352 results on '"Veelken R"'
Search Results
102. Sympathetic blockade prevents the decrease in cardiac VEGE expression and capillary supply in experimental renal failure.
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Amann, K., Odoni, G., Benz, K., Campean, V., Jacobi, J., Hilgers, K. F., Hartner, A., Veelken, R., and Orth, S. R.
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CHRONIC kidney failure ,KIDNEY diseases ,SYMPATHETIC nervous system ,GROWTH factors ,GENE expression ,CARDIAC hypertrophy ,MESSENGER RNA - Abstract
Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n = 10) or subtotal nephrectomy (SNX, n = 10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258 ± 2,078 units) than in both sham groups (11,709 ± 4,169 and 8,998 ± 4,823 units); this decrease was significantly prevented by renal denervation (8,190 ± 3,889, P < 0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression. [ABSTRACT FROM AUTHOR]
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- 2011
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103. Is a shared decision-making approach effective in improving hypertension management?
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Deinzer A, Veelken R, Kohnen R, Schmieder RE, Deinzer, Anja, Veelken, Roland, Kohnen, Ralf, and Schmieder, Roland E
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The authors assessed whether patient empowerment in the management of hypertension improved more with the practice of shared decision making (SDM) than by education programs. In a prospective controlled clinical study, 15 general practitioners in Nuremberg, Germany who were specially trained to conduct SDM consultations participated in a 12-month study. Hypertensive patients (N=86) were included; N=40 were in the SDM group and N=46 were in the control group, if blood pressures were > or = 135 / 85 mm Hg (self measurement) and patients had no signs of cardiovascular complications or severe hypertension. All participants in the SDM group and the control group were enrolled in an education program on hypertension in small groups. The SDM group participants also had 4 special consultations to share medical decisions. The main outcome measures were the effect of SDM on blood pressure control. After 1 year blood pressure had decreased in all participants: Delta-9.26 +/- 10.2 mm Hg/Delta-5.33 +/- 9.5 mm Hg in the SDM group (P<0.001) compared to Delta-6.0 +/- 11.8 mm Hg/Delta-3.0 +/- 8.3 mm Hg in the control group. There was no significant difference between the 2 groups. The study group practiced more SDM than controls, but blood pressure control was not significantly better. Patient empowerment by means of an education program in small groups and creating awareness of hypertensive disease helps to improve the outcome of hypertension treatment. SDM, however, did not improve management when compared to an education program, which is much easier to implement in general practice. [ABSTRACT FROM AUTHOR]
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- 2009
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104. Statin treatment reduces glomerular inflammation and podocyte damage in rat deoxycorticosterone-acetate-salt hypertension.
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Hartner A, Klanke B, Cordasic N, Amann K, Schmieder RE, Veelken R, Hilgers KF, Hartner, Andrea, Klanke, Bernd, Cordasic, Nada, Amann, Kerstin, Schmieder, Roland E, Veelken, Roland, and Hilgers, Karl F
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- 2009
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105. Epicardial serotonin receptors in circulatory control in conscious Sprague-Dawley rats
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Veelken, R., primary, Sawin, L. L., additional, and DiBona, G. F., additional
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- 1990
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106. Angiotensin II type 1 receptor blockade prevents lethal malignant hypertension: relation to kidney inflammation.
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Hilgers, K F, Hartner, A, Porst, M, Veelken, R, and Mann, J F
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- 2001
107. Effect of renal nerve ablation on renal perfusion and arterial wave reflection in treatment resistant hypertension
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Ott, C., Schmid, A., Titze, S., Ditting, T., Janka, R., Hilgers, K.F., Veelken, R., Uder, M., and Schmieder, R.E.
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- 2011
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108. Impact of dietary sodium intake on left ventricular diastolic filling in early essential hypertension.
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Langenfeld, M. R. W., Schobel, H., Veelken, R., Weihprecht, H., and Schmieder, R. E.
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Aims Dietary sodium intake modulates left ventricular hypertrophy in established essential hypertension independent of blood pressure level. We conducted this study to elucidate the relationship between sodium intake and left ventricular structural or functional changes in early essential hypertension.Methods Forty-four young male patients (age 25.9 ± 2.6 years) with mild essential hypertension that had never been treated and 45 normotensive male control subjects of similar age were examined. Dietary sodium intake was measured from 24 h urinary sodium excretion, blood pressure from 24 h ambulatory monitoring (SpaceLabs 90207), left ventricular structure from 2-D guided M-mode echocardiography, and diastolic filling of the left ventricle (as the main compound of diastolic function in a young population) by pulse-wave Doppler sonography.Results In hypertensive patients, daily sodium excretion correlated with the ratio of late (A) to early (E) maximum velocity (Vmax AlE; r= +0.27, P=0.07), velocity time integrals (AlE; r= +0.54, P<0.001) as well as atrial contribution, as a percent of left ventricular filling (VH A TCO; r= +0.52, P<0.001) independent of heart rate, whereas the opposite correlations were observed in normotensives (all P<0·001). Stepwise multiple regression analysis confirmed these results. Sodium excretion emerged as the strongest independent determinant of impaired diastolic filling in hypertensive patients (velocity time integrals AlE: R2 =0.49, β= +0.57, P=0.0001; VH ATCO: R2 = 0.48, β= +0.56, P<0.0001; Vmax AlE: ns). In normotensive subjects, sodium excretion was a similar strong, but inverse determinant of diastolic filling (velocity time integrals AlE: R2 =0.40, β= −0.43, P=0.0028). Heart rate was a strong determinant of diastolic filling in hypertensive patients (β= +0.55, P=0.0002) and in normotensive subjects (β= +0.34, P=0·011). Left ventricular mass and enddiastolic volume index were not related to diastolic filling in either group.Conclusion In early essential hypertension, sodium excretion is correlated with impaired left ventricular diastolic filling independent of left ventricular mass. The reninangiotensin-aldosterone system might be a mediator of the observed correlation. [ABSTRACT FROM PUBLISHER]
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- 1998
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109. Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.
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Hilgers, Karl F., Veelken, Roland, Mai, Monika, Ganten, Ursula, Ganten, Detlev, Luft, Friedrich C., Mann, Johannes F.E., Hilgers, K F, Veelken, R, Mai, M, Ganten, U, Ganten, D, Luft, F C, and Mann, J F
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- 1993
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110. Angiotensinases restrict locally generated angiotensin II to the blood vessel wall.
