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Biomedical subjects

C Haller

Publications and source records attributed to C Haller.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Diuretic therapy in congestive heart failure--new views on spironolactone therapy].

Cardiac pump failure leads to a reduction of the effective arterial volume. This is sensed by the kidney via afferent sympathetic fibres. The renal response to the perceived lack of volume is the retention of sodium and water. Although initially homeostatic, this renal counterregulation is maladaptive later on and may contribute to further cardiac compromise by increasing preload (volume retention) and afterload (hyperreninism). The renal sodium retention in congestive heart failure is a consequence of the activation of the sympathetic nervous system and of the renin-angiotensin-aldosterone system. The retention of osmotically free water is partly caused by the nonosmotic secretion of antidiuretic hormone from the posterior pituitary and partly by a diminished osmoregulatory capacity of the kidney due to diuretic therapy and/or (pre-)renal insufficiency. In the near future specific blocking drugs of vasopressin receptors should become available which could make a significant contribution to the management of hyponatremia in this setting. For the management of extracellular volume overload a negative sodium balance is the central objective. A moderate reduction of sodium intake is helpful to achieve this goal and has the additional benefit of reducing thirst and renal potassium loss. However, the majority of patients require (loop) diuretics in addition. Patients who are refractory to high and repeated doses of loop diuretics may respond to a combination of diuretics which act on different nephron segments. Diuretics increase the risk of hypokalemia which can trigger life-threatening tachyarrhythmia, particularly in patients with cardiac dysfunction. Hypokalemia is therefore an indicator of an adverse outcome. Secondary hyperaldosteronism--which can persist despite effective therapy with ACE-inhibitors--is the major cause of hypokalemia in this setting. The randomized aldactone evaluation study (RALES) has shown that spironolactone (25 mg/day) reduced the risk of hypokalemia and decreased morbidity, mortality and clinical symptoms in patients with heart failure. The recent encouraging results with vasopressin receptor antagonists and spironolactone point to the fact that the therapeutic modification of maladaptive homeostatic renal mechanisms plays an increasingly important role in the modern diuretic management of heart failure beyond symptomatic relief from volume overload.

Antidiuretic Hormone Receptor Antagonists↗
PubMed1999

Developmental dissociation of thymic dendritic cell and thymocyte lineages revealed in growth factor receptor mutant mice.

Thymocytes and thymic dendritic cell (DC) lineages develop simultaneously and may originate from a common intrathymic progenitor. Mice deficient for two growth factor receptor molecules [c-kit and the common cytokine receptor gamma chain (gamma(c))] lack all thymocytes including T cell progenitors. Despite this lack of pro-T cells, thymic DC compartments were identified in c-kit(-)gamma(c)(-) mice. Thus, c-kit- and gamma(c)-mediated signals are not essential to generate thymic DCs. In addition, pro-T cells do not appear to be obligatory progenitors of thymic DCs, because DC development is dissociated from the generation of thymocytes in these mice. Thymic DCs in c-kit(-)gamma(c)(-) mice are phenotypically and functionally normal. In contrast to wild-type mice, however, thymic DCs in c-kit(-)gamma(c)(-) and, notably, in RAG-2-deficient mice are CD8alpha(neg/low), indicating that CD8alpha expression on thymic DCs is not independent of thymocytes developing beyond the "RAG-block."

Animals↗
PubMed1999

[Cell polarity in the cardiovascular system].

The importance of cell polarity as a fundamental biological principle is increasingly recognized in the cardiovascular system. Polar cell mechanisms underlie not only the development of the heart and blood vessels, but also play a major role in the adult organism for polarized endothelial functions such as the separation of the intra- and extravascular compartment and the vectorial exchange of substances between these compartments. Endothelial cells are connected through intercellular junctions which separate the functionally and structurally distinct luminal and abluminal cell surfaces. The luminal plasma membrane is in contact with the blood and takes part in the regulation of hemostasis. The abluminal cell membrane connects the endothelial cell with the basement membrane and modulates blood flow through the release of vasoactive substances. Results from epithelial model systems have shown that the polarized cell phenotype is generated by specific protein sorting and regulated protein trafficking between the trans-Golgi network and the cell surface. The polarized distribution of cell membrane proteins is maintained by anchorage with the cytoskeleton and limitation of lateral diffusion by tight junctions. Disturbances of cell polarity may contribute to the pathogenesis of disease states, including ischemic and radiocontrast-induced acute renal failure and carcinomas. Recent results have demonstrated the importance of cholesterol for protein traffic from the trans-Golgi network to the apical cell membrane. This novel intracellular function of cholesterol could point to a connection between cell polarity and the pathogenesis of arteriosclerosis. The polarity of the endothelium also has to be taken into account when developing gene-therapeutic strategies, since therapeutic success will not only depend on the efficient expression of the desired gene product, but also on its correct cellular location or secretion into the correct extracellular compartment. These examples demonstrate the biological and potentially clinical relevance of cell polarity in the cardiovascular system.

