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Biomedical subjects

J Schaper

Publications and source records attributed to J Schaper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Acute cerebellitis with near-fatal cerebellar swelling and benign outcome under conservative treatment with high dose steroids.

Acute cerebellar swelling is an emergency because of brainstem compression as well as upward or downward cerebellar herniation. Few childhood cases are on record, with fatal outcome in three out of six. We report a girl with probable Epstein-Barr virus-associated cerebellar swelling who recovered completely with steroid treatment after a stormy course. Review of the literature showed that all three patients, including our own, who recovered fully, received high-dose steroids in contrast to none of the four patients who died or survived with sequelae. Neuroimaging and evoked potential studies are useful for early diagnosis and disease monitoring. We conclude that for the time being high-dose steroid treatment is advocated in patients with acute infectious or parainfectious cerebellar swelling.

Acute Disease↗
PubMed1998

The delivery of angiogenic factors to the heart by microsphere therapy.

Microspheres offer the possibility of local noninvasive delivery of drugs over an extended period of time. We adsorbed fibroblast growth factor (FGF) to microspheres of precapillary size that were injected via a coronary catheter. We showed that FGF was released from these microspheres and taken up by endothelial cells, which proliferated following translocation of FGF to the nucleus. This method for application of growth factors allows the precise delivery of angiogenic substances to any selected part of the heart or other organs without causing inflammation or ischemia.

Animals↗
PubMed1998

DALI-the first human whole-blood low-density lipoprotein and lipoprotein (a) apheresis system in clinical use: procedure and clinical results.

BACKGROUND: The DALI low-density lipoprotein (LDL) apheresis system is the first whole-blood apheresis system in regular clinical use. DALI stands for direct adsorption of lipoproteins, which describes the basic principle of operation of this newly developed LDL apheresis procedure. METHODS: The selective removal of LDLs and lipoprotein (a) [Lp(a)] is performed in human whole blood by adsorption onto polyacrylate-coated polyacrylamide beads in an adsorber. This article describes the results of the first open multicentre clinical trial in 14 patients in whom the safety and the efficacy of the system were tested. All patients were treated on average 17 times on a weekly basis. In total, 238 sessions were carried out during the study without severe side-effects. On average, 7675 mL of the patients' whole blood was processed in about 2 h. Anticoagulation in the extracorporeal system was carried out by first giving a heparin bolus followed by continuous addition of an acid citrate dextrose (ACD-A) infusion during the treatment. RESULTS: The processing of nearly 1.6 times the patient blood volumes resulted in a reduction in the median LDL-cholesterol level by 66-77% (dependent on the system configuration). The Lp(a) concentrations were reduced by 59-73% (dependent on the system configuration). HDL-cholesterol, blood cell count and the other clinical parameters were not significantly affected. CONCLUSION: Based on this short-term evaluation, the DALI apheresis system is a well-tolerated, effective and simple way of reducing LDL and Lp(a) in human whole blood. The system has been introduced to clinical practice. However, to use the DALI apheresis system in clinical routine, further evaluation of long-term effects is required.

Adult↗
PubMed1998

The extracellular matrix in hibernating myocardium--a significant factor causing structural defects and cardiac dysfunction.

Recently, we described chronic intracellular degeneration accompanied by fibrosis as typical structural features of hibernating myocardium and we concluded that cellular degeneration as a sign of the incomplete adaptation to the reduced blood flow is characteristic of hibernation. This study has been extended by analyzing the composition of the extracellular matrix proteins of the diseased myocardium. Areas of hibernating myocardium were identified in 38 patients by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection and low-dose dobutamine echocardiography. These areas were biopsied at cardiac surgery and were studied by electron microscopic and immunofluorescence techniques. Electron microscopy showed an enlarged extracellular space containing numerous particles of cellular debris, macrophages, fibroblasts, homogeneous matrix material and collagen fibrils. The basement membrane of the cardiomyocytes was thickened by an augmentation of laminin, fibronectin and collagen VI, but these proteins also were present in the matrix itself. Collagen fibrils were numerous and macrophages (CD68) and fibroblasts (vimentin) were increased. In situ hybridization showed an increase in mRNA for laminin, fibronectin and collagen. This observation is consistent with the conclusion that fibrotic scar formation was occurring continuously. It is postulated that fibrosis is the consequence of myocyte loss due to chronic underperfusion in the hibernating tissue. This will further injure myocytes so that a vicious cycle is established that leads to progressive loss of structural integrity and functional capacity. Since these changes are progressive, revascularization should be performed at the earliest time point possible in patients with areas of hibernating myocardium.

Aged↗
PubMed1997

Hibernating myocardium: an incomplete adaptation to ischemia.

BACKGROUND: We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. METHODS AND RESULTS: In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). CONCLUSIONS: Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.

Adaptation, Physiological↗
PubMed1997

Time course of mitosis and collateral growth following coronary microembolization in the porcine heart.

In ischaemic porcine myocardium, the growth of collateral vessels by angiogenesis is observed in clusters in the vicinity of focal necroses. Because mitosis of endothelial cells is a prerequisite for angiogenesis, the purpose of this study has been to evaluate the time course of mitosis as an indicator of vascular growth in a porcine model of coronary microembolization. Ischaemia was induced by injection of 25-microm microspheres in the left circumflex artery, followed by tissue collection from non-ischaemic and ischaemic areas of the same heart after 24, 72 or 168 h microembolization. Tissue was studied by histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry and electron microscopy. The number of blood vessels in ischaemic myocardium was compared with that in normal control tissue. Capillary growth started as early as 24 h after microembolization, as indicated by increasing numbers of proliferating, histone H3- and PCNA/cyclin-positive cells in the necrotic inflammatory foci of the ischaemic area. At 72 h and 168 h, the number of blood vessels was significantly higher in ischaemic than in normal myocardium, whereas at 168 h, mitosis of cells was, as in normal myocardium, a rare event. Coronary microembolization of porcine myocardium thus leads to an increased cellular proliferation rate between 24 h and less than 7 days after the onset of microembolization, followed by enhanced capillary growth. In-situ hybridization with histone H3 and PCNA/cyclin immunohistochemistry seem to be reliable markers for proliferation and vascular growth in non-cancerogenic tissue.

Animals↗
PubMed1997

Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is localized over the entire plasma membrane of endothelial cells.

The subcellular localization of PECAM-1 in endothelial cells was examined by using advanced morphological techniques, such as confocal scanning microscopy and immunolabeling procedures for electron microscopy. The localization of PECAM-1 was studied immunohistochemically with five specific monoclonal antibodies and one polyclonal antibody (all anti-human) in human and rabbit myocardium and in isolated endothelial cells. In vivo, PECAM-1 was localized uniformly on the plasma membrane of all vascular endothelial cells, predominantly on the luminal side of vessels. No specific increase in labeling was found at sites of cell-to-cell contact. In vitro, primary isolated cells (human umbilical vein endothelial cells) showed continuous labeling of the entire cell membrane. Cells of higher passages were labeled in a manner similar to freshly isolated cells. Our findings refute the commonly accepted hypothesis that PECAM-1 is localized only at cell-to-cell contacts. Further, we have not been able to confirm the hypothesis regarding the important mechanical role of PECAM-1 in stabilizing the endothelial monolayer. Since PECAM-1 is also expressed on platelets and is known to bind to itself, the way in which PECAM-1-positive endothelial cells are protected against binding of PECAM-1-positive platelets remains unclear. In view of these findings, the role of PECAM-1 in the leukocyte migration cascade needs to be re-evaluated.

Animals↗
PubMed1997

Effects of positive inotropic stimulation on postischemic myocardium with graded dysfunction.

OBJECTIVE: To investigate the effects of moderate prolonged and of maximum short-term positive inotropic stimulation of postischemic myocardium as a function of the severity of stunning. METHODS: Stunned isolated rat hearts (n = 116) after 30 min and 45 min of ischemia were stimulated with dopamine to raise systolic function (double product) back to control levels. In the isovolumetrically beating hearts, left ventricular developed pressure, double product, dp/dtmax, coronary flow, and myocardial oxygen consumption were determined during steady-state conditions. After maximum stimulation the contractile reserve was examined. Measurements of adenine nucleotides (n = 47) and electron microscopy (n = 9) were made. RESULTS: 30 min ischemia resulted in moderate postischemic dysfunction (LVP 81 +/- 3%; P < 0.05). After 45 min ischemia, function was more severely reduced (LVP 66 +/- 5%; P < 0.01). Coronary flow tended to be lower after ischemia. Myocardial oxygen consumption was not reduced in parallel with the dysfunction. Adenine nucleotides were gradually reduced after ischemia (ATP: 2.5 +/- 0.2 and 1.2 +/- 0.1 vs. 4.2 +/- 0.2 mumol/gww; P < 0.01). Contractile reserve also decreased in relation to the previous ischemic injury (after 45 min ischemia max. LVP 105 +/- 10% vs. max. LVP 152 +/- 8% in controls, P < 0.01). Prolonged stimulation did not result in further reduction in adenine nucleotides and function. CONCLUSIONS: Contractile reserve is decreased in postischemic myocardium in parallel with the previous ischemic burden. Depending on the degree of contractile dysfunction a disturbed function-flow-oxygen consumption relation is present. Prolonged stimulation of stunned myocardium with dopamine back to the control level of function has no harmful short-term effects, indicating sufficient mitochondrial energy generation.

Adenosine Triphosphate↗
PubMed1997

Coordinate expression of the insulin-like growth factor system after microembolisation in porcine heart.

OBJECTIVES: Coronary microembolisation in the pig heart induces angiogenesis in a model of sterile inflammation due to focal necrosis. We have recently shown in this model that insulin-like growth factor I (IGF-I) is involved in inflammation-linked angiogenic processes due to its enhanced transcription after 72 h of ischaemia by infiltrating monocytes in areas of microsphere-induced focal necrosis where capillary sprouting could be detected. To obtain further insights into this process we studied by means of Northern blot analysis and in situ hybridisation the gene expression of other members of the IGF family, i.e. the six IGF binding proteins (IGFBPs), the insulin receptor, and the type I IGF receptor. METHODS: Myocardial injury was induced by injection of 25 microns non-radioactive microspheres into the left circumflex artery (LCx) in pigs that were killed after 3-24, 72, or 168 h of microembolisation. Tissue was collected from a non-ischaemic control area and the LCx region of the same heart for further analysis. RESULTS: We found decreased IGFBP-5 (2.7-fold; P < 0.02) mRNA concentrations after 72 h of microembolisation in ischaemic tissue versus control tissue from the same heart, preceded by a 1.9-fold elevated level of IGFBP-3 mRNA at 3-24 h (P < 0.05). IGFBP-6 was increased in ischaemic tissue at all time points studied. In situ hybridisation identified myocytes as the main producers of IGFBP-3 and IGFBP-6 mRNA. The mRNA levels of IGFBP-2, IGFBP-4, the insulin receptor, and the type I IGF receptor were constitutively expressed but did not change after microembolisation. Neither in heart nor in other organs studied transcripts of IGFBP-1 could be detected. Furthermore, we demonstrated that mRNA of the other components of the IGF system was expressed in almost all porcine organs except liver. CONCLUSION: These results indicate a coordinate gene expression of the IGF system in microembolised porcine myocardium, compatible with a role of IGF-I, IGFBP-3, IGFBP-5, and IGFBP-6 in inflammation-linked angiogenesis and/or repair processes.

Animals↗
PubMed1997

The role of Fas/APO 1 and apoptosis in the development of human atherosclerotic lesions.

The possibility that Fas/APO 1 is involved in the apoptosis of advanced human coronary atherosclerosis was examined in the present study. Coronary arteries with atherosclerosis were obtained from human hearts with chronic ischemic heart disease at cardiac transplantation. Normal vessels were used as controls. Fas/APO 1 was detected by immunohistochemistry with a monoclonal antibody. Apoptotic cells were stained in situ by terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) and DNA fragmentation into oligonucleosomes was checked by gel electrophoresis. Bcl-2, an antiapoptotic oncoprotein, was detected by immunohistochemistry and Western blot. Apoptotic cells were present in the neointima in all stages of atherosclerosis, and in intraplaque small vessels. In initial lesions, only a few cells were undergoing apoptosis. By contrast, in advanced lesions, many cells were found to undergo apoptosis. Apoptosis was further confirmed by genomic DNA analysis using gel electrophoresis. Apoptotic cells were either smooth muscle cells or macrophages, but also endothelial and blood borne cells. Fas/APO 1 was present in foam cells. Most of the Fas/APO 1 positive cells were stained for the macrophage marker CD68 and for alpha-smooth muscle actin in serial sections. Several anti-Fas/APO 1 positive foam cells were revealed to undergo apoptosis by double staining. Bcl-2 was detected in Fas/APO 1 expressing plaques. A number of CD3-positive T-lymphocytes were found around foam cells expressing Fas/APO 1. This data suggests that Fas/APO 1 regulated apoptosis is involved in the development of advanced human atherosclerotic lesions and that it probably determines the amount of tissue mass in the diseased vessels.

Antibodies, Monoclonal↗
PubMed1997

CT and MR imaging in primary cerebral non-Hodgkin's lymphoma.

PURPOSE: To determine the morphological appearance and topographical distribution of primary cerebral non-Hodgkin's lymphoma (NHL). MATERIAL AND METHODS: CT and MR examinations of 68 patients with primary cerebral NHL were analyzed. The NHLs were classified by the Kiel classification and immunohistological data, as centroblastic (25), immunoblastic (24), lymphoblastic (5), Burkitt (1), non-subclassifiable type B (11), and T-cell lymphoma (2). RESULTS: Centroblastic lymphomas tended to predominate in the parietal lobe (56.5%) and the corpus callosum (59.1%) while immunoblastic lymphomas were mainly distributed in the frontal lobe (52.8%). About 2/3 of all NHLs showed a multifocal occurrence. Important for differential diagnosis, ventricular involvement was proved in 83.3% of these cases. In the remaining 26 patients with a solitary lymphoma, a periventricular location could be detected in only 8 cases. Central necroses were frequent in HIV-positive patients (7/11, 63.6%) but rare in the HIV-negative patients (9/57, 15.8%). On T2-weighted SE MR images, 8/11 centroblastic lymphomas gave a signal that was isointense with, or lower than, that of the contralateral white matter, while 8/10 immunoblastic lymphomas gave a higher signal. CONCLUSION: The radiological finding of multifocal brain lesions with ventricular involvement is relatively specific for primary cerebral NHL. However, subclassification on the basis of the CT or MR imaging results is not yet possible.

Adult↗
PubMed1997

Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure.

BACKGROUND: In the present study, the hypothesis was tested that cell adhesion molecules are expressed in failing human hearts and that a chronic inflammatory process contributes to chronic degeneration known to occur in cardiac incompetence. The cell adhesion molecules: ICAM-1, VCAM-1, PECAM-1, and E-selectin were studied, in addition to cellular markers of inflammation. METHODS AND RESULTS: Tissue was obtained at transplantation from patients with either myocarditis, chronic ischaemic heart disease, or dilated cardiomyopathy. Controls were taken from patients with normal ventricles. Cell adhesion molecules were qualitatively evaluated and counted using specific antibodies and confocal microscopy. Additionally, semiquantitative evaluation of the presence of the CD3 antigen (T-lymphocytes), CD68 (macrophages), CD11a/CD18 (ICAM-1 receptor) and human tumour necrosis factor-a were used as indicators of chronic inflammation. PECAM-1 stained all endothelial cells but ICAM-1 was only present in 80% of all capillaries in control tissue. The ratio ICAM-1/PECAM-1 was significantly enhanced in all groups of diseased hearts. Myocytes in myocarditic hearts expressed ICAM-ICAM. CD3 positive lymphocytes, CD68 positive macrophages and CD11a/CD18 positive cells were more abundantly present than in control. Macrophages expressing tumour necrosis factor-a were found in failing myocardium but not in control tissue. CONCLUSION: Independent of the cause of heart failure, chronic low grade inflammation is present in failing human myocardium. This may significantly contribute to the structural deterioration that is the basis of reduced cardiac function in congestive heart failure.

Adult↗
PubMed1997

Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion.

Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6 +/- 19.23 versus 25.1 +/- 2.59 mL/min per 100 mm Hg; P < .01; peripheral conductance, 119.3 +/- 22.37 versus 45.4 +/- 6.80 mL/min per 100 mm Hg; P < .05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting.

Angiography↗
PubMed1996

[Critique of compulsory responsibilities of insured persons in endangerment according to the therapeutic drug law].

The authors discuss the 5th amendment of the law which regulates the application of therapeutical drugs in Germany (Arzneimittelgesetz), regarding the probands' insurance according to section 40 (3), from the viewpoint of the ethics committee of the Medical Chamber of Rheinland-Pfalz introduced under State (Land) law to protect patients and probands. The authors criticize a number of regulations which might have disadvantages for patients and probands in the case of damage (injury), after they have participated in therapeutical drug trials for the benefit of the general public and by taking a certain personal risk. To overcome these problems, specific proposals for the improvement of the law are being made.

Clinical Trials as Topic↗
PubMed1996

Ultrastructural Evaluation of Postischemic Cell Death (Lethal Reperfusion Injury) in Porcine Hearts.

This study investigated whether reperfusion results in an increase of ultrastructurally determined myocardial injury in pig hearts. The left anterior descending coronary artery (LAD) was distally occluded in 12 pigs for 35-45 minutes and then reperfused for 3 hours. At the end of ischemia, as well as after 3 hours of reperfusion, one transmural biopsy was removed from the center of the risk region and subdivided into four-specimens, representing the subendocardial (I), subendo-midmyocardial (II), subepi-midmyocardial (III), and subepicardial layers (IV). The degree of injury was assessed by electronmicroscopy and was scored as reversible (1), an almost equal mixture of reversible and irreversible (2), and totally irreversible (3) damage. In addition, infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Infarct sizes ranged from 29.3% to 93% (mean 61.2%). The scores of injury of the four tissue layers before and after reperfusion did not differ significantly: layer I, 2.4 +/- 0.8/2.3 +/- 0.9; layer II, 2.2 +/- 0.9/2.0 +/- 0.9; layer III, 1.8 +/- 0.9/2.0 +/- 0.9; and layer IV, 1.6 +/- 0.9/1.3 +/- 0.6. The means of the four layers were almost identical at the end of ischemia (2.1 +/- 0.8) and after 3 hours of reperfusion (2.0 +/- 0.6). A linear regression analysis with 95% confidence limits of the score values before and after reperfusion indicated that maximally 25% of a mean final infarct size of about 50% may be due to lethal reperfusion injury. This study suggests that cell death in regional ischemia and reperfusion occurs predominantly during ischemia and not during reperfusion.

Journal Article↗
PubMed1996

Expression of adhesion molecules is specific and time-dependent in cytokine-stimulated endothelial cells in culture.

The time course of expression of the adhesion molecules E-selectin, VCAM-1, ICAM-1 and PECAM-1 was studied in interleukin-1 beta-stimulated human umbilical vein cells (HUVEC) and the subcellular sites of synthesis were determined by means of fluorescence immunohistochemistry. The maximal number of cells labelled for E-selectin was observed at 2-4 h, for VCAM-1 at 4-8 h and ICAM-1 at 6-72 h. At 8 h, E-selectin and VCAM-1 started to disappear, but ICAM-1-positive cells persisted. PECAM-1 was constitutively expressed. De novo synthesis for E-selectin started at 1 h and for both, VCAM-1 and ICAM-1 at 1.5-2 h. Maximal synthetic activity was observed at 2.5-4 h for E-selectin and at 4-6 h for VCAM-1 and ICAM-1; thereafter, synthesis slowly decreased. Transport granules occurred at 1.5 h for E-selectin and 4 h for VCAM-1; they were absent for ICAM-1. Diffuse cellular and membrane labelling indicative of the functional activity of the adhesion molecules began at 2-4 h for E-selectin, and 4 h for VCAM, but was constitutively present for ICAM-1. In conclusion, each adhesion molecule shows a specific time-dependent course of appearance and disappearance in interleukin-1 beta-stimulated HUVECs in accordance with their physiological role in vivo. These morphological results confirm data obtained by flow cytometry and Western blotting, but they provide new information about the behaviour of individual cells with regard to the sites of synthesis and cellular localization of the adhesion molecules.

Antigens, Differentiation, Myelomonocytic↗
PubMed1996

Tumor necrosis factor-alpha in macrophages of heart, liver, kidney, and in the pituitary gland.

Tumor necrosis factor-alpha (TNFalpha) is an important mediator in bacterial lipopolysaccharide (LPS)-induced fever and shock. New data on TNFalpha-producing macrophages in heart, pituitary gland, kidneys and liver in correlation with TNFalpha plasma levels are reported here. In adult rabbits, core temperature and TNFalpha plasma levels are significantly increased at 3 and 24 h after treatment with LPS. After a delay of 6-12 h, the number of TNFalpha-containing macrophages, determined by immunohistochemistry, increases more than fivefold in all organs investigated. With the exception of the pituitary gland, the increase in cell number is correlated with the degree of cellular injury, indicating the involvement of TNFalpha in LPS-induced organ damage that is accompanied by the synthesis of the cytokine. Cortisol levels also increase for at least 24 h after LPS treatment, show peak values 6 h after interleukin-1 treatment, and are unchanged after TNFalpha treatment, indicating the different effects of these factors on the hypothalamo-hypophyseal-adrenocortical axis. This study provides evidence that macrophageal TNFalpha of multi-organ origin is involved in LPS-induced tissue injury and supports the concept of a systemic inflammatory response syndrome. We also show for the first time that in the anterior lobe of the pituitary gland TNFalpha is a normal constituent in cells producing growth hormone but not ACTH. Moreover, most cells of the intermediate lobe are positive for TNFalpha.

Animals↗