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Matthias Mueller

Publications and source records attributed to Matthias Mueller.

13 recordsLinked to original sources
PubMed2006

Differential regulation of glucocorticoid synthesis in murine intestinal epithelial versus adrenocortical cell lines.

Glucocorticoids are steroid hormones with important functions in development, immune regulation, and glucose metabolism. The adrenal glands are the predominant source of glucocorticoids; however, there is increasing evidence for extraadrenal glucocorticoid synthesis in thymus, brain, skin, and vascular endothelium. We recently identified intestinal epithelial cells as an important source of glucocorticoids, which regulate the activation of local intestinal immune cells. The molecular regulation of intestinal glucocorticoid synthesis is currently unexplored. In this study we investigated the transcriptional regulation of the steroidogenic enzymes P450 side-chain cleavage enzyme and 11beta-hydroxylase, and the production of corticosterone in the murine intestinal epithelial cell line mICcl2 and compared it with that in the adrenocortical cell line Y1. Surprisingly, we observed a reciprocal stimulation pattern in these two cell lines. Elevation of intracellular cAMP induced the expression of steroidogenic enzymes in Y1 cells, whereas it inhibited steroidogenesis in mICcl2 cells. In contrast, phorbol ester induced steroidogenic enzymes in intestinal epithelial cells, which was synergistically enhanced upon transfection of cells with the nuclear receptors steroidogenic factor-1 (NR5A1) and liver receptor homolog-1 (NR5A2). Finally, we observed that basal and liver receptor homolog-1/phorbol ester-induced expression of steroidogenic enzymes in mICcl2 cells was inhibited by the antagonistic nuclear receptor small heterodimer partner. We conclude that the molecular basis of glucocorticoid synthesis in intestinal epithelial cells is distinct from that in adrenal cells, most likely representing an adaptation to the local environment and different requirements.

Adrenal Cortex↗
PubMed2006

The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine.

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis.

Adrenal Glands↗
PubMed2006

2D-GRAPPA-operator for faster 3D parallel MRI.

When using parallel MRI (pMRI) methods in combination with three-dimensional (3D) imaging, it is beneficial to subsample the k-space along both phase-encoding directions because one can then take advantage of coil sensitivity variations along two spatial dimensions. This results in an improved reconstruction quality and therefore allows greater scan time reductions as compared to subsampling along one dimension. In this work we present a new approach based on the generalized autocalibrating partially parallel acquisitions (GRAPPA) technique that allows Fourier-domain reconstructions of data sets that are subsampled along two dimensions. The method works by splitting the 2D reconstruction process into two separate 1D reconstructions. This approach is compared with an extension of the conventional GRAPPA method that directly regenerates missing data points of a 2D subsampled k-space by performing a linear combination of acquired data points. In this paper we describe the theoretical background and present computer simulations and in vivo experiments.

Adult↗
PubMed2006

Autocalibrated coil sensitivity estimation for parallel imaging.

Parallel imaging has proven to be a robust solution to the problem of acquisition speed in MRI. These methods are based on extracting spatial information from an array of multiple surface coils in order to speed up image acquisition. One of the most essential elements of any parallel imaging method is the information describing the coil sensitivity distribution throughout the sample. This paper covers some of the advanced methods to obtain coil sensitivity-related information, focusing particularly on the class of methods referred to as autocalibrating. These methods all acquire the data for coil sensitivity estimation directly before, during or directly after the reduced data acquisition. After a review of standard methods for coil sensitivity estimation, some of the basic and advanced autocalibrating methods are reviewed, and some example applications shown.

Algorithms↗
PubMed2006

Transplantation in truncus arteriosus combined with interrupted aortic arch.

We present the case of an infant with truncus arteriosus combined with a dysplastic truncal valve not amenable to repair and interrupted aortic arch. Due to the disappointing results of truncal valve replacement we decided to perform cardiac transplantation. The infant survived transplantation and was discharged 4 weeks after surgery.

Aorta, Thoracic↗
PubMed2005

Parallel magnetic resonance imaging using the GRAPPA operator formalism.

In this article it is shown that GRAPPA reconstruction can be reformulated as a matrix operator, similar to ladder or propagator operators used in quantum mechanics, that shifts data in k-space. Using this formalism, it is shown that there exists an infinitesimal GRAPPA operator that shifts data in k-space by arbitrarily small amounts. Other desired k-space shifts can then be accomplished through repeated applications of this infinitesimal GRAPPA operator. Implications of these ideas are described.

Algorithms↗
PubMed2004

High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib.

Imatinib, a specific inhibitor of the Abl, Kit and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is effective in all phases of chronic myelogenous leukemia. While responses in chronic phase are usually durable, resistance frequently develops in patients with advanced disease after an initial response. Several mechanisms of resistance have been demonstrated in vivo, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene. We analyzed cytogenetics and screened for mutations of the BCR-ABL kinase domain as well as the activation loops of KIT and PDGFRA and B in 49 patients with CML or Ph-positive acute lymphoblastic leukemia with resistance to imatinib. Mutations in the kinase domain of BCR-ABL were detected in 51.6% of patients with secondary resistance but not in patients with primary resistance. Three of these mutations have not been described before (T315D, F359D and D276G). By contrast, KIT and PDGFRA and B were consistently wildtype. Clonal evolution prior to imatinib was present in 68.8% of patients with primary resistance and in 45.5% with secondary resistance. Additional cytogenetic aberrations developed in 18.2% of patients at the time of relapse. Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of KIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Benzamides↗
PubMed2004

SMASH, SENSE, PILS, GRAPPA: how to choose the optimal method.

Fast imaging methods and the availability of required hardware for magnetic resonance tomography (MRT) have significantly reduced acquisition times from about an hour down to several minutes or seconds. With this development over the last 20 years, magnetic resonance imaging (MRI) has become one of the most important instruments in clinical diagnosis. In recent years, the greatest progress in further increasing imaging speed has been the development of parallel MRI (pMRI). Within the last 3 years, parallel imaging methods have become commercially available, and therefore are now available for a broad clinical use. The basic feature of pMRI is a scan time reduction, applicable to nearly any available MRI method, while maintaining the contrast behavior without requiring higher gradient system performance. Because of its faster image acquisition, pMRI can in some cases even significantly improve image quality. In the last 10 years of pMRI development, several different pMRI reconstruction methods have been set up which partially differ in their philosophy, in the mode of reconstruction as well in their advantages and drawbacks with regard to a successful image reconstruction. In this review, a brief overview is given on the advantages and disadvantages of present pMRI methods in clinical applications, and examples from different daily clinical applications are shown.

Artifacts↗
PubMed2004

Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development.

The mammalian target of rapamycin (mTOR) is a key component of a signaling pathway which integrates inputs from nutrients and growth factors to regulate cell growth. Recent studies demonstrated that mice harboring an ethylnitrosourea-induced mutation in the gene encoding mTOR die at embryonic day 12.5 (E12.5). However, others have shown that the treatment of E4.5 blastocysts with rapamycin blocks trophoblast outgrowth, suggesting that the absence of mTOR should lead to embryonic lethality at an earlier stage. To resolve this discrepancy, we set out to disrupt the mTOR gene and analyze the outcome in both heterozygous and homozygous settings. Heterozygous mTOR (mTOR(+/-)) mice do not display any overt phenotype, although mouse embryonic fibroblasts derived from these mice show a 50% reduction in mTOR protein levels and phosphorylation of S6 kinase 1 T389, a site whose phosphorylation is directly mediated by mTOR. However, S6 phosphorylation, raptor levels, cell size, and cell cycle transit times are not diminished in these cells. In contrast to the situation in mTOR(+/-) mice, embryonic development of homozygous mTOR(-/-) mice appears to be arrested at E5.5; such embryos are severely runted and display an aberrant developmental phenotype. The ability of these embryos to implant corresponds to a limited level of trophoblast outgrowth in vitro, reflecting a maternal mRNA contribution, which has been shown to persist during preimplantation development. Moreover, mTOR(-/-) embryos display a lesion in inner cell mass proliferation, consistent with the inability to establish embryonic stem cells from mTOR(-/-) embryos.

Alleles↗
PubMed2004

S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway.

Activation of 40S ribosomal protein S6 kinases (S6Ks) is mediated by anabolic signals triggered by hormones, growth factors, and nutrients. Stimulation by any of these agents is inhibited by the bacterial macrolide rapamycin, which binds to and inactivates the mammalian target of rapamycin, an S6K kinase. In mammals, two genes encoding homologous S6Ks, S6K1 and S6K2, have been identified. Here we show that mice deficient for S6K1 or S6K2 are born at the expected Mendelian ratio. Compared to wild-type mice, S6K1(-/-) mice are significantly smaller, whereas S6K2(-/-) mice tend to be slightly larger. However, mice lacking both genes showed a sharp reduction in viability due to perinatal lethality. Analysis of S6 phosphorylation in the cytoplasm and nucleoli of cells derived from the distinct S6K genotypes suggests that both kinases are required for full S6 phosphorylation but that S6K2 may be more prevalent in contributing to this response. Despite the impairment of S6 phosphorylation in cells from S6K1(-/-)/S6K2(-/-) mice, cell cycle progression and the translation of 5'-terminal oligopyrimidine mRNAs were still modulated by mitogens in a rapamycin-dependent manner. Thus, the absence of S6K1 and S6K2 profoundly impairs animal viability but does not seem to affect the proliferative responses of these cell types. Unexpectedly, in S6K1(-/-)/S6K2(-/-) cells, S6 phosphorylation persisted at serines 235 and 236, the first two sites phosphorylated in response to mitogens. In these cells, as well as in rapamycin-treated wild-type, S6K1(-/-), and S6K2(-/-) cells, this step was catalyzed by a mitogen-activated protein kinase (MAPK)-dependent kinase, most likely p90rsk. These data reveal a redundancy between the S6K and the MAPK pathways in mediating early S6 phosphorylation in response to mitogens.

Animals↗
PubMed2003

Refractoriness and conduction interaction during modulation of non-ischemic ventricular fibrillation by flecainide.

PURPOSE: To study refractoriness and conduction interaction during modulation of non-ischemic ventricular fibrillation (VF) by flecainide. METHODS: Isolated feline and rabbit hearts were used. (a) In the feline hearts (n = 8), electrophysiological parameters were measured before and after flecainide administration (0.6, 1.2 x 10(-6) M). During pacing the parameters were: epicardial conduction time, refractoriness and 1:1 pacing/response capture. During 8 min of electrically-induced tachyarrhythmias they included heart rate and normalized entropy reflecting the degree of organization. (b) In rabbit hearts (n = 4), three-dimensional mapping was performed before and after flecainide administration (2 x 10(-6) M). To follow changes in organization, local RR-intervals and differences in activation time between adjacent epicardial electrodes were measured immediately and 80 sec after VF induction. RESULTS: In feline hearts with flecainide, fibrillation was more difficult to induce, more frequently terminated spontaneously and was slower and more organized; conduction time was markedly lengthened, and refractoriness less than 1:1 capture, was moderately prolonged. An inverse correlation was observed between arrhythmia properties, rate and organization, and changes in refractoriness and conduction time. In rabbit, the number of wave fronts was reduced, RR-intervals were prolonged but at the same time activation time differences between adjacent electrodes were smaller following flecainide administration. CONCLUSIONS: It is suggested that flecainide modulation of VF properties is associated with conduction suppression and refractoriness prolongation, which act in a synergistic, additive way.

Animals↗
PubMed2002

Stenting of the arterial duct and banding of the pulmonary arteries: basis for combined Norwood stage I and II repair in hypoplastic left heart.

BACKGROUND: Outcome of patients with hypoplastic left heart (HLH) is mainly influenced by the successful first-step palliation according to the Norwood procedure. An alternative approach is heart transplantation (HTX). The feasibility of ductal stenting in newborns with duct-dependent systemic blood flow and bilateral pulmonary artery banding has been reported. But it remains to be elucidated whether this approach allows a new strategy for patients with HLH. METHODS AND RESULTS: In patients with various forms of HLH (n=11) and prostaglandin E-1 administration, ductal stenting was performed with balloon expandable Jo stents or Saxx stents. Bilateral pulmonary artery banding was surgically accomplished 1 to 3 days after the transcatheter procedure. Unrestricted blood flow through the interatrial septum was secured by balloon dilatation atrial septotomy, as required. Interventional procedures were performed with no mortality. Stent and ductal patency were achieved for up to 331 days. Two patients underwent HTX, and 8 patients had a palliative 1-stage procedure with reconstruction of the aortic arch and bidirectional cavopulmonary connection at the age of 3.5 to 6 months. There were 2 deaths. One patient with preoperative right heart failure died after the reconstructive surgery, and 1 patient died 4 months after ductal stenting and bilateral banding awaiting HTX. CONCLUSIONS: The present study is the first clinical trial showing that stenting the duct followed by bilateral pulmonary artery banding in newborns with HLH allows the combination of neoaortic reconstruction, which is part of first-stage palliation of HLH, with the establishment of a bidirectional cavopulmonary connection. Additionally, it allows the chance for HTX after extended waiting periods.

Alprostadil↗