Adult↗
PubMed1999

Cell-cell contacts in the human cell line ECV304 exhibit both endothelial and epithelial characteristics.

Endothelial cells separate the intra- and extravascular space and regulate transport processes between these compartments. Since intercellular junctions are required for these specific cell functions, the cell-cell contacts in the permanent cell line ECV304 were systematically analyzed and compared with human umbilical vein endothelial cells (HUVECs) in primary culture and with the epithelial Madin Darby Canine Kidney (MDCK) cell line. Filter-grown ECV304 cells generate a distinct electrical resistance and a permeability barrier between cell culture compartments. Electron microscopy of ECV304 cells revealed lateral membrane interdigitations, typically found in endothelial cells in vivo, with direct membrane contact sites, which prevented the diffusion of lanthanum. By immunoblot and immunofluorescence analysis, the expression and cellular localization of the tight junction and adherens-type junction proteins occludin, ZO-1, symplekin, beta-catenin, and plakoglobin were analyzed. ECV304 cells display further characteristics of endothelial cells, including the expresssion of thrombomodulin and of the vitronectin receptor CD51, as well as the secretion of plasminogen activator inhibitor 1 (PAI-1) and endothelin. However, ECV304 cells also express proteins characteristically found in epithelial cells, including E-cadherin and the desmosomal proteins desmoplakin, desmocollin, and desmoglein; occasionally desmosomal structures can be identified by electron microscopy. In conclusion, ECV304 cells express many endothelial markers and form specialized intercellular junctions that display some epithelial features. Thus this reportedly endothelial-derived permanent human cell line may be dedifferentiated toward an epithelial phenotype.

Animals↗
PubMed1999

Comparative cytotoxicity of ionic and non-ionic radiocontrast agents on MDCK cell monolayers in vitro.

BACKGROUND: Intravascular radiocontrast agents may cause acute renal failure, particularly in patients with pre-existing renal insufficiency. Direct cytotoxic effects of radiocontrast agents on renal tubular cells may contribute to the pathogenesis of radiocontrast-induced nephropathy. METHODS: We analysed the cytotoxicity of the ionic radiocontrast agents diatrizoate (monomeric) and ioxaglate (dimeric), as well as of the non-ionic radiocontrast agents iohexol (monomeric) and iodixanol (dimeric) on the renal epithelial Madin Darby Canine Kidney (MDCK) cell line grown on permeable supports. The toxicity assays assessed cell viability, transmonolayer resistance and inulin permeability between the apical and basal cell culture compartment. In addition, the distribution of the tight-junction-associated membrane proteins ZO-1 and occludin was analysed using immunofluorescence microscopy. RESULTS: In all assays the high osmolal ionic compound diatrizoate had significant cytotoxic effects that included the partial redistribution of the tight-junction-associated membrane proteins into a cytoplasmic compartment. To a lesser extent this redistribution also occurred with the dimeric ionic compound ioxaglate, but not with the non-ionic radiocontrast agents. With regards to cell viability, transmonolayer resistance and inulin permeability the radiocontrast agents with reduced osmolality were significantly less toxic than diatrizoate, independent of their ionic strength. CONCLUSIONS: Physicochemical factors contribute to the cytotoxicity of radiocontrast agents in vitro. The redistribution of tight-junction-associated membrane proteins by the ionic radiocontrast agents corresponds with the loss of the barrier function of the epithelial cell monolayer, which is a major pathophysiological mechanism in acute renal failure. The radiocontrast agents with reduced osmolality are less cytotoxic than diatrizoate, independent of their ionicity. Hyperosmolality appears to be a more important determinant of the cytotoxicity of diatrizoate than ionic strength.

Animals↗
PubMed1998

Polarized expression of heterologous membrane proteins transfected in a human endothelial-derived cell line.

