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O Huber

Publications and source records attributed to O Huber.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Results of a combined adult-child liver transplantation in Switzerland].

Between July 1987 and August 1998, 173 orthotopic liver transplantations (OLT) were performed in Geneva. We studied a homogeneous group of 114 OLT performed during the 6 years between 1992 and 1997 on 107 patients (89 adults and 18 children; 7 retransplantations). Although Geneva has the largest transplantation programme in Switzerland and is the only centre performing paediatric liver transplantation, the mean number of procedures per year was 19, corresponding to only a small transplantation programme in Europe. It could be reasonably questioned, therefore, whether Swiss patients are not at a disadvantage as compared with patients from European countries with larger liver transplantation centres. Although the perioperative morbidity was still considerable, the results of this series -90% of actuarial patient survival at 1 and 2 years and 84% at 5 years-compare favourably with the results of the European Liver Transplantation Registry: 76% of actuarial patient survival at 1 year and 65% at 5 years. In this series, 95 patients (89%) were alive on January 1, 1998. As no patient was refused on the severity of the liver disease and as more than 10% of OLT were performed as emergencies, a bias due to the selection of the best cases cannot explain the good results. This series demonstrates that a small liver transplantation centre may obtain results that compare favourably with the results of large European centres, and that Swiss patients are not at a disadvantage as compared with patients of other European countries.

Adult↗
PubMed1999

Desmosomal localization of beta-catenin in the skin of plakoglobin null-mutant mice.

Plakoglobin, a protein belonging to the Armadillo-repeat gene family, is the only component that adherens junctions and desmosomes have in common. Plakoglobin null-mutant mouse embryos die because of severe heart defects and may exhibit an additional skin phenotype, depending on the genetic background. Lack of plakoglobin affects the number and structure of desmosomes, resulting in visible defects when cells are subjected to increasing mechanical stress, e.g. when embryonic blood starts circulating or during skin differentiation. By analysing plakoglobin-negative embryonic skin differentiation in more detail, we show here that, in the absence of plakoglobin, its closest homologue, beta-catenin, becomes localized to desmosomes and associated with desmoglein. This substitution may account for the relatively late appearance of the developmental defects seen in plakoglobin null-mutant embryos. beta-catenin cannot, however, fully compensate a lack of plakoglobin. In the absence of plakoglobin, there was reduced cell-cell adhesion, resulting in large intercellular spaces between keratinocytes, subcorneal acantholysis and necrosis in the granular layer of the skin. Electron microscopic analysis documented a reduced number of desmosomes, and those present lacked the inner dense plaque and had fewer keratin filaments anchored. Our analysis underlines the central role of plakoglobin for desmosomal assembly and function during embryogenesis.

Animals↗
PubMed1999

Mutations affecting transmembrane segment interactions impair adhesiveness of E-cadherin.

Lateral clustering of E-cadherin molecules is required for the adhesive properties of this cell-cell adhesion molecule. Both the extracellular domain and the cytoplasmic region of E-cadherin were previously reported to contribute to lateral clustering, but little is known about a role of the transmembrane domain in this respect. Following our previous findings indicating self-assembly of artificial transmembrane segments based on leucine residues, we asked whether the leucine-rich transmembrane segment of E-cadherin participates in lateral clustering. Here, we demonstrate that its transmembrane domain self-assembles as analyzed using the ToxR reporter system. Certain point mutations within the transmembrane domain markedly reduced self-assembly. To study whether the same point mutations also affect E-cadherin-mediated adhesion in vivo, wild-type and mutant E-cadherin cDNAs were transfected into Ltk(-) cells. Indeed, cell aggregation assays revealed significantly reduced adhesiveness when mutations had been introduced which disrupted transmembrane segment interaction. In control experiments, cell-surface expression, interaction with catenins and the cytoskeleton as well as trypsin-resistance of the protein were unaffected. These data suggest that interactions between the transmembrane segments are important for the lateral association of E-cadherin molecules required for cell-cell adhesion.

Amino Acid Sequence↗
PubMed1999

E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation.

Beta-catenin is a multifunctional protein found in three cell compartments: the plasma membrane, the cytoplasm and the nucleus. The cell has developed elaborate ways of regulating the level and localization of beta-catenin to assure its specific function in each compartment. One aspect of this regulation is inherent in the structural organization of beta-catenin itself; most of its protein-interacting motifs overlap so that interaction with one partner can block binding of another at the same time. Using recombinant proteins, we found that E-cadherin and lymphocyte-enhancer factor-1 (LEF-1) form mutually exclusive complexes with beta-catenin; the association of beta-catenin with LEF-1 was competed out by the E-cadherin cytoplasmic domain. Similarly, LEF-1 and adenomatous polyposis coli (APC) formed separate, mutually exclusive complexes with beta-catenin. In Wnt-1-transfected C57MG cells, free beta-catenin accumulated and was able to associate with LEF-1. The absence of E-cadherin in E-cadherin-/- embryonic stem (ES) cells also led to an accumulation of free beta-catenin and its association with LEF-1, thereby mimicking Wnt signaling. beta-catenin/LEF-1-mediated transactivation in these cells was antagonized by transient expression of wild-type E-cadherin, but not of E-cadherin lacking the beta-catenin binding site. The potent ability of E-cadherin to recruit beta-catenin to the cell membrane and prevent its nuclear localization and transactivation was also demonstrated using SW480 colon carcinoma cells.

Adenomatous Polyposis Coli Protein↗
PubMed1998

Pontin52, an interaction partner of beta-catenin, binds to the TATA box binding protein.

beta-catenin, the vertebrate homolog of the Drosophila Armadillo protein, has been shown to have dual cellular functions, as a component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. At Wnt signaling, beta-catenin becomes stabilized in the cytoplasm and subsequently available for interaction with transcription factors of the lymphocyte enhancer factor-1/T-cell factor family, resulting in a nuclear localization of beta-catenin. Although beta-catenin does not bind DNA directly, its carboxyl- and amino-terminal regions exhibit a transactivating activity still not well understood molecularly. Here we report the identification of an interaction partner of beta-catenin, a nuclear protein designated Pontin52. Pontin52 binds beta-catenin in the region of Armadillo repeats 2-5 and, more importantly, also binds the TATA box binding protein. We provide evidence for an in vivo multiprotein complex composed of Pontin52, beta-catenin, and lymphocyte enhancer factor-1/T-cell factor. Our results suggest involvement of Pontin52 in the nuclear function of beta-catenin.

Amino Acid Sequence↗
PubMed1998

[Importance of endoscopic hemostasis in peptic ulcer hemorrhage in a teaching hospital].

INTRODUCTION: The results of endoscopic treatment for bleeding peptic ulcers in a teaching hospital are little reported. Most studies are published by a limited number of specialized authors with a reported success rate of 76-83%. The aim of this study is to evaluate the success rate in a teaching hospital. PATIENTS AND METHOD: We retrospectively studied 150 patients hospitalized in our service between 1994 and 1995. They comprised 59 females (median age 80.5 [24-93] years) and 91 males (median age 61.5 [26-98]). 49% were aged 70 or over. 39 patients (29%) had a past history of peptic ulcer disease, the others being admitted for an initial episode of bleeding ulcer. Biopsies for urease test were obtained in 84 patients. In this group the prevalence of Helicobacter pylori infection was respectively 88% and 58% in subjects with a history of ulcer disease and in those with an initial episode of bleeding ulcer. 46% and 54% respectively had taken nonsteroidal anti-inflammatory drugs during the previous weeks. Neither of these two risk factors was present in 9 patients without a previous history of ulcer disease; they were present in none of those with a history. RESULTS: All patients underwent emergency esogastroduodenoscopy; 48 underwent endoscopic hemostasis. 12 gastroenterologists were involved in these procedures. The definitive success rate is 81%. The success rate for a first hemostasis for a posterior bulbar ulcer is 41% vs 88% for the other localizations, a difference which is statistically significant (p = 0.002). Endoscopic hemostasis showed a higher failure rate where the bleeding stigmata was a spurting vessel (44% vs 18%) but this was not significant (p = 0.18). CONCLUSION: Endoscopic treatment for bleeding peptic ulcer is effective in a teaching hospital. The technique shows a higher failure rate for posterior bulbar ulcers. In view of the risk of recurrence, patients should be kept in hospital after a first procedure.

Adult↗
PubMed1998

Prospective randomized comparison of imipenem-cilastatin and piperacillin-tazobactam in nosocomial pneumonia or peritonitis.

Nosocomial pneumonia and acute peritonitis may be caused by a wide array of pathogens, and combination therapy is often recommended. We have previously shown that imipenem-cilastatin monotherapy was as efficacious as the combination of imipenem-cilastatin plus netilmicin in these two settings. The efficacy of imipenem-cilastatin is now compared to that of piperacillin-tazobactam as monotherapy in patients with nosocomial pneumonia or acute peritonitis. Three hundred seventy one patients with nosocomial pneumonia or peritonitis were randomly assigned to receive either imipenem-cilastatin (0.5 g four times a day) or piperacillin-tazobactam (4.5 g three times a day). Three hundred thirteen were assessable (154 with nosocomial pneumonia and 159 with peritonitis). For nosocomial pneumonia, clinical-failure rates in the piperacillin-tazobactam group (13 of 75 [17%]) and in the imipenem-cilastatin group (23 of 79 [29%]) were similar (P = 0.09), as were the numbers of deaths due to infection (6 in the imipenem-cilastatin group [8%], 7 in the piperacillin-tazobactam group [9%]) (P = 0.78). For acute peritonitis, clinical success rates were comparable (piperacillin-tazobactam, 72 of 76 [95%]; imipenem-cilastatin, 77 of 83 [93%]). For infections due to Pseudomonas aeruginosa, 45 patients had nosocomial pneumonia (21 in the piperacillin-tazobactam group and 24 in the imipenem-cilastatin group) and 10 had peritonitis (5 in each group). In the patients with nosocomial pneumonia, clinical failure was less frequent in the piperacillin-tazobactam group (2 of 21 [10%]) than in the imipenem-cilastatin [corrected] group (12 of 24 [50%]) (P = 0.004). Bacterial resistance to allocated regimen was the main cause of clinical failure (1 in the piperacillin-tazobactam group and 12 in the imipenem-cilastatin group). For the patients with peritonitis, no difference in clinical outcome was observed (five of five cured in each group). The overall frequencies of adverse events related to treatment in the two groups were similar (24 in the piperacillin-tazobactam group, 22 in the imipenem-cilastatin group). Diarrhea was significantly more frequent in the piperacillin-tazobactