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Biomedical subjects

D Häussinger

Publications and source records attributed to D Häussinger.

At least 73 records · Page 4Linked to original sources
PubMed2001

Association between duplex Doppler sonographic flow pattern in right hepatic vein and various liver diseases.

PURPOSE: The aim of this study was to evaluate the association between the Doppler sonographic waveforms in the right hepatic vein and various liver diseases. METHODS: We performed Doppler sonography of the right hepatic vein in 225 individuals (189 patients with liver disease and 36 control subjects). Patients were categorized on the basis of their histologic diagnosis: cirrhosis (n = 122), fibrosis (n = 23), fatty liver disease (n = 11), metastatic liver disease (n = 8), and noncirrhotic liver disease with neither fatty infiltration nor metastases (n = 25). The waveforms of the hepatic veins were categorized as type 1, triphasic; type 2, biphasic; or type 3, flat. RESULTS: Type 1 waveforms were found in 100% of the control subjects and in patients with each of the various liver diseases, including 40% of those with cirrhosis. Type 2 waveforms were not found in control subjects or in patients with either fatty infiltration or metastatic liver disease. Type 2 waveforms were, however, found in 16% of patients with cirrhosis, 13% of patients with fibrosis, and 4% of patients with other noncirrhotic liver diseases. Type 3 waveforms were found in 43% of patients with liver cirrhosis, 13% of patients with liver fibrosis, 27% of patients with fatty liver disease, and 50% of patients with metastatic liver disease. In contrast, type 3 waveforms were not found in any control subjects or in patients with other noncirrhotic liver diseases without fatty liver or metastases. CONCLUSIONS: Type 3 waveforms in the right hepatic vein are suggestive of liver cirrhosis, although they may also occur in patients with fibrosis, fatty liver disease, or metastatic liver disease.

Adult↗
PubMed2001

Magnetic resonance imaging of bone marrow changes in Gaucher disease during enzyme replacement therapy: first German long-term results.

OBJECTIVE: Since 1991, enzyme replacement therapy (ERT) has been available for patients with Gaucher disease in Germany. The aim of this study was to analyse the MR pattern of bone marrow involvement and response to ERT in Gaucher disease type I. PATIENTS AND DESIGN: Thirty patients with Gaucher disease type I had MRI examinations prior to initiation of ERT with alglucerase/imiglucerase and during follow-up. Median MR follow-up and duration of ERT were 36 months. Coronal T1- and T2-weighted spin-echo images of the lower extremities were obtained to evaluate changes in the appearance of yellow marrow. MR images were categorized as having either a homogeneous (type A) or non-homogeneous patchy (type B) appearance of bone involvement and response to ERT was assessed by two radiologists. RESULTS: Overall, 19 of 30 patients (63%) showed an increased signal intensity on T1- and T2-weighted images after 36 months of ERT, consistent with partial reconversion of fatty marrow during treatment. Focal bone lesions surrounded by a low signal intensity (SI) rim did not respond to ERT, suggesting bone infarcts. Of the 11 patients with bone infarcts (low SI rim lesion), 82% had the non-homogeneous type B pattern (P=0.0021). In 86% of patients with splenectomy, bone infarcts were seen (P<0.05). CONCLUSIONS: MRI using T1- and T2-weighted spin-echo sequences is a valuable, non-invasive method for monitoring bone marrow response in patients receiving ERT. A non-homogeneous patchy signal intensity of bone marrow involvement correlates with the presence of bone infarcts (P=0.0021).

Adult↗
PubMed2001

Identification of osmosensitive and ammonia-regulated genes in rat astrocytes by Northern blotting and differential display reverse transcriptase-polymerase chain reaction.

BACKGROUND/AIMS: The hepatic encephalopathy (HE) is in part the result of astrocyte swelling with alterations of glial function. Detoxification of ammonia may be one mechanism by which astrocyte swelling is triggered in HE. METHODS: The differential display polymerase chain reaction (DDRT-PCR) and Northern blot analysis were used for study the functional consequence of cell volume changes and ammonia on gene expression in primary rat astrocytes. RESULTS: Differentially expressed cDNA products were identified with about 92% homology to genes coding for mouse proline rich protein expressed in brain (PRTB), rat clusterin, elongin, and human Kelch motif containing protein. As shown by Northern blot analysis, PRTB and clusterin mRNA levels were upregulated by 19-64% after 4-8 h by both ammonia and hypoosmolarity. Elongin mRNA expression increased by 97% in response to ammonia but slightly by hypoosmolarity. Further, hypoosmotic exposure for 1-24 hours but not ammonia led to an increase of 80% in KMCP mRNA levels. CONCLUSIONS: The identification of these genes offers the opportunity to identify unrecognized molecular mechanisms of HE. The finding that several genes are induced by both, hypoosmolarity and ammonia, supports the view that astrocyte swelling is a major, but not the only pathogenetic event in HE.