The generation and maintenance of cell polarity in endothelial cells is poorly understood, partly because of a lack of a permanent endothelial in vitro model system. Here we evaluated the spontaneously immortalized human endothelial-derived cell line ECV304 as an in vitro model system for the study of the polarized expression of heterologous membrane proteins. Several stable ECV304 clones were generated by calcium phosphate transfection/G418 selection with cDNAs encoding membrane proteins of known cell surface distribution in the epithelial Madin Darby canine kidney (MDCK) cell line: influenza hemagglutinin and uvomorulin/E-cadherin were used as markers for the apical, respectively lateral cell membrane, the human lymphocyte surface marker CD7 served as an example of a circumferentially distributed membrane protein. Analysis of the transfected ECV304 clones using conventional and confocal immunofluorescence microscopy and immunoelectron microscopy revealed the same membrane distribution of the heterologous proteins in ECV304 cells as in MDCK cells. This polarized expression of heterologous membrane proteins in the endothelial-derived ECV304 cell line indicates efficient protein sorting/membrane trafficking mechanisms. The apical, lateral and basal cell membrane domains could be distinguished in ECV304 cells by confocal immunofluorescence microscopy. The permanent endothelial-derived ECV304 cell line may be a useful in vitro model system for the study of endothelial cell polarity.

Animals↗
PubMed1998

Radiocontrast-induced natriuresis associated with increased urinary urodilatin excretion.

OBJECTIVE: Intravascular radiocontrast agents induce a pronounced diuresis. The aim of the present study was to investigate the (patho-)physiological mechanisms of the radiocontrast-induced diuresis. DESIGN: The fractional excretion of sodium, the urinary excretion of the renal natriuretic peptide urodilatin and the plasma concentration of atrial natriuretic peptide were measured in 42 unselected patients immediately before and after intravascular radiocontrast administration during coronary angiography. SETTING: Cardiac catheterization laboratory of a university hospital. RESULTS: After angiography both the plasma concentration of atrial natriuretic peptide (median post-pre difference: 3.9 pmol L(-1), quartiles -1.2; 7.0) and the urinary excretion of urodilatin (median post-pre difference: 67.0 nmol urodilatin/mol creatinine, quartiles 39.7; 152.1) were increased. The urinary urodilatin excretion was correlated with an increase in the fractional excretion of sodium (median post-pre difference: 1.7%, quartiles 0.6; 3.1). There was no correlation between the serum concentration of atrial natriuretic peptide and urinary sodium excretion. For the radiocontrast-induced increase in both urodilatin and sodium excretion there was no indication for differences between patients without (31) and with (11) intravenous saline infusion. CONCLUSION: The radiocontrast-induced diuresis is a natriuresis which is associated with an increased urinary excretion of urodilatin. The association between natriuresis and urinary urodilatin excretion irrespective of baseline volume status corroborates the hypothesis that urodilatin contributes to the sodium excretion after radiocontrast administration in a paracrine manner. This finding has pathophysiological and potentially therapeutic implications in radiocontrast-induced nephropathy.

Atrial Natriuretic Factor↗
PubMed1998

Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity.

BACKGROUND: Radiocontrast-induced nephropathy is a clinically important complication of invasive cardiological procedures. It has been associated with DNA fragmentation of renal tubular cells, which is a hallmark feature of programmed cell death (apoptosis). We investigated the mechanism of this DNA fragmentation in an in vitro model of radiocontrast cytotoxicity on renal epithelial cells. METHODS: Madin Darby canine kidney (MDCK) cell monolayers were incubated (for 2-8 h) with isoiodine doses (37-111 mg iodine/ml) of the highly hyperosmolal, ionic radiocontrast agent diatrizoate or of the less hyperosmolal, non-ionic substance iopamidol. Mannitol, urea, and NaCl control media of corresponding hyperosmolality were used to evaluate the contribution of hypertonicity, hyperosmolality and/or ionic strength to radiocontrast toxicity. DNA fragmentation was assessed using fluorescence-activated cell sorting (FACS), agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated deoxyuridine nick end labelling (TUNEL), cell morphology was analysed in Giemsa-stained cytospins. RESULTS: Diatrizoate induced concentration- and time-dependent DNA fragmentation of MDCK cells which was associated with morphological signs of apoptosis. Cycloheximide (1 microg/ml) did not prevent diatrizoate-induced DNA fragmentation, indicating that it is not dependent on protein synthesis. Diatrizoate-mediated cell death was associated with cell detachment from the tissue culture matrix. However, the DNA fragmentation is not a consequence of cell detachment since the prevention of cell attachment on agarose-coated dishes induced significantly less DNA fragmentation than diatrizoate. Iopamidol caused no detectable DNA breakdown. In contrast, hypertonic mannitol and sodium chloride, but not hyperosmolal urea, induced DNA fragmentation in MDCK cells, albeit less than diatrizoate. CONCLUSIONS: The DNA fragmentation of MDCK cells induced by diatrizoate is related to its hypertonicity in this in vitro model of radiocontrast cytotoxicity. Nuclear disintegration with subsequent cell death may contribute to the pathophysiology of radiocontrast-induced nephropathy, particularly in the hypertonic/hypoxic environment of the renal medulla. The present results underscore the importance of avoiding hyperosmolal urine states in patients at high risk of radiocontrast-induced nephropathy.