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Hilgers, K F, Bingener, E, Stumpf, C, Müller, D N, Schmieder, R E, and Veelken, R
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- 1998
111. Dissociation of renal nerve and excretory responses to volume expansion in prehypertensive Dahl salt-sensitive and Dahl salt-resistant rats.
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Veelken, R, Sawin, L L, and DiBona, G F
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- 1989
112. Effect of urapidil, clonidine, and prazosin on sympathetic tone in conscious rats.
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LUFT, FRIEDRICH C., VEELKEN, ROLAND, BECKER, HANS, GANTEN, DETLEV, LANG, RUDOLF E., UNGER, THOMAS, Luft, F C, Veelken, R, Becker, H, Ganten, D, Lang, R E, and Unger, T
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- 1986
113. Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients.
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Renders, L, Mayer-Kadner, I, Koch, C, Schärffe, S, Burkhardt, K, Veelken, R, Schmieder, R E, and Hauser, I A
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Hyperlipidaemia is an important risk factor for cardiovascular disease in renal transplant recipients. The aim of this study was to test the efficacy and possible drug-drug interactions of the new HMG-CoA reductase inhibitors (statins) atorvastatin and cerivastatin in cyclosporin A (CsA)-treated renal transplant patients. Subjects and methods. Thirty patients with stable graft function and LDL cholesterol of 130 mg/dl were randomly assigned to active treatment groups (10 mg atorvastatin or 0.2 mg cerivastatin), or a control group. CsA blood trough levels were controlled on a weekly basis and adapted if they changed more than 25% from baseline values (100-150 ng/ml). Lipid levels and routine laboratory parameters before and after a treatment period of 3 months were compared.
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- 2001
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114. Der Siemens-Digitalrechner 2002 - Ein Rückblick nach 25 Jahren
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Veelken, R.
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- 1983
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115. Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension
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Schobel, H. P., Karsten Heusser, Schmieder, R. E., Veelken, R., Fischer, T., and Luft, F. C.
116. Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization.
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Unger, T, primary, Carolus, S, additional, Demmert, G, additional, Ganten, D, additional, Lang, R E, additional, Maser-Gluth, C, additional, Steinberg, H, additional, and Veelken, R, additional
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- 1988
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117. Editorial
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Veelken, R., primary
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- 1973
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118. Putative Central Effects of Urapidii and Prazosin in Conscious Spontaneously Hypertensive Rats
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Veelken, R, primary, Luft, F, additional, Becker, H, additional, Unger, Th, additional, Lang, R E, additional, and Ganten, D, additional
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- 1985
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119. Effects of intravenous AVP on cardiac output, mesenteric hemodynamics, and splanchnic nerve activity
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Veelken, R., primary, Danckwart, L., additional, Rohmeiss, P., additional, and Unger, T., additional
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- 1989
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120. An approach to measuring cardiac output with Doppler flow probes in conscious rats
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Veelken, R., primary, Schelling, P., additional, and Unger, T., additional
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- 1988
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121. Role of the α8 Integrin Chain in Diabetic Glomerular Disease.
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Hartner, A., Porst, M., Cordasic, N., Veelken, R., Klanke, B., and Hilgers, K. F.
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KIDNEYS ,INTEGRINS ,KIDNEY glomerulus ,HYPERTENSION ,STREPTOZOTOCIN - Abstract
Objective: In the kidney, the α8 integrin chain is expressed in glomerular mesangial cells. Mice with a homozygous deletion of α8 have a reduced renal mass, but the structure and function of the glomerulus is not impaired. During experimental DOCA-salt induced hypertension, α8 plays a protective role in the glomerulus. We hypothesized that α8 is also involved in maintaining the integrity of the glomerular capillary tuft in diabetic glomerular disease. Results: Immunohistochemical studies showed that streptozotocin (STZ) diabetes increased glomerular deposition of α8 in rats. To test the functional role of α8, STZ diabetes was induced in mice with a homozygous deletion of the α8 gene (-/-) and wildtype (+/+)controls. To adjust for the reduced renal mass in α8-/- mice, +/+ mice were uninephrectomized one week before induction of the disease. Blood glucose was not different in STZ diabetic -/- and +/+ mice (371.6 ± 40.6 mg/dl in -/- versus 417 ± 50.4 mg/dl in +/+, n.s.) after four weeks of diabetes. However, α8-/- mice developed significantly higher albuminuria than +/+ (186.6 ± 45.1µg/24 h in -/- versus 68.8 ± 15.8µg/24 h in +/+, p < 0.05). Blood glucose and albuminuria did not differ between untreated -/- and +/+. Evaluation of glomerular collagen IV staining by densitometry revealed a significant increase in collagen IV deposition in glomeruli of STZ diabetic -/- mice (6.1 ± 0.5% versus 3.8 ± 0.6% in untreated -/-, p < 0.05). In contrast, no differences in collagen IV deposition were observed in STZ diabetic +/+ mice (3.1 ± 0.5% versus 2.9 ± 0.3% in untreated +/+, n.s.) at this early stage of diabetic nephropathy. Conclusions: Taken together, α8-/- mice developed more severe glomerular lesions after onset of STZ diabetes than wildtypes. Thus, α8 seems to play a protective role for the maintenance of functional and structural integrity of the glomerulus during the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]
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- 2004
122. Statin Treatment Reduces Glomerular Inflammation and Injury in Hypertensive Nephrosclerosis.
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Klanke, B., Codasic, N., Hartner, A., Veelken, R., and Hilgers, K. F.
