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Biomedical subjects

Christoph Richter

Publications and source records attributed to Christoph Richter.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of alcohol withdrawal syndrome with a combination of tiapride/carbamazepine: results of a pooled analysis in 540 patients.

This was a retrospective study to examine the efficacy, practicability and medical safety of a combination of tiapride and unretarded (fast acting formula) carbamazepine in the treatment of alcohol withdrawal syndrome. In five hospitals using this combination for treatment of alcohol withdrawal, 540 patients who had been treated with this combination were identified. An intensive evaluation of patients files and charts was performed. Details of alcohol history and comorbid disorders were extracted from patient files. Severity of alcohol withdrawal had been assessed using the CIWA-A-Score. Gender differences and differences between patients in their first and at least second withdrawal were computed by means of variance analyses (GLM). At baseline (day 1) mean dosage given was 796 for tiapride and 543 mg for carbamazepine. A pooled analysis of the results showed that, in general, medication was well tolerated. Withdrawal symptomatology as indicated by CIWA-A scores clearly decreased over time. Although a significant number of patients had a history of alcohol withdrawal delirium (103) and epileptic seizures (151), few patients suffered from them during treatment (8 and 5, respectively). Only 24 (4.4%) patients dropped out because of lack of efficacy or change of medication, 15 (2.8%) because of side effects. No case of malignant neuroleptic syndrome was recorded. Data analysis showed gender differences and differences between patients in their first and at least second withdrawal for side effects, complications, and in some CIWA-A-scores. In general, severe complications of withdrawal syndrome were more frequent in men compared to women and in patients with repeated inpatient treatment. In line with previous research, the results from this study give further evidence that a combination of the anticonvulsant carbamazepine and tiapride is an effective and safe treatment for alcohol withdrawal treatment.

Adult↗
PubMed2006

p38 MAP kinase drives the expression of mast cell-derived IL-9 via activation of the transcription factor GATA-1.

Mast cells are able to produce a huge panel of mediators including the Th2-type cytokine IL-9, which is considered to be a key mediator for the pathogenesis of allergic asthma, but detailed information on the regulation of IL-9 transcription in mast cells has been scarce. Herein we provide evidence that the erythroid/myeloid transcription factor GATA-1, which is not expressed in Th2 cells, is a potent activator of IL-9 expression in murine bone marrow-derived mast cells (BMMC). Furthermore, in mast cells, but not in Th2 cells, production of IL-9 is sensitive to inhibition of p38 MAP kinase. As transactivation mediated by GATA-1 is also sensitive to inhibition of p38 MAP kinase, and GATA-1 is a target for p38 MAP kinase-mediated phosphorylation in vitro, we conclude that both signaling molecules represent a part of a mast cell-specific signaling network that regulates the expression of IL-9.

Animals↗
PubMed2005

NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells.

The phenotype of NFATc2(-/-) c3(-/-) (double knockout [DKO]) mice implies a disturbed regulation of T cell responses, evidenced by massive lymphadenopathy, splenomegaly, and autoaggressive phenomena. The population of CD4(+) CD25(+) T cells from DKO mice lacks regulatory capacity, except a small subpopulation that highly expresses glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) and CD25. However, neither wild-type nor DKO CD4(+) CD25(+) regulatory T cells (T reg cells) are able to suppress proliferation of DKO CD4(+) CD25(-) T helper cells. Therefore, combined NFATc2/c3 deficiency is compatible with the development of CD4(+) CD25(+) T reg cells but renders conventional CD4(+) T cells unresponsive to suppression, underlining the importance of NFAT proteins for sustaining T cell homeostasis.

Animals↗
PubMed2004

Menadione induces a low conductance state of the mitochondrial inner membrane sensitive to bongkrekic acid.