Ammonia↗
PubMed2001

Combination therapy of active HBsAg vaccination and interferon-alpha in interferon-alpha nonresponders with chronic hepatitis B.

Treatment with interferon-alpha leads to cessation of viral replication in 30-40% of patients with chronic hepatitis B. Preliminary data suggest that therapeutic vaccination in patients with chronic HBV infection may be beneficial. The present trial was conducted to assess the efficacy of combination therapy of interferon-alpha with HBsAg vaccination in patients who previously failed to respond to interferon-alpha alone. Eighteen patients positive for HBsAg and HBeAg were included. Mean ALT was 81+/-23 units/liter and 7 (39%) patients had HBV-DNA levels >2000 pg/ml. Patients received 5 million IU interferon-alpha 2b (Intron A) thrice weekly for six months and recombinant HBsAg (Gen H-B-Vax) at the beginning and 4 and 12 weeks after initiation of interferon therapy. No serious side effects were seen during the trial period. Loss of HBeAg was seen in 39% (7/18), HBV DNA was undetectable in 50% (9/18), and ALT was normal in 56% 10/18) of patients six months after completion of therapy. Simultaneous administration of interferon-a and HBsAg vaccination in patients previously not responding to interferon alone appears to be safe, well-tolerated, and it achieved response rates similar to or even higher than interferon in treatment naive patients. This combination therapy seems to offer a new and promising approach for patients with chronic hepatitis B virus infection.

Adult↗
PubMed2001

Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells.

BACKGROUND AND AIMS: Hepatic stellate cell (HSC) transformation and proliferation play an important role in liver fibrogenesis, and HSC apoptosis may be involved in the termination of this response. METHODS: Expression of the peripheral benzodiazepine receptor (PBR) and PBR-ligand-induced apoptosis were studied in cultured rat liver HSC. RESULTS: Transformation of HSC led to a transient expression of PBR at the messenger RNA and protein level, which was maximal after about 3 and 7 days of culture, respectively, and declined thereafter. Immunoreactive PBR showed a punctate staining and colocalized with mitochondrial manganese-dependent superoxide dismutase and adenine nucleotide translocator 1. The selective PBR ligands 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195) and 4' chlorodiazepam (Ro5-4864), but not the centrally acting benzodiazepine ligand clonazepam, induced dose-dependent apoptosis in HSC. The apoptotic potency of PK11195 paralleled the level of PBR expression. PK11195 induced dephosphorylation of protein kinase B/Akt and Bad and a downregulation of Bcl-2. Collapse of the mitochondrial membrane potential preceeded PBR-ligand-induced apoptosis. No apoptosis was induced by PK11195 in parenchymal cells, despite the presence of PBR, and PK11195 had no effect in these cells on Bad phosphorylation and Bcl-2 expression. CONCLUSIONS: Transformation of HSC leads to a transient expression of PBR and renders the cells sensitive to PBR-ligand-induced apoptosis, involving protein kinase B/Akt and Bad-dependent mechanisms.

Animals↗
PubMed2001

Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats.

BACKGROUND & AIMS: Canalicular secretion of bile acids is stimulated by tauroursodesoxycholate (TUDC). This study investigates the underlying mechanisms. METHODS: TUDC effects on mitogen-activated protein (MAP) kinases, taurocholate (TC) excretion, proteolysis, and the localization of the bile salt export pump (Bsep) were studied in rat hepatocytes and perfused liver. RESULTS: TUDC induced a transient and concentration-dependent activation of p38(MAPK) and of extracellular signal-regulated kinase 2 (Erk-2), but not of c-Jun-N-terminal kinase (JNK). In perfused liver, TUDC concentrations of 20 micromol/L was sufficient to elicit the MAP kinase responses and TC choleresis. SB 202190, a specific inhibitor of p38(MAPK), had no effect on TUDC- induced Erk activation but abolished the stimulatory effect of TUDC on TC excretion in perfused liver, indicating the requirement of p38(MAPK) in addition to the reported Erk dependence for the choleretic response. TUDC-induced stimulation of TC excretion was accompanied by a p38(MAPK)-dependent insertion of subcanalicular immunoreactive Bsep into the canalicular membrane. In addition TUDC induced a p38(MAPK)-sensitive inhibition of proteolysis. CONCLUSIONS: TUDC-induced stimulation of canalicular TC excretion involves a MAP kinase-dependent translocation of subcanalicular Bsep to the canalicular membrane. Dual activation of Erks and p38(MAPK) is required for the choleretic effect of both TUDC and hypo-osmotic cell swelling.

Animals↗
PubMed2001

Regulation of the dynamic localization of the rat Bsep gene-encoded bile salt export pump by anisoosmolarity.

Canalicular transport via the bile salt export pump (Bsep) represents the rate-controlling step in taurocholate excretion, whose capacity is under osmotic control. The short-term effects of anisoosmolarity and Ca(2+)-withdrawal on the localization of Bsep and the tight junction proteins Zo-1 and occludin were studied in perfused rat liver by immunohistochemistry, confocal microscopy, and densitometry. Under normoosmotic conditions, Bsep was found in the canalicular membrane and showed a punctate intracellular localization. Hypoosmolarity resulted in the translocation of intracellular Bsep to the canalicular membrane, whereas hyperosmolarity induced a retrieval of Bsep. Following hyperosmolar retrieval of Bsep and multidrug resistance protein 2 (Mrp2) from the canalicular membrane, in the putative intracellular vesicles Bsep and Mrp2 colocalized in 15% of these vesicles, whereas 85% stained either positive for Bsep (61%) or Mrp2 (24%). Anisotonicity had no effect on the linear staining patterns of occludin and Zo-1, indicating no increase in paracellular permeability. Omission of calcium produced cholestasis characterized by a disruption of occludin, whereas the localization of Zo-1, Bsep, and Mrp2 remained unaffected. It is concluded (1) that hyperosmolarity induces retrieval of Bsep from the canalicular membrane, which correlates to cholestasis. Hypoosmolarity leads to choleresis accompanied by a rapid recruitment of intracellular Bsep to the canalicular membrane. (2) Bsep- and Mrp2-specific vesicles participate in the short-term osmoregulation of canalicular secretion, however, a cause-effect relationship between bile salt excretion and transporter localization remains to be established. (3) Ca(2+)-depletion induces cholestasis by disruption of occludin-determined tight junctional permeability, whereas internalization of canalicular transporters play a minor role.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Protein kinase C-dependent distribution of the multidrug resistance protein 2 from the canalicular to the basolateral membrane in human HepG2 cells.

The subcellular localization of hepatobiliary transport proteins directly affects the rate of bile formation, e.g., the conjugate export pump multidrug resistance protein 2 (MRP2) is regulated on a short-term scale by retrieval from and insertion into the canalicular membrane in the liver. This study reports on the effects of protein kinase C on MRP2 localization and activity in human hepatoblastoma HepG2 cells. MRP2 was detected in HepG2 cells by immunocytochemistry and Western blot analysis. Functional activity was assessed by confocal laser scanning microscopy using fluorescent MRP2 substrates. In untreated HepG2 cells MRP2 was almost exclusively localized at the apical membrane. Treatment of HepG2 cells with phorbol-12-myristate-13-acetate (PMA) resulted in a rapid decrease of apically localized MRP2 and a loss of more than 90% of pseudocanaliculi within 4 hours. This was accompanied by a reduced pseudocanalicular secretion of the MRP2 substrate glutathione-methylfluorescein. Interestingly, PMA treatment (1-100 nmol/L) led to the appearance of immunoreactive MRP2 at the basolateral membrane within 30 minutes. This was shown by its colocalization with MRP1, human dipeptidylpeptidase IV (DPPIV), and transfected rat Ntcp. The effects of PMA on MRP2 localization were sensitive to the protein kinase C (PKC) inhibitor Gö6850 but insensitive to inhibition of MEK by PD098059. Basolateral MRP2-appearance was not inhibited by cycloheximide or by disruption of microtubules or microfilaments. In rat livers cholestasis was induced by PMA (100 nmol) and MRP2 was detected at the basolateral membrane in some areas, colocalizing with Ntcp. The data suggest that retargeting of canalicular MRP2 to the basolateral membrane due to PKC activation may represent a novel mechanism that may contribute to cholestasis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

[New methods in abdominal ultrasound: do they have a clinical value? Panoramic imaging, harmonic imaging technologies and contrast medium enhanced ultrasound].

Important improvements and technical developments in ultrasonography during the last years have been made. The aim of this article is to describe the new techniques in ultrasonography, such as SieScape, Color-SieScape, 3-D-power-Doppler, tissue harmonic imaging, second harmonic imaging, phase inversion ultrasonography and contrast media to demonstrate their clinical implications.

Abdomen↗
PubMed2001

[Gaucher disease: MR evaluation of bone marrow features during treatment with enzyme replacement].

PURPOSE: Enzyme replacement therapy (ERT) arrests and reverses the hematological and visceral symptoms of adult Gaucher disease, the most frequent lysosomal storage disorder. There are only a few studies available evaluating bone disease during ERT. The aim of this study was to investigate the features of bone marrow (bm) by magnetic resonance imaging (MRI) in these patients during ERT. MATERIALS AND METHODS: MRI was performed prospectively in thirty adult type I Gaucher patients before and during ERT with a mean follow-up of 3 years. Spin-echo sequences (T(1)/T(2)) of the lower extremities were obtained and the reconversion (response) or lack of reconversion (non-response) to fatty marrow during treatment was analyzed. The morphological features of bm involvement, a homogeneous or non-homogeneous distribution of bm changes and focal bone lesions surrounded by a rim of reduced signal intensity (SI), were analyzed. RESULTS: Infiltration of bm by Gaucher cells is characterized by a reduction of SI on both T(1)- and T(2)-weighted sequences. Bone marrow responses were seen in 19 patients (63 %) during treatment. Focal bone lesions, surrounded by a rim of reduced SI, did not respond to ERT and correlated with a non-homogenous distribution of bone involvement and splenectomy. CONCLUSION: In adult patients with type I Gaucher disease receiving ERT, treatment effects on bone disease can be demonstrated by MRI using Spin-echo sequences due to the partial reconversion of fat marrow. A non-homogeneous type of signal appearance and a status post splenectomy correlate with the presence of bone infarcts.

Adult↗
PubMed2001

Glutamine and cell signaling in liver.

In the liver, glutamine plays an important role in ammonia detoxication and the regulation of pH homeostasis ("intercellular glutamine cycle"). In addition, this amino acid regulates liver metabolism and transport by mechanisms that cannot be attributed to its metabolism. Examples include the stimulation of protein and glycogen synthesis and bile acid secretion and the inhibition of proteolysis in liver. The major trigger for such effects is an increased hepatocyte hydration due to the cumulative uptake of glutamine into the cells, which activates osmosignaling pathways involving mitogen-activated protein kinases (MAPK). Glutamine- and hypoosmolarity-induced cell swelling activates extracellular signal-regulated kinases (ERK) and p38(MAPK). Activation of these MAPK results in an increased capacity of bile acid excretion into bile due to a rapid translocation of canalicular transport ATPases from a subcanalicular storage compartment to the canalicular membrane. Similarly, glutamine augments biliary excretion of cysteinyl leukotrienes in endotoxin-treated rat livers. Also, the antiproteolytic effect of glutamine is largely due to glutamine-induced cell swelling, which activates osmosignaling pathways. Here, the glutamine-induced p38(MAPK) activation mediates the inhibition of autophagic proteolysis at the level of autophagosome formation.

Animals↗
PubMed2001

Role of p38(MAPK) in cell volume regulation of perfused rat liver.

In perfused rat liver, hypoosmotic exposure (225 mosmol/L) leads to a volume-regulatory decrease by release of K(+), Cl(-) and HCO(3)(-) through Ba(2+)-, DIDS- and quinidine-sensitive ion channels. The underlying signal transduction mechanisms, however, are unknown. As hypoosmotic hepatocyte swelling leads to a rapid activation of extracellular signal regulated kinases (Erks) and of p38(MAPK), the role of mitogen-activated protein kinases (MAPK) and PI-3-kinase in mediating the RVD in perfused rat liver was studied. The presence of the MEK inhibitor PD 098 059, which blocks the hypoosmotic activation of Erks, had no effect on the extent and time course of cell volume regulatory K(+) efflux. However, inhibitors of p38(MAPK) such as SB 203 580 and PD 169 316, but not their inactive analogue SB 202 474, significantly delayed and diminished the volume-regulatory K(+) efflux. Accordingly, in presence of these p38(MAPK) inhibitors, the hepatocytes remained in a more swollen state after completion of RVD. Inhibition of hypoosmotic Erk activation by pertussis or cholera toxin, erbstatin or genistein had no effect on RVD by hypoosmolarity. Likewise, neither inhibition of PI-3-kinase by wortmannin or LY 294 002 nor inhibition of S 6 phosphorylation by rapamycin nor protein kinase inhibition by H-7, H-89 or KT 5823 led to a significant change of RVD upon hypoosmolarity. The amount and time course of K(+) release by oxidative stress upon addition of t-BOOH or H(2)O(2) remained unaffected by inhibition of p38(MAPK) by SB 203 580, suggesting a specific inhibition of RVD-dependent K(+) release by this inhibitor. The findings suggest that swelling-induced activation of p38(MAPK), but not of Erks and PI-3-kinase, is involved in RVD in liver, whereas p38(MAPK) is apparently not involved in the net K(+) release induced by oxidative stress.

Animals↗
PubMed2001

Insulin resistance induced by loop diuretics and hyperosmolarity in perfused rat liver.

Insulin-induced cell swelling was recently suggested to reflect an independent signal for metabolic insulin effects such as inhibition of hepatic proteolysis, which is transmitted at the level of autophagosome formation via p38MAPK activation [Häussinger et al., Gastroenterology 116 (1999), 921-935]. Here, the role of insulin-induced cell swelling in the overall context of insulin signalling towards proteolysis inhibition was studied in perfused rat liver. Loop diuretics and hyperosmolarity, which impair insulin-stimulated cell swelling, strongly blunt Erk-2 and p38MAPK activation as well as proteolysis inhibition by insulin, but are without effect on insulin-induced tyrosine phosphorylation of IR-beta and IRS-1. Inhibitors of phosphatidylinositol-3-kinase (PI3-kinase) also block insulin-induced cell swelling, MAP kinase activation and proteolysis inhibition, but the antiproteolytic response to hypoosmolarity remains unaffected. We suggest that PI3-kinase-mediated cell swelling induced by insulin is required to amplify the insulin signal to MAP kinases and thus proteolysis regulation. The perturbation of insulin-induced cell swelling may be of pathophysiological relevance for the development of insulin resistance in clinical situations associated with hyperosmotic dehydration and loop diuretic treatment.

Animals↗
PubMed2001

The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription.

In this study we show that activation of p38MAPK by IL-6 acts as an inhibitory signal on IL-6-mediated activation of STAT and the alpha2-macroglobulin promoter. We analyzed the role of MKK6/p38MAPK for IL-6 signal transduction and transcriptional activation of the suppressor of cytokine signaling (SOCS) 3 promoter. Pretreatment of cells with the p38MAPK-specific inhibitor SB202190 downregulates the induction of SOCS3-mRNA expression by IL-6. Accordingly, overexpression of a constitutively active MKK6 in HepG2 cells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter reporter construct, whereas overexpression of a dominant negative mutant of MKK6 downregulated the IL-6-mediated activation of the SOCS3 promoter. These data indicate that p38MAPK-activation is crucial for IL-6-induced SOCS3 expression and downregulation of IL-6-mediated gene induction.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2001

Malaria and tourism: retrospective analysis of German malaria cases imported from the Dominican Republic.

We report on malaria acquired by German tourists to formerly non-endemic tourist resorts in the Dominican Republic between July 1999 and March 2000. Falciparum malaria is endemic in the western provinces and the hinterland of the Dominican Republic. By contrast, the risk of contracting malaria has always been considered so low in the main tourist resorts in the eastern part of the country that antimalarial chemoprophylaxis was not recommended.

Disease Outbreaks↗