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STATINS (Cardiovascular agents) ,HYPERTENSION ,INFLAMMATION ,LABORATORY rats ,BLOOD pressure - Abstract
Objective: Statins may protect organs from hypertension induced injury by mitigating inflammation. We tested the hypothesis that fluvastatin reduces glomerular inflammation and sclerosis in a low-renin model of hypertension. Methods: Two weeks after uninephrectomy, male Sprague- Dawley rats received deoxycorticosterone-acetate (DOCA) pellets subcutaneously, or were sham operated. All animals received 1% NaCl for drinking, and were followed for 6 weeks. DOCA rats were treated with fluvastatin (5 mg/kg, daily gavage) or vehicle. Blood pressure was measured weekly by tail cuff plethysmography, and intraarterially in conscious rats at the end of the experiment. After 6 weeks, urine was collected for 24 hours. Rats were sacrificed, and kidneys were harvested for fixation in methyl-carnoy. Sections of paraffin-embedded tissue were examined by light microscopy and immunohistochemistry. Macrophages were counted after staining for ED-1. Results: During treatment, 10 of 24 vehicle-treated DOCA hypertensive rats died whereas 10 of 11 fluvastatin-treated DOCA rats, and all 12 normotensive controls, survived. Mean arterial pressure was elevated in vehicle-treated DOCA rats (168 ± 7 versus 121 ± 4mmHg in normotensive rats, p < 0.05) and somewhat lower in fluvastatin-treated DOCA rats (156 ± 4 mmHg, p > 0.05 versus vehicle). Urinary protein excretion was grossly elevated in vehicle-treated DOCA rats (554 ± 53 versus 27 ± 3 mg/day/rat in normotensive controls) and somewhat reduced by fluvastatin (432 ± 77 mg/day/rat). DOCA rats developed marked glomerulosclerosis (index: 2.0 ± 0.1 versus 0.4 ± 0.1 in controls, p < 0.05) which was alleviated by fluvastatin (1.5 ± 0.2, p < 0.05 versus vehicle). Glomerular infiltration of macrophages in DOCA rat kidneys (4.1 ± 0.6 versus 0.9 ± 0.1 macrophages per glomerular cross-section in normotensive controls, p < 0.05) was reduced by fluvastatin (2.4 ± 0.6 macrophages per cross-section, p < 0.05). Conclusions: We conclude that statins reduce mortality as well as the extent of proteinuria and glomerulosclerosis in a low-renin model of severe hypertensive glomerular disease. Reduction of glomerular macrophage infiltration may contribute to the protective effect of statins in hypertensive glomerulosclerosis. [ABSTRACT FROM AUTHOR]
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- 2004
123. Editorial comment. The acute renal effects of Angiotensin II receptor blockers.
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Veelken, R, Hilgers, KF, and Mann, JFE
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- 1998
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124. Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney
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Cordasic Nada, Wittmann Michael, Veelken Roland, Hartner Andrea, and Hilgers Karl F
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background In experimental models of diabetes mellitus, aggravation of renal injury by concomitant hypertension has been described. Inflammatory mechanisms contribute to renal damage in both diseases. We investigated whether hypertension and diabetes mellitus act synergistically to induce macrophage infiltration and matrix expansion in the kidney. Methods Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats (TGR) and normotensive Sprague-Dawley control rats. Quantitative immunohistochemical examination of kidney tissue sections was used to measure macrophage infiltration and matrix expansion. The expression of MCP-1, Osteopontin, RANTES, ICAM-1 and VCAM-1 was evaluated by real-time RT-PCR. The localization of MCP-1 was studied by immunohistochemistry. Results Macrophage infiltration was present in the kidney of normotensive diabetic rats. Hypertensive rats exhibited a more marked infiltration of macrophages, regardless of whether diabetes was present or not. Gene expression of ICAM-1, VCAM-1 and RANTES was unaltered whereas Osteopontin and MCP-1 were induced by hypertension. Immunoreactive MCP-1 was slightly increased in diabetic rat kidney podocytes, and more markedly increased in hypertensive animals. Glomerular matrix accumulation was induced by diabetes and hypertension to a similar degree, and was highest in hypertensive, diabetic animals. Conclusion Diabetes mellitus caused a mild, and angiotensin-dependent hypertension a more marked infiltration of macrophages in the kidney. Combination of both diseases led to additive effects on matrix expansion but not on inflammation. Hypertension appears to be a much stronger stimulus for inflammation of the kidney than STZ diabetes, at least in mRen2-transgenic rats.
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- 2005
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125. Is Increased Sympathetic Nerve Activity Related to Renal Structural Damage in a Non-hypertensive Rat Model of Myocardial Infarction.
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Veelken, R., Hilgers, K. F., Linz, P., Scheller, S., and Amann, K.
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NERVOUS system , *DISEASE risk factors , *CHRONIC kidney failure , *INFLAMMATION , *MYOCARDIAL infarction - Abstract
Objective: The role of the sympathetic nervous system as an independent risk factor in the progression of renal failure in hypertension has received more attention recently. First results in hypertensive models as well as patients suggest a deleterious influence. However, in how far sympathetic overactivity can induce renal damage without cofactors (e.g. high blood pressure or inflammation) is unknown. Hence, we tested the hypothesis that increased renal sympathetic nerve activity (RSNA) in rats after myocardial infarction (CHF) induces signs of renal structural damage. Methods: Rats underwent coronary artery ligation causing myocardial infarction. 21 days later respective groups of animals were sacrificed, kidneys removed and renal morphology evaluated by quantitative histology. Additionally, RSNA regulation was assessed by a systemic volume challenge: animals were subjected to volume expansion (VE: 0.9% NaCl; 10% of BW) to decrease RSNA without affecting blood pressure, heart rate or renal perfusion. For CHF and controls, we studied intact animals and rats with renal denervation (DNX). The protocol included direct measurements of blood pressure (BP), heart rate (HR), RSNA with respective electrodes, glomerular filtration rate (GFR) and renal blood flow (RPF) with inulin and PAH clearances were measured. Results: Body and kidney weight and BP were not significantly different between the groups. Signs of vascular and glomerular damage were small exhibiting no significant differences between CHF and controls. The excretion of the infused amount of salt and water was markedly reduced after 2 hours in rats with CHF as compared to controls (68% ± 5* versus 105% ± 7 and after renal denervation 104% ± 8). Mean ± SEM, n = 6,*: p < 0.05 versus control. The RSNA decreases to VE were impaired in CHF as compared to controls. BP, HR, RPF or GFR were not affected by VE. Conclusions: Although functional assessment exhibited clear signs of increased renal sympathetic nerve activity in rats after myocardial infarction, no signs of gross structural damage to the kidneys due to the increased sympathetic activity were observed. Hence, renal sympathetic activity is likely to induce structural renal damage in dependence of respective co-factors (e.g. increased blood pressure or inflammation). [ABSTRACT FROM AUTHOR]
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- 2004
126. Renal Innervation Aggravates Renal Damage in Anti-Thy 1 Nephritis in Rats.
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Veelken, R., Hilgers, K. F., Hartner, A., Amann, K., and Tiegs, G.
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KIDNEY diseases , *IMMUNOGLOBULINS , *INFLAMMATION , *GLOMERULONEPHRITIS , *LABORATORY rats - Abstract
Objective: Anti-Thy1 nephritis in rats is characterized by a severe inflammatory and mesangioproliferative response after mesangiolysis induced by the antibody. Modulation of inflammation by neural input has been studied in other organs but not in the kidney. We tested the hypothesis that the renal innervation markedly contributes to the inflammatory response of the kidney. Methods: Anti-Thy1 nephritis was induced by i.v. injection of 1 mg/kg body weight ER4 antibody to Sprague-Dawley rats. Six animals underwent bilateral renal denervation (DNX) one week prior to injection whereas 8 rats were sham operated (CON). Urine was collected for 24 hour albumin excretion 2 and 5 days after injection. Rats were sacrificed at day 6 after anti-Thy1, and the kidneys were harvested. Inflammatory and proliferative changes were investigated by immunohistochemistry and real-time RT-PCR for the mRNA encoding the cytokine TNF-α. Results: Rats suffering from anti-Thy1 nephritis exhibited albuminuria which was attenuated after DNX (64 + 6 g/24 h in CON versus -25 + 6 g/24 h, p < 0.05). Infiltration of macrophages was reduced in the interstitium (25 + 3 cells per high-power field in CON versus 13 + 3 in DNX, p < 0.05). but not in glomeruli (3.5 + 0.6 cells per glomerulus in CON versus 3.1 + 0.8 in DNX) after denervation. DNX animals exhibited less mesangiolysis (score 1.40 + 0.11 in CON versus 0.90 + 0.22 in DNX, p < 0.05) and less PCNA positive cells (12.5 + 2.4 cells/glomerulus in CON versus 7.35 + 1.95 * cells/glomerulus in DNX, * p < 0.05). In addition, TNF-α expression in the kidney was significantly inhibited in DNX animals (14.4 + 2.8 in CON versus 4.0 + 1.8 in DNX; p < 0.05). Conclusions: The presence of an intact renal innervation contributes to structural damage as well as to inflammation in the kidney in the anti-Thy1 model of glomerulonephritis in rats. [ABSTRACT FROM AUTHOR]
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- 2004
127. T-Type Ca-Channels of Mesangial Cells Cultured in High Glucose Media.
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Linz, P., Wopperer, S., Amann, K., Hilgers, K. F., and Veelken, R.
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DIABETES ,CELLS ,CALCIUM channels ,BARIUM ,NIFEDIPINE - Abstract
Objective: Mesangial cells (MC) contractility is altered in diabetes mellitus. Mesangial contraction is dependant on voltage-gated Ca-influx. In how far T-type (Cav3)--Ca-currents are involved is unknown. We tested the hypothesis that T-type (Cav3)--Ca-currents in cultured MCs are altered at different glucose levels. Methods: We used voltage-ramps in whole-cell-patches and 110mM Barium as charge carrier. Currents were distinguished from L-type-channel flux by using nifedipin and further identified with the help of mibefradil. Results: In low glucose medium (1 g/l) 5 out of 35 cells (=14%) expressed T-type-channels with randomly distributed peakcurrents ranging from -300 nA/pF to -1,600 nA/pF exhibiting an activation potential of U(akt)= -20 ± 8.8mV. In contrast, in high glucose medium (5 g/l) 5 out of 40 cells (=12%) showed very uniform T-type-currents with I(peak)= -347 ± 81 nA/pF and U(akt) = -12.8 ± 8.4 mV (mean + SD). Taking L-type-currents into account T-type-currents represented about 2% of the total inward flux. Activation potentials of L-type channels were -1 ± 8mV (low, n = 72) and -2 ± 9 mV (high, n = 70). Conclusions: These results indicate that a subpopulation of MCs exhibit T-type Ca-currents. The low activation potential of these T-type calcium channels suggests a possible role of these channels in facilitating mesangial contractility. This may be of functional importance in the presence of high glucose concentration as in diabetes when these channels exhibit a more homogenous response to stimulation. [ABSTRACT FROM AUTHOR]
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- 2004
128. I033: Results of an outcome survey in 2414 unselected patients with diabetes type 2: Effects of cilazapril on renal and cardiovascular function.
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Delles, C., Veelken, R., and Schmieder*, R.E.
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- 1999
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129. Uptake of renin by the endothelium mediates vascular angiotensin prodiction in situ.
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Hilgers, K.F., Veelken, R., Kohler, H., Müller, D.N., Botkin, S., Schmieder, R.E., and Gomez, R.A.
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- 1997
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130. 91Vascular conversion of angiotensin I in strokeprone spontaneously hypertensive and WistarKyoto rats
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Hilgers, Karl F., Veelken, R., Geiger, H., Ganten, Detlev, Luft, F. C., and Mann, Johannes F.E.
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- 1993
131. Afferent neurons of the kidney with impaired firing pattern in inflammation - role of sodium currents?
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Lale N, Ditting T, Hilgers KF, Linz P, Ott C, Schmieder RE, Schiffer M, Amann K, Veelken R, and Rodionova K
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Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as "tonic," i.e., sustained action potential (AP) firing, or "phasic," i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na
+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+ : - 969 ± 47 vs. - 758 ± 47 nA/pF, P < 0.01; K+ : 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([- 365- - 1429 nA] vs. [- 412- - 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions., (© 2023. The Author(s).)- Published
- 2023
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132. Prognostic Factors for Postoperative Bleeding Complications and Prolonged Intensive Care after Percutaneous Hepatic Chemosaturation Procedures with Melphalan.
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Struck MF, Werdehausen R, Kirsten H, Gössmann H, Veelken R, van Bömmel F, Stehr S, Denecke T, and Ebel S
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Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.
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- 2023
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133. No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats.
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Hartner A, Dambietz T, Cordasic N, Willam C, Burzlaff N, Brötsch M, Daniel C, Schiffer M, Amann K, Veelken R, Schley G, and Hilgers KF
- Abstract
Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified "preconditioning" approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hartner, Dambietz, Cordasic, Willam, Burzlaff, Brötsch, Daniel, Schiffer, Amann, Veelken, Schley and Hilgers.)
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- 2023
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134. Myocardial infarction with a preserved ejection fraction-the impaired function of the cardio-renal baroreflex.