When rat liver mitochondria are allowed to cycle Ca(2+) and are incubated in the presence of the pro-oxidant menadione, they undergo swelling, membrane potential (DeltaPsi) collapse, and ion release. These effects, which are inhibited by cyclosporin A (CsA), are fully consistent with the opening of the so-called permeability transition pore. However, when Ca(2+) cycling is abolished by EGTA, the mitochondria remain energized (DeltaPsi collapse and swelling are avoided), but Ca(2+) efflux, promoted by the chelating agent, is stimulated by menadione. This stimulation goes together with the release of Mg(2+), K(+), and adenine nucleotides (AdN) and is inhibited by bongkrekic acid (BKA). The effect of menadione is also characterized by biphasic NAD(P)H oxidation which becomes monophasic in the presence of BKA, CsA, or EGTA and by the oxidation of thiol groups not restrained by the above-mentioned inhibitors. These results suggest that BKA acts indirectly by preserving in the matrix a critical amount of AdN without modifying the monophasic oxidation of pyridine nucleotides by menadione. A critical number of thiol groups also seems to be involved in the phenomenon. Their oxidation most probably causes a conformational change on adenine nucleotide translocase with the opening of the "low-conductance state" of the mitochondrial permeability transition, resulting in ion permeability without DeltaPsi disruption and mitochondrial swelling.

Animals↗
PubMed2004

Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of Th2 cells.

CD25+ T regulatory (Treg) cells play a central role regarding the maintenance of peripheral tolerance via suppression of autoaggressive CD4+ T cells, CD8+ T cells, and Th1 cells. In this study we demonstrate that CD25+ Treg cells can also suppress the differentiation of murine conventional CD4+ T cells toward Th2 cells in a contact-dependent manner. However, the cytokine production and proliferation of established Th2 cells could not be inhibited by freshly isolated CD25+ Treg cells, whereas a strong inhibition of differentiated Th2 cells by in vitro preactivated CD25+ Treg cells could be observed. Inhibition of both conventional CD4+ T cells and Th2 cells is accompanied by a strong enhancement of the expression of FoxP3 in the suppressed T cells. Hence, our study indicates that CD25+ Treg cells have a therapeutic potential for Th2-mediated diseases and suggests a novel mechanism of suppression mediated by the transcriptional repressor FoxP3.

Animals↗
PubMed2004

Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells.

Down-regulation of autoreactive T cell responses in vivo includes cell-contact-dependent as well as contact-independent mechanisms. Infectious tolerance is a contact-dependent mechanism used by naturally occurring CD25(+) T regulatory cells (Tregs) to confer suppressive activity upon conventional CD4(+) T cells thereby generating secondary T helper suppressor cells(Th(sup)), which inhibit T cell activation via soluble mediators. Here, we describe two distinct subsets of human Tregs, characterized by expression of either the alpha(4)beta(7) integrin or the alpha(4)beta(1) integrin. Upon activation, both subsets show an enhanced expression of FoxP3, recently described as a key transcription factor of murine Tregs. In addition, both are able to convey suppressive capacity to conventional CD4(+) T cells. However, the properties of Treg subsets are rather distinct: alpha(4)beta(7) (+)Tregs induce IL-10-producing Th(sup) (Tr1-like), whereas alpha(4)beta(1) (+) Tregs induce TGF-beta-producing Th(sup) (Th3-like). Our findings reconcile conflicting results by clearly demonstrating that suppression through naturally occurring CD25(+) Tregs is primary cell-contact-dependent but is subsequently followed by cell-contact-independent T cell inhibition mediated by second-generation Tr1- and Th3-like Th(sup) via the soluble factors IL-10 and TGF-beta.

Humans↗
PubMed2004

Fibrinolysis of acute peripheral arterial occlusion with tenecteplase--a new weight-optimized treatment regimen.