Animals↗
PubMed1998

Immunological and functional analyses of the extracellular domain of human tissue factor.

Tissue factor (TF) initiates the extrinsic pathway of blood coagulation via formation of an enzymatic complex with coagulation factor VII/VIIa (FVII/VIIa). Although FVII is the only known ligand for TF, several reports in recent years have shown that the function of TF may not be limited to serving as a trigger of coagulation but that TF could also play a role in cellular signaling, metastasis, adhesion and embryogenesis. To explore the loci of the extracellular domain of TF important for its function, we analyzed the functional and immunological epitopes of TF1-219 by the use of both E. coli expressed TF variants encompassing various portions of the extracellular domain of TF and different anti-TF monoclonal antibodies (mAbs). N- and C-terminally truncated TF variants were analyzed for their VIIa-dependent procoagulant activity (PCA). The results obtained are in agreement with previously performed mutant and structural analyses of the interaction of FVII/FVIIa with the extracellular domain of TF. In addition, we observed that combination of two TF variants, Ec-TF1-122 and Ec-TF120-219, yields a soluble and active two-chain TF molecule with remarkable PCA. The reaction patterns of anti-TF mAbs with truncated TF variants and synthetic TF-derived peptides demonstrated that at least three distinct conformation-dependent epitope areas of TF (residues 1-25, 175-202, and 181 -214, respectively) are detected by these mAbs raised against native TF. In fact, mAbs, which are directed to the same epitope area of TF, behave very similar in various applications including immunohistochemistry and clotting tests. Since mAbs directed to the C-terminal epitope area of TF (residues 181-214) influence TF activity independent of FVIIa-binding, this region may be involved in functions of TF distinct from haemostasis.

Antibodies, Monoclonal↗
PubMed1998

Cardiac troponin T in patients with end-stage renal disease: absence of expression in truncal skeletal muscle.

In patients with end-stage renal disease (ESRD), the serum concentration of cardiac troponin T (cTnT) may be increased without cardiac ischemia. One reason for this unexplained increase could be the extracardiac expression of cTnT. However, truncal skeletal muscle biopsies of five patients with ESRD showed no evidence of the expression of either cTnT mRNA (reverse transcription-PCR) or protein (immunoblot, immunofluorescence). We also measured the serum concentration of cTnT in 97 patients with ESRD. The serum cTnT concentration determined in both first and second generation cTnT assays was significantly lower P <0.01 in patients with a low cardiac risk than in patients with positive indicators of coronary artery disease. The correlation between cTnT and indicators of coronary artery disease is consistent with the hypothesis that cTnT in the serum of patients with ESRD originates from the heart.

Abdominal Muscles↗
PubMed1998

Urinary and plasma urodilatin measured by a direct RIA using a highly specific antiserum.

Urodilatin (95-126) (URO) appears to play a major physiologic role in fluid homeostasis and produces major changes when administered intravenously. Here we describe a monospecific, high-affinity antiserum against URO with no cross-reactivity (<0.01%) against the structural highly homologous atrial natriuretic peptide 99-126 (ANP-99-126), ANP analogs, and related peptides such as brain natriuretic peptide. A competitive RIA was developed, based on this antiserum. Urine samples with or without ethanol extraction and plasma samples without pretreatment were analyzed by the RIA, which had a detection limit of 10.5 ng/L, a linear measuring range between 10.5 and 1000 ng/L, and recoveries of 93-102% in urine and 90-104% in plasma. The intraassay CVs were 8.2% and 8.1% for urine samples with 269 and 669 ng/L URO; the interassay CV was 9.7% at 839 ng/L. Using this assay, we present URO data for urine from healthy volunteers receiving low and routine sodium diets and from clinical urine specimens; we also present pharmacokinetic data for URO in plasma from patients suffering from bronchial asthma and treated by URO infusion.

Animals↗