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Pickny L, Hindermann M, Ditting T, Hilgers KF, Linz P, Ott C, Schmieder RE, Schiffer M, Amann K, Veelken R, and Rodionova K
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Introduction: In experimental myocardial infarction with reduced ejection fraction causing overt congestive heart failure, the control of renal sympathetic nerve activity (RSNA) by the cardio-renal baroreflex was impaired. The afferent vagal nerve activity under these experimental conditions had a lower frequency at saturation than that in controls. Hence, by investigating respective first neurons in the nodose ganglion (NG), we wanted to test the hypothesis that after myocardial infarction with still-preserved ejection fraction, the cardiac afferent nerve pathway is also already impaired. Material and methods: A myocardial infarction was induced by coronary artery ligature. After 21 days, nodose ganglion neurons with cardiac afferents from rats with myocardial infarction were cultured. A current clamp was used to characterize neurons as "tonic," i.e., sustained action potential (AP) firing, or "phasic," i.e., <5 APs upon current injection. Cardiac ejection fraction was measured using echocardiography; RSNA was recorded to evaluate the sensitivity of the cardiopulmonary baroreflex. Renal and cardiac histology was studied for inflammation and fibrosis markers. Results: A total of 192 neurons were investigated. In rats, after myocardial infarction, the number of neurons with a tonic response pattern increased compared to that in the controls (infarction vs. control: 78.6% vs. 48.5%; z-test, * p < 0.05), with augmented production of APs (23.7 ± 2.86 vs. 15.5 ± 1.86 APs/600 ms; mean ± SEM, t -test, * p < 0.05). The baseline activity of RSNA was subtly increased, and its control by the cardiopulmonary baroreflex was impaired following myocardial infarction: the fibrosis marker collagen I augmented in the renal interstitium. Discussion: After myocardial infarction with still-preserved ejection fraction, a complex impairment of the afferent limb of the cardio-renal baroreflex caused dysregulation of renal sympathetic nerve activity with signs of renal fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pickny, Hindermann, Ditting, Hilgers, Linz, Ott, Schmieder, Schiffer, Amann, Veelken and Rodionova.)
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- 2023
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135. The Liver Maximum Capacity Test (LiMAx) Is Associated with Short-Term Survival in Patients with Early Stage HCC Undergoing Transarterial Treatment.
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Fischer J, Wellhöner S, Ebel S, Lincke T, Böhlig A, Gerhardt F, Veelken R, Goessmann H, Steinhoff KG, Denecke T, Sabri O, Berg T, and Bömmel FV
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Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are recommended to treat patients with early or intermediate hepatocellular carcinoma (HCC). The liver maximum capacity test (LiMAx) has been supposed to predict the risk of post-interventional liver failure. We investigated the correlation of LiMAx with short-term survival as primary endpoint and the occurrence of adverse events after therapy as secondary endpoint. Our study cohort prospectively included 69 patients receiving TACE (n = 57) or TARE (n = 12). LiMAx test and serological analyses were performed on the day before and 4 weeks after treatment. Hepatic and extrahepatic complications were monitored for 4 weeks. The LiMAx results were not associated with altered liver function and the occurrence of adverse events. The survival rates of patients with BCLC A with LiMAx ≤ 150 μg/kg/h were lower after 30 days (75.0 ± 15.3% vs. 100%, p = 0.011), 90 days (62.5 ± 17.7% vs. 95.8 ± 4.1%, p = 0.011) and 180 days (50.0 ± 17.7% vs. 95.8 ± 4.1%, p = 0.001) compared to those with higher LiMAx levels. The LiMAx test is not suitable to predict liver function abnormalities or the occurrence of complications 4 weeks after therapy but enables the identification of patients with early stage HCC and reduced short-term survival after treatment.
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- 2022
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136. Analysis of patient's X-ray exposure in hepatic chemosaturation procedures: a single center experience.
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Ebel S, Reinhardt M, Beeskow AB, Teske F, Struck MF, Veelken R, van Boemmel F, Berg T, Moche M, Gutberlet M, Gößmann H, and Denecke T
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- Fluoroscopy adverse effects, Fluoroscopy methods, Humans, Radiation Dosage, X-Rays, Liver diagnostic imaging, Liver surgery
- Abstract
Background: Hepatic chemosaturation is a technique in which a high dose of the chemotherapeutic agent melphalan is administered directly into the liver while limiting systemic side effects. We reviewed our institutional experience regarding patient's X-ray exposure caused by the procedure., Methods: Fifty-five procedures, performed between 2016 and 2020 in 18 patients by three interventional radiologists (radiologist), were analyzed regarding the patient's exposure to radiation. Dose-area-product (DAP) and fluoroscopy time (FT) were correlated with the experience of the radiologist and whether the preprocedural evaluation (CS-EVA) and the procedure were performed by the same radiologist. Additionally, the impact of previous liver surgery on DAP/FT was analyzed., Results: Experienced radiologist require less DAP/FT (50 ± 18 Gy*cm
2 /13.2 ± 3.84 min vs. 69 ± 20 Gy*cm2 /15.77 ± 7.82 min; p < 0.001). Chemosaturations performed by the same radiologist who performed CS-EVA required less DAP/FT (41 ± 12 Gy*cm2 /11.46 ± 4.41 min vs. 62 ± 11 Gy*cm2 /15.55 ± 7.91 min; p < 0.001). Chemosaturations in patients with prior liver surgery with involvement of the inferior cava vein required significantly higher DAP/FT (153 ± 27 Gy*cm2 /25.43 ± 4.57 min vs. 56 ± 25 Gy*cm2 /14.44 ± 7.55 min; p < 0.001)., Conclusion: There is a significant learning curve regarding the procedure of hepatic chemosaturation. Due to dose reduction the evaluation and chemosaturation therapy should be performed by the same radiologist. Procedures in patients with previous liver surgery require higher DAP/FT., (© 2022. The Author(s).)- Published
- 2022
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137. Yttrium-90 radioembolization-induced abscopal effect on hepatocellular carcinoma.
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Steinhoff KG, Petersen TO, Purz S, Veelken R, Van Boemmel F, Denecke T, Berg T, and Sabri O
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- Humans, Radiopharmaceuticals therapeutic use, Treatment Outcome, Yttrium Radioisotopes therapeutic use, Carcinoma, Hepatocellular therapy, Embolization, Therapeutic, Liver Neoplasms therapy
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- 2022
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138. Repeated percutaneous hepatic perfusion with melphalan can maintain long-term response in patients with liver cancers.