Peripheral arterial occlusions are associated with high morbidity. Thrombolysis has become established as effective treatment in clinical practice. Tenecteplase is a new thrombolytic agent that offers advantages over existing drugs with respect to mechanism of action and adverse effects. This case report describes successful thrombolysis of an acute thromboembolic brachial artery subtotal occlusion in a 76-year-old woman. In contrast to previously published data, tenecteplase was administered in a weight-adapted dose regimen over six hours, with application of one-fourth of the dose usually given in patients with myocardial infarction. Tenecteplase was immediately effective, and proved safe and well tolerated.

Aged↗
PubMed2004

Tenecteplase for the treatment of massive and submassive pulmonary embolism.

BACKGROUND: Data on thrombolytic therapy disclose benefits from thrombolytic therapy in patients with massive and submassive pulmonary embolism (PE). Previously published case reports have described the successful use of tenecteplase under these conditions. METHODS: Four patients with massive and submassive PE received a weight-optimized dosing regimen of tenecteplase, administered as an intravenous bolus. RESULTS: All patients experienced clinically relevant improvement of dyspnea following thrombus regression. Regression of right ventricular enlargement was documented in three cases. Tenecteplase was well tolerated and did not cause bleeding complications. Thirty-day mortality was zero. CONCLUSIONS: These data support the use of this new thrombolytic agent in patients with massive and submassive PE; however, sufficiently powered, randomized trials have not yet taken place for these indications.

Aged↗
PubMed2004

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure.

BACKGROUND: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). OBJECTIVE: To evaluate the effect of lower doses of tezosentan in patients with AHF. SUBJECTS AND METHODS: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. RESULTS: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. CONCLUSIONS: In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

Aged↗
PubMed2003

Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB.

We have recently demonstrated that relaxin (RLX) acts as compensatory mediator in human heart failure. RLX inhibits the stimulation of endothelin-1, the most potent vasoconstrictor in heart failure. Upregulation of the endothelin type-B receptor (ET(B)), which mediates endothelin-1 clearance and endothelial release of NO, represents a pivotal mode of RLX action. However, signal transduction and abundance of this phenomenon are unknown. Therefore, we investigated RLX-induced regulation of ET(B) in human umbilical vein endothelial, epithelial (HeLa), and vascular smooth muscle cells. In human umbilical vein endothelial cells and HeLa cells, but not in human vascular smooth muscle cells, RLX upregulated ET(B) expression and activated extracellular signal-regulated kinase-1/2 (ERK-1/2) and nuclear factor-kappaB (NF-kappaB), a transcription factor. PD-98059, a selective inhibitor of the mitogen-activated protein kinase kinase-1 (MEK-1)-ERK-1/2 pathway, abolished ERK-1/2 and NF-kappaB activation and ET(B) upregulation. NF-kappaB inhibition also prevented RLX-mediated ET(B) stimulation. In NF-kappaB-luciferase reporter assays, we demonstrated complete inhibition of RLX-induced NF-kappaB activation in cells transfected with dominant-negative Raf-1, MEK-1, or ERK-1/2 constructs, whereas dominant-negative Ras had no effect. In rat aorta and mesenteric artery, RLX pretreatment, in an ET(B)-dependent fashion, mitigated the maximum contractile response to endothelin-1, by 38+/-4% and 43+/-6%, and the endothelin-1 sensitivity (-log[EC(50)]: aorta, 8.2+/-0.2 for vehicle versus 7.2+/-0.2 for RLX; mesenteric artery, 8.0+/-0.2 for vehicle versus 7.1+/-0.1 for RLX). RLX pretreatment augmented the dilator effect of the ET(B) agonist endothelin-3 by 100+/-8% and 133+/-13%. In conclusion, RLX stimulates endothelial and epithelial ET(B) via a Ras-independent Raf-1-MEK-1-ERK-1/2 pathway that activates NF-kappaB. On vascular smooth muscle cells, ET(B), a contributor to endothelin-mediated vasoconstriction, remains unaffected. This renders RLX a functional endothelin-1 antagonist.

