by fragmentation of DNA and attenuation of this process by protein synthesis inhibitors. In differentiated TR14 cells, okadaic acid increases the fraction of cells in the S phase, induces the appearance of cyclin B1 and cyclin D1 markers of the cell cycle, and triggers a time-dependent increase in DNA fragmentation after release of a thymidine block. Fully differentiated NT2-N cells are forced to enter the mitotic cycle as shown by DNA staining. Chromatin condensation and chromosome formation are initiated, but the cells fail to complete their mitotic cycle. These data suggest that okadaic acid forces differentiated neuronal cells into the mitotic cycle. This pattern of cyclin up-regulation and cell cycle shift is compared with apoptosis induced by neurotrophic factor deprivation in differentiated rat pheochromocytoma PC12 cells.

Anaphase↗
PubMed1998

Temporal changes in intracranial pressure in a modified experimental model of closed head injury.

OBJECT: The authors describe an experimental model of closed head injury in rodents that was modified from one developed by Marmarou and colleagues. This modification allows dual control of the dynamic process of impact compared with impulse loading that occurs at the moment of primary brain injury. The principal element in this weight-drop model is an adjustable table that supports the rat at the moment of impact from weights positioned at different heights (accelerations). The aim was to obtain reproducible pathological intracranial pressure (ICPs) while maximally reducing the incidence of mortality and skull fractures. METHODS: Intracranial pressure was investigated in different experimental settings, including two different rat strains and various impact-acceleration conditions and posttrauma survival times. Identical impact-acceleration injuries produced a considerably higher mortality rate in Wistar rats than in Sprague-Dawley rats (50% and 0%, respectively). Gradually increasing severity of impact-acceleration conditions resulted in findings of a significant correlation between the degree of traumatic challenge and increased ICP at 4 hours (p < 0.001, R2=0.73). When the impact-acceleration ratio was changed to result in a more severe head injury, the ICP at 4, 24, and 72 hours was significantly elevated in comparison with that seen in sham-injured rats (4 hours: 19.7+/-2.8 mm Hg, p=0.004; 24 hours: 21.8+/-1.1 mm Hg, p=0.002; 72 hours: 11.9+/-2.5 mm Hg, p=0.009). Comparison of the rise in ICP between moderate and severe impact-acceleration injury at 4 and 24 hours revealed a significantly higher value after severe injury (4 hours: p=0.008; 24 hours: p=0.004). Continuous recordings showed that ICP mounted very rapidly to peak values, which declined gradually toward a pathological level dependent on the severity of the primary insult. Histological examination after severe trauma revealed evidence of irreversible neuronal necrosis, diffuse axonal injury, petechial bleeding, glial swelling, and perivascular edema. CONCLUSIONS: This modified closed head injury model mimics several clinical features of traumatic injury and produces reliable, predictable, and reproducible ICP elevations with concomitant morphological alterations.

Animals↗
PubMed1998

Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant.

Left ventricular biopsies from 21 patients with clinically diagnosed chronic hibernating myocardium (CHM) were examined by light- and electron microscopy. A mean of 27% of cardiomyocytes were structurally altered and were characterized as hibernating, because of reduced amount of myofibrils and increased glycogen content. Electron microscopy of these cells showed reduction of T-tubules and numerous small mitochondria, but few changes associated with degeneration, acute ischemia or apoptosis. The structural changes found in CHM are reminiscent of dedifferentiation rather than degeneration. The expression patterns of some structural proteins show resemblance with those in embryonic cardiomyocytes. Histochemically, mitochondrial NADH-oxidase and proton translocating ATPase activities were absent, whereas cytochrome c activity was present. Intracellular calcium distribution indicated normally bound sarcolemmal calcium and absence of excess mitochondrial calcium accumulation. Nuclear chromatin ranged from normal to dispersed with only a few nuclei that were clumped. These results suggest that cardiomyocytes from human CHM hearts are structurally altered, but viable, and lack morphologic and cytochemical characteristics suggestive of apoptosis or acute ischemia.

Apoptosis↗
PubMed1997

Aberrant tau phosphorylation and neurite retraction during NGF deprivation in PC12 cells.

Recently apoptotic markers have been found in Alzheimer's Disease (AD) brain. To investigate the relation between tau phosphorylation and apoptosis, immunocytochemistry of AT8 (indicating the degree of phosphorylation at the tau Ser202/Thr205 site) was quantitatively determined the degree of tau phosphorylation at the Ser202 site was monitored during neuronal apoptosis in differentiated PC12 cells after nerve growth factor (NGF) deprivation. During this programmed cell death a prominent retraction of neurites took place that was associated with a clear increase in the level of AT8 signalaberrant phosphorylated tau at the Ser202 site. The broad spectrum kinase inhibitor staurosporine attenuated both this increase in tau phosphorylation, neurite retraction, and apoptosis. We suggest that at some point during programmed cell death, kinases with tau as substrate become activated and that the resulting loss of cytoskeletal integrity leads to neurite instability.

Animals↗
PubMed1997

Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat.

BACKGROUND: After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. METHODS AND RESULTS: Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes. CONCLUSIONS: Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.

Animals↗
PubMed1997

Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells.

Most studies on the antipsoriatic mode of action of dimethylfumarate focused on its antiproliferative effects in keratinocytes. Because inflammatory skin diseases are associated with an upregulation of endothelial cell adhesion molecules and because the presence of inflammatory cells in dermis and epidermis is considered an important feature in psoriasis, we tested the effect of DMF on cytokine-induced adhesion molecule expression in HUVEC, using in situ ELISA and Northern blotting. Dimethylfumarate inhibited ICAM-1, VCAM-1, and E-selectin expression and reduced adhesion of U937 cells to stimulated HUVEC. Monoethylfumarate and fumaric acid had no effect. Similar inhibitory effects for DMF on VCAM-1 expression were observed after stimulation of HUVEC with LPS, PMA, IL-4, and IL-1 alpha or in combinations with TNF alpha. These data are in agreement with previously reported effects of DMF on intracellular thiol levels and inhibition of NF-kappa B activation. The inhibitory effect on cytokine-induced endothelial adhesion molecule expression may represent another target of dimethylfumarate in psoriasis.

Blotting, Northern↗
PubMed1997

Intracranial pressure in a modified experimental model of closed head injury.

Intracranial pressure (ICP) was studied in a modified experimental model of closed head injury, in which the dynamic process of impact versus impulse loading was separately controlled. In this model, mortality of Wistar rats was considerably higher as compared to Sprague-Dawley rats subjected to similar traumatic conditions. Therefore Sprague-Dawley rats were used for all further experiments. Twenty-four rats, divided into 4 groups, underwent either sham or gradually increasing impact-acceleration trauma. Four hours after closed head injury, ICP measurements showed a significant correlation between the severity of the traumatic challenge and the resultant pressure rise (r2 = 0.731; p < 0.001). At the moment of impact there was a momentary blood pressure peak immediately followed by a transient period of hypotension. ICP measurements following directly to an impact-acceleration trauma, revealed an abrupt rise in ICP reaching pathological levels within 5 minutes. In conclusion, this modified model of closed head injury produces a predictable and reproducible pathologic ICP in Sprague-Dawley rats.

Animals↗