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Veelken R, Maiwald B, Strocka S, Petersen TO, Moche M, Ebel S, Denecke T, Rehak M, Struck MF, Forstmeyer D, Rademacher S, Seehofer D, Berg T, and van Bömmel F
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- Antineoplastic Agents, Alkylating therapeutic use, Bile Ducts, Intrahepatic, Chemotherapy, Cancer, Regional Perfusion, Humans, Melphalan therapeutic use, Middle Aged, Perfusion, Retrospective Studies, Bile Duct Neoplasms diagnostic imaging, Bile Duct Neoplasms drug therapy, Carcinoma, Hepatocellular diagnostic imaging, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms diagnostic imaging, Liver Neoplasms drug therapy
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Chemosaturation (CS; CHEMOSAT®, Delcath Systems Inc.) temporarily administers melphalan into the liver by percutaneous hepatic perfusion (PHP). CS-PHP can effectively control growth in liver tumors, but efficacy and tolerability of sequential treatments are unclear. We analyzed outcomes of sequential CS-PHP treatment. Patients with either unresectable intrahepatic metastases of ocular melanoma (OM, n = 9), cholangiocarcinoma (CCA, n = 3), or hepatocellular carcinoma (HCC, n = 1) were recruited retrospectively. Response was assessed by tomography imaging. Ten patients (mean age 60 years) with more than one CS-PHP treatment were included. CS-PHP was administered 2-6 times in the OM patients, 3 times in the CCA, and the HCC patient received 6 treatments. Overall response rate (ORR) to CS-PHP was 80%, and stable disease was achieved in one patient. Median hepatic progression-free survival (hPFS) was 336 days (range 0-354) for OM, 251 days for the CCA patient, and 256 days for the HCC patient. At the end of observation (153-701 days after first CS-PHP), 6/10 patients were still alive (5/9 with OM, 0 with CCA, and 1 with HCC). Death cases were not related to CS-PHP. Adverse events were mostly hematologic, grade I-IV, and self-resolving. The liver function was not deteriorated by CS-PHP. We conclude that repeated CS-PHP treatments were effective and well tolerated in the long term., (© 2021. The Author(s).)
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- 2022
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139. A Forgotten Ureteral Stent: Potential Risks for the Urinary Function.
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Distler FA, Veelken R, Wagner A, Klein T, Huettenbrink C, and Pahernik S
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- Adult, Foreign Bodies complications, Humans, Male, Risk Assessment, Ureteral Obstruction etiology, Foreign Bodies surgery, Stents, Ureter, Ureteral Obstruction surgery, Urinary Catheters
- Abstract
A 32-year-old man presented with painless macrohaematuria. An endoscopic stone removal of the upper moiety of a left double kidney with ureter duplex was performed 4 years ago. The inserted ureteral catheter (DJ) was not removed although it was communicated to the patient and written in the discharge report. The DJ led to a large bladder stone, a total incrustation of the DJ, and a staghorn calculus of the upper moiety. Furthermore, renal function scintigraphy showed no clinically significant function of the upper moiety. Therefore, a heminephrectomy was performed with corresponding ureterectomy and sectio alta for bladder stone removal., (© 2021 S. Karger AG, Basel.)
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- 2022
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140. Renal Nerve Ablation in Nephritis and Beyond.
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Rodionova K, Ditting T, and Veelken R
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- Humans, Sympathectomy, Nephritis
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- 2021
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141. Responsiveness of afferent renal nerve units in renovascular hypertension in rats.
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Rodionova K, Hilgers KF, Rafii-Tabrizi S, Doellner J, Cordasic N, Linz P, Karl AL, Ott C, Schmieder RE, Schiffer M, Amann K, Veelken R, and Ditting T
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- Animals, Ganglia, Spinal, Glomerulonephritis classification, Glomerulonephritis pathology, Male, Rats, Rats, Sprague-Dawley, Afferent Pathways, Glomerulonephritis chemically induced, Hypertension, Renovascular physiopathology, Kidney innervation
- Abstract
Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1-4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension., (© 2021. The Author(s).)
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- 2021
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142. Percutaneous hepatic melphalan perfusion: Single center experience of procedural characteristics, hemodynamic response, complications, and postoperative recovery.
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Struck MF, Kliem P, Ebel S, Bauer A, Gössmann H, Veelken R, van Bömmel F, Dennecke T, Stehr SN, and Girrbach FF
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- Adult, Aged, Aged, 80 and over, Catheterization, Peripheral methods, Female, Fluid Therapy, Hepatic Artery surgery, Humans, Hypotension chemically induced, Hypotension therapy, Intensive Care Units, Liver blood supply, Liver pathology, Liver Neoplasms secondary, Male, Melphalan administration & dosage, Middle Aged, Norepinephrine administration & dosage, Respiration, Artificial, Retrospective Studies, Treatment Outcome, Catheterization, Peripheral adverse effects, Hypotension epidemiology, Liver Neoplasms drug therapy, Melphalan adverse effects, Perfusion methods
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Background: Percutaneous hepatic melphalan perfusion (PHMP) for the selective treatment of hepatic metastases is known to be associated with procedural hypotension and coagulation disorders. Studies on anesthetic management, perioperative course, complications, and postoperative recovery in the intensive care unit (ICU) have not been published., Methods: In a retrospective observational study, we analyzed consecutive patients who were admitted for PHMP over a 6-year period (2016-2021). Analyses included demographic, treatment, and outcome data with regard to short-term complications until ICU discharge., Results: Fifty-three PHMP procedures of 16 patients were analyzed. In all of the cases, procedure-related hypotension required the median (range) highest noradrenaline infusion rate of 0.5 (0.17-2.1) μg kg min-1 and fluid resuscitation volume of 5 (3-14) liters. Eighty-four PHMP-related complications were observed in 33 cases (62%), of which 9 cases (27%) involved grade III and IV complications. Complications included airway constriction (requiring difficult airway management), vascular catheterization issues (which resulted in the premature termination of PHMP, as well as to the postponement of PHMP and to the performance of endovascular bleeding control after PHMP), and renal failure that required hemodialysis. Discharge from the ICU was possible after one day in most cases (n = 45; 85%); however, in 12 cases (23%), prolonged mechanical ventilation was required. There were no procedure-related fatalities., Conclusions: PHMP is frequently associated with challenging cardiovascular conditions and complications that require profound anesthetic skills. For safety reasons, PHMP should only be performed in specialized centers that provide high-level hospital infrastructures and interdisciplinary expertise., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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143. Predictive performance of newer Asian hepatocellular carcinoma risk scores in treated Caucasians with chronic hepatitis B.