Animals↗
PubMed2003

The streptococcal exotoxin streptolysin O activates mast cells to produce tumor necrosis factor alpha by p38 mitogen-activated protein kinase- and protein kinase C-dependent pathways.

Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-alpha). Mast cell-derived TNF-alpha plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF-alpha peaked approximately 4 h after stimulation with SLO. Production of TNF-alpha was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-alpha. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-alpha. However, hyperstimulation of mast cells might also lead to overproduction of TNF-alpha, which would then promote the development of toxic streptococcal syndromes.

Animals↗
PubMed2003

Singlet-oxygen generation from A2E.

Singlet-oxygen generation was measured in solutions containing equilibrium mixtures of the retinal lipofuscins, 2-[2, 6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 1E,3E,5E,7Eoctatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) and double bond isomer of A2E (iso-A2E), using steady-state irradiation and using cholesterol as a singlet-oxygen trap. The amount of singlet oxygen generated by equilibrium mixtures of A2E and iso-A2E was compared with that generated by tetraphenylporphine (TPP) under the same conditions. Studies were carried out in ethanol-d6, acetone-d6, 80% cyclohexane-d(12)-20% acetone-d6 (vol/vol) and hexafluorobenzene. Using 420 nm irradiation and assuming a singlet-oxygen quantum yield of 0.60 +/- 0.12 for TPP, the singlet-oxygen quantum yields were 0.8 +/- 0.3 x 10(-3), 1.2 +/- 0.4 x 10(-3), 2 +/- 1 x 10(-3) and 4 + 1 x 10(-3), respectively. In acetone-d6, the quantum yields were smaller at longer wavelengths, with values of 0.3 +/- 0.1 x 10(-3) and 0.4 +/- 0.2 x 10(-3) at 461 and 493 nm, respectively. Singlet-oxygen generation was greatest in solvents with the lowest dielectric constants. In view of the relatively small quantum yields, the contribution of singlet-oxygen generation to the phototoxic properties of A2E and of iso-A2E will require further study.

Aging↗
PubMed2002

Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure.

The peptide urotensin-II (U-II) has been described as most potent vasoconstrictor identified so far, but plasma values in humans and its role in cardiovascular pathophysiology are unknown. We investigated circulating urotensin-II and its potential role in human congestive heart failure (CHF). We enrolled control individuals (n=13; cardiac index [CI], 3.5+/-0.1 l/min/m2; pulmonary wedge pressure [PCWP], 10+/-1 mm Hg), patients with moderate (n=10; CI, 2.9+/-0.3 l/min/m2; PCWP, 14+/-2 mm Hg) and severe CHF (n=11; CI, 1.8+/-0.2 l/min/m2; PCWP, 33+/-2 mm Hg). Plasma levels of urotensin-II differed neither between controls, patients with moderate and severe CHF nor between different sites of measurement (pulmonary artery, left ventricle, coronary sinus, antecubital vein) within the single groups. Hemodynamic improvement by vasodilator therapy in severe CHF (CI, +78+/-3%; PCWP, -55+/-3%) did not affect circulating U-II over 24 h. Preprourotensin-II mRNA expression in right atria, left ventricles, mammary arteries and saphenous veins did not differ between controls with normal heart function and patients with end-stage CHF. In conclusion, urotensin-II plasma levels and its myocardial and vascular gene expression are unchanged in human CHF. Circulating urotensin-II does not respond to acute hemodynamic improvement. These findings suggest that urotensin-II does not play a major role in human CHF.

Adult↗
PubMed2002

Inactivation of NADP(+)-dependent isocitrate dehydrogenase by nitric oxide.