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Papatheodoridis GV, Dalekos GN, Idilman R, Sypsa V, Van Boemmel F, Buti M, Calleja JL, Goulis J, Manolakopoulos S, Loglio A, Papatheodoridi M, Gatselis N, Veelken R, Lopez-Gomez M, Hansen BE, Savvidou S, Kourikou A, Vlachogiannakos J, Galanis K, Yurdaydin C, Esteban R, Janssen HLA, Berg T, and Lampertico P
- Abstract
Background & Aims: Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC., Methods: We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively., Results: HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78-0.82). NPVs were always >99% (99.3-100%), whereas PPV ranged between 13% and 24%., Conclusions: In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease., Lay Summary: Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis., Competing Interests: GVP has served as advisor/lecturer for Abbvie, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Roche, and Spring Bank and has received research grants from Abbvie and Gilead. GND has served as advisor/lecturer for Abbvie, Bayer, Bristol-Myers Squibb, Gilead, Janssen, Novartis, and Roche and has received grant support from Bristol-Myers Squibb, Gilead, and Roche. VS has served as advisor/lecturer for Abbvie, Gilead, and Janssen and has received research grants from Abbvie and Gilead. FVB has served as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, Novartis, and Roche; has received research grants from Bristol-Myers Squibb, Gilead, Janssen, Roche, and Siemens; and has served as consultant for Abbvie, Gilead, and Roche. MB has served as advisor/lecturer for Abbvie, Arbutus, Bristol-Myers Squibb, Gilead, Glaxo Smith-Kleine, Merck, Roche, and Spring Bank. JLC has served as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck. JG has served as advisor/lecturer for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, and Roche and has received a research grant from Bristol-Myers Squibb. SM has served as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche and has received grants from Bristol-Myers Squibb and Gilead. AL has served as lecturer for Gilead and MYR Pharmaceuticals. JV has served as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, Novartis, and Roche. CY has served as speaker's bureau and/or advisor for AbbVie, Bristol-Myers Squibb, Gilead, Merck, and Roche and has received a research grant from Bristol-Myers Squibb. RE has served as advisor/lecturer for Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, and Novartis. HLAJ has served as consultant for and has received grants from AbbVie, Arbutus, Bristol Myers Squibb, Enyo, Gilead Sciences, Janssen, Medimmune, Merck, Roche, Vir Biotechnology Inc., and Viroclinics. TB has served as advisor/consultant/lecturer for Abbvie, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme/Merck, Novartis, Roche, and Vertex and has received research support from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme/Merck, Novartis, and Roche. PL has served as speaker’s bureau/advisor for Abbvie, Eiger, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck/ Merck Sharp & Dohme, MYR Pharma, and Roche. RI, MP, NG, RV, ML-G, BEH, SS, AK, and KG have nothing to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)
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- 2021
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144. Neurogenic substance P-influences on action potential production in afferent neurons of the kidney?
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Rodionova K, Hilgers KF, Linz P, Schätzl J, Raschke G, Ott C, Schmieder RE, Schiffer M, Amann K, Veelken R, and Ditting T
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- Animals, Cells, Cultured, Ganglia, Spinal cytology, Kidney cytology, Neurons, Afferent drug effects, Neurons, Afferent metabolism, Rats, Rats, Sprague-Dawley, Substance P metabolism, TRPV Cation Channels metabolism, Action Potentials, Kidney innervation, Neurons, Afferent physiology, Substance P pharmacology
- Abstract
We recently showed that a substance P (SP)-dependent sympatho-inhibitory mechanism via afferent renal nerves is impaired in mesangioproliferative nephritis. Therefore, we tested the hypothesis that SP released from renal afferents inhibits the action potential (AP) production in their dorsal root ganglion (DRG) neurons. Cultured DRG neurons (Th11-L2) were investigated in current clamp mode to assess AP generation during both TRPV1 stimulation by protons (pH 6) and current injections with and without exposure to SP (0.5 µmol) or CGRP (0.5 µmol). Neurons were classified as tonic (sustained AP generation) or phasic (≤ 4 APs) upon current injection; voltage clamp experiments were performed for the investigation of TRPV1-mediated inward currents due to proton stimulation. Superfusion of renal neurons with protons and SP increased the number of action potentials in tonic neurons (9.6 ± 5 APs/10 s vs. 16.9 ± 6.1 APs/10 s, P < 0.05, mean ± SD, n = 7), while current injections with SP decreased it (15.2 ± 6 APs/600 ms vs. 10.2 ± 8 APs/600 ms, P < 0.05, mean ± SD, n = 29). Addition of SP significantly reduced acid-induced TRPV1-mediated currents in renal tonic neurons (- 518 ± 743 pA due to pH 6 superfusion vs. - 82 ± 50 pA due to pH 6 with SP superfusion). In conclusion, SP increased action potential production via a TRPV1-dependent mechanism in acid-sensitive renal neurons. On the other hand, current injection in the presence of SP led to decreased action potential production. Thus, the peptide SP modulates signaling pathways in renal neurons in an unexpected manner leading to both stimulation and inhibition of renal neuronal activity in different (e.g., acidic) environmental contexts.
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- 2021
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145. AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects?
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Rodionova K, Hindermann M, Hilgers K, Ott C, Schmieder RE, Schiffer M, Amann K, Veelken R, and Ditting T
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- Angiotensin II metabolism, Animals, Arterial Pressure drug effects, Denervation, Glomerular Filtration Rate drug effects, Heart Rate drug effects, Kidney physiology, Male, Rats, Sprague-Dawley, Sodium metabolism, Water metabolism, Rats, Angiotensin II Type 1 Receptor Blockers pharmacology, Benzimidazoles pharmacology, Biphenyl Compounds pharmacology, Kidney drug effects, Kidney innervation, Tetrazoles pharmacology
- Abstract
Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX)., Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied., Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF., Conclusion: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats., (© 2021 The Author(s) Published by S. Karger AG, Basel.)
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- 2021
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146. Neurogenic tachykinin mechanisms in experimental nephritis of rats.
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Rodionova K, Hilgers KF, Paulus EM, Tiegs G, Ott C, Schmieder R, Schiffer M, Amann K, Veelken R, and Ditting T
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- Animals, Aprepitant pharmacology, Capsaicin pharmacology, Chemokines metabolism, Dendritic Cells metabolism, Kidney drug effects, Kidney metabolism, Kidney physiopathology, Macrophages metabolism, Male, Nephritis physiopathology, Neurokinin-1 Receptor Antagonists pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Neurokinin-1 metabolism, Sympathetic Nervous System drug effects, Sympathetic Nervous System physiopathology, TRPV Cation Channels agonists, TRPV Cation Channels metabolism, Nephritis metabolism, Sympathetic Nervous System metabolism, Tachykinins metabolism
- Abstract
We demonstrated earlier that renal afferent pathways combine very likely "classical" neural signal transduction to the central nervous system and a substance P (SP)-dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 ± 5.1 to 21.6 ± 1.5 mV s (*p < 0.05) in controls, a response impaired in nephritis. Suppressed RSNA transiently but completely recovered after systemic administration of a neurokinin 1 (NK1-R) blocker. NK-1 receptors occurred mainly on CD11
+ dendritic cells (DCs). An enhanced frequency of CD11c+ NK1R+ cell, NK-1 receptor+ macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c+ NK1R+ cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.- Published
- 2020
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147. Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B.
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Papatheodoridis GV, Dalekos GN, Idilman R, Sypsa V, Van Boemmel F, Buti M, Calleja JL, Goulis J, Manolakopoulos S, Loglio A, Papatheodoridi M, Gatselis N, Veelken R, Lopez-Gomez M, Hansen BE, Savvidou S, Kourikou A, Vlachogiannakos J, Galanis K, Yurdaydin C, Esteban R, Janssen HLA, Berg T, and Lampertico P
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- Antiviral Agents therapeutic use, Elasticity Imaging Techniques methods, Elasticity Imaging Techniques statistics & numerical data, Female, Follow-Up Studies, Guanine therapeutic use, Hepatitis B virus drug effects, Hepatitis B virus isolation & purification, Hepatitis B, Chronic complications, Hepatitis B, Chronic diagnosis, Hepatitis B, Chronic drug therapy, Hepatitis B, Chronic ethnology, Humans, Incidence, Liver Transplantation statistics & numerical data, Male, Middle Aged, Risk Assessment, White People statistics & numerical data, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular virology, Guanine analogs & derivatives, Liver Cirrhosis diagnostic imaging, Liver Cirrhosis etiology, Liver Cirrhosis therapy, Liver Neoplasms epidemiology, Liver Neoplasms pathology, Liver Neoplasms virology, Tenofovir therapeutic use
- Abstract
Background & Aims: A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort., Methods: We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset., Results: The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038)., Conclusion: In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF., Lay Summary: In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis., Competing Interests: Conflict of interest GV Papatheodoridis: advisor/lecturer for Abbvie, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Roche, Spring Bank; research grants Abbvie, Gilead. GN Dalekos: advisor/lecturer for Abbvie, Bayer, Bristol-Myers Squibb, Gilead, Janssen, Novartis, Roche; grant support from Bristol-Myers Squibb, Gilead, Roche. R Idilman: Nothing to declare. V Sypsa: advisor/lecturer for Abbvie, Gilead, Janssen; research grants from Abbvie, Gilead. F van Boemmel: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme, Novartis, Roche; research grants from Bristol- Myers Squibb, Gilead, Janssen, Roche, Siemens; consultant for Abbvie, Gilead, Roche. M Buti: advisor/lecturer for Abbvie, Arbutus, Bristol-Myers Squibb, Gilead, Glaxo Smith-Kleine, Merck, Roche, Spring Bank. JL Calleja: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck. J Goulis: advisor/lecturer for Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Roche; research grant from Bristol-Myers Squibb. S Manolakopoulos: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche; grants from Bristol-Myers Squibb, Gilead. A Loglio: lecturer for Gilead, MYR Pharmaceuticals. M Papatheodoridi: Nothing to declare. N Gatselis: advisor for Gilead. R Veelken: Nothing to declare. M Lopez-Gomez: Nothing to declare. BE Hansen: Nothing to declare. S Savvidou: Nothing to declare. A Kourikou: Nothing to declare. I Vlachogiannakos: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, Novartis, Roche. K Galanis: Nothing to declare. C Yurdaydin: speaker's bureau and/or advisor for AbbVie, Bristol-Myers Squibb, Gilead, Merck, Roche; research grant from Bristol-Myers Squibb. R Esteban: advisor/lecturer for Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis. HLA Janssen: consultant for and grants from AbbVie, Arbutus, Bristol-Myers Squibb, Enyo, Gilead Sciences, Janssen, Medimmune, Merck, Roche, Vir Biotechnology Inc., Viroclinics. T Berg: advisor/consultant/lecturer for Abbvie, Alexion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme/Merck, Novartis, Roche, and Vertex; Research support from Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme/Merck, Novartis and Roche. P Lampertico: speaking bureau/advisor for Abbvie, Eiger, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck/Merck Sharp & Dohme, MYR Pharma, Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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148. Central processing of afferent renal pathways-significance and implications.
- Author
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Rodionova K and Veelken R
- Subjects
- Afferent Pathways, Interleukin-1beta, Kidney, Paraventricular Hypothalamic Nucleus, Reflex
- Published
- 2020
- Full Text
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149. Afferent renal innervation in anti-Thy1.1 nephritis in rats.
- Author
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Rodionova K, Veelken R, Hilgers KF, Paulus EM, Linz P, Fischer MJM, Schenker M, Reeh P, Tiegs G, Ott C, Schmieder R, Schiffer M, Amann K, and Ditting T
- Subjects
- Afferent Pathways drug effects, Animals, Neurons drug effects, Rats, Sprague-Dawley, Substance P metabolism, Calcitonin Gene-Related Peptide pharmacology, Kidney drug effects, Nephritis drug therapy, Neurons, Afferent drug effects
- Abstract
Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm
2 ) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.- Published
- 2020
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150. NCX1 represents an ionic Na+ sensing mechanism in macrophages.
- Author
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Neubert P, Homann A, Wendelborn D, Bär AL, Krampert L, Trum M, Schröder A, Ebner S, Weichselbaum A, Schatz V, Linz P, Veelken R, Schulte-Schrepping J, Aschenbrenner AC, Quast T, Kurts C, Geisberger S, Kunzelmann K, Hammer K, Binger KJ, Titze J, Müller DN, Kolanus W, Schultze JL, Wagner S, and Jantsch J
- Subjects
- Alternative Splicing genetics, Animals, Calcium metabolism, Extracellular Space metabolism, Gene Silencing drug effects, Ion Channel Gating drug effects, Ions, Lipopolysaccharides pharmacology, Macrophages drug effects, Mice, Nitric Oxide biosynthesis, RAW 264.7 Cells, Sodium Chloride pharmacology, Macrophages metabolism, Sodium metabolism, Sodium-Calcium Exchanger metabolism
- Abstract
Inflammation and infection can trigger local tissue Na+ accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na+-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na+ sensing in MΦs remained unclear. High extracellular Na+ levels (high salt [HS]) trigger a substantial Na+ influx and Ca2+ loss. Here, we show that the Na+/Ca2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na+ influx, concomitant Ca2+ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
- Full Text
- View/download PDF
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