Recently, we demonstrated that the control of cytosolic and mitochondrial redox balance and oxidative damage is one of the primary functions of NADP(+)-dependent isocitrate dehydrogenase (ICDH) through to supply NADPH for antioxidant systems. NO donors such as S-nitrosothiols, diethylamine NONOate, spermine NONOate, and 3-morpholinosydnomine N-ethylcarbamide (SIN-1)/superoxide dismutase inactivated ICDH in a dose- and time-dependent manner. The inhibition of ICDH by S-nitrosothiol was partially reversed by thiol, such as dithiothreitol or 2-mercaptoethanol. Loss of enzyme activity was associated with the depletion of the cysteine-reactive 5,5'-dithiobis-(2-nitrobenzoate) and the loss of fluorescent probe N,N'-dimethyl-N(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethyleneamine accessible thiol groups. Using electrospray ionization mass spectrometry with tryptic digestion of protein, we found that nitric oxide forms S-nitrosothiol adducts on Cys305 and Cys387. These results indicate that S-nitrosylation of cysteine residues on ICDH is a mechanism involving the inactivation of ICDH by NO. The structural alterations of modified enzyme were indicated by the changes in protease susceptibility and intrinsic tryptophan fluorescence. When U937 cells were incubated with 200 microM SNAP for 1 h, a significant decrease in both cytosolic and mitochondrial ICDH activities were observed. Furthermore, stimulation with lipopolysaccharide significantly decreased intracellular ICDH activity in RAW 264.7 cells, and this effect was blocked by NO synthase inhibitor N(omega)-methyl-L-arginine. This result indicates that ICDH was also inactivated by endogenous NO. The NO-mediated damage to ICDH may result in the perturbation of cellular antioxidant defense mechanisms and subsequently lead to a pro-oxidant condition.

Animals↗
PubMed2002

Lens epithelial cell apoptosis and intracellular Ca2+ increase in the presence of xanthurenic acid.

BACKGROUND: Xanthurenic acid is an endogenous product of tryptophan degradation by indoleamine 2,3-dioxygenase (IDO). We have previously reported that IDO is present in mammalian lenses, and xanthurenic acid is accumulated in the lenses with aging. Here, we studied the involvement of xanthurenic acid in the human lens epithelial cell physiology. METHODS: Human lens epithelial cells primary cultures were used. Control cells, and cells in the presence of xanthurenic acid grow in the dark. Western blot analysis and immunofluorescence studies were performed. RESULTS: In the presence of xanthurenic acid human lens epithelial cells undergo apoptosis-like cell death. In the control cells gelsolin stained the perinuclear region, whereas in the presence of 10 microM xanthurenic acid gelsolin is translocated to the cytoskeleton, but does not lead to cytoskeleton breakdown. In the same condition caspase-3 activation, and DNA fragmentation was observed. At low (5 to 10 microM) of xanthurenic acid concentration, the elongation of the cytoskeleton was associated with migration of mitochondria and cytochrome c release. At higher concentrations xanthurenic acid (20 microM and 40 microM) damaged mitochondria were observed in the perinuclear region, and nuclear DNA cleavage was observed. We observed an induction of calpain Lp 82 and an increase of free Ca2+ in the cells in a xanthurenic acid concentration-dependent manner. CONCLUSIONS: The results show that xanthurenic acid accumulation in human lens epithelial cells disturbs the normal cell physiology and leads to a cascade of pathological events. Xanthurenic acid induces calpain Lp82 and caspases in the cells growing in the dark and can be involved in senile cataract development.

Apoptosis↗
PubMed2002

Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro.

Friedreich ataxia is an inherited disorder caused by decreased expression of frataxin protein. Increasing evidence suggests that this protein might detoxify reactive oxygen species (ROS) by an unknown mechanism. Here we demonstrate that transgenic overexpression of human frataxin increases cellular antioxidant defense via activation of glutathione peroxidase and elevation of reduced thiols, thereby reducing the incidence of malignant transformation induced by ROS, as observed by soft agar assays and tumour formation in nude mice. These findings expand the understanding of antioxidant properties of frataxin, and tentatively suggest a role in the early induction of cancer.

3T3 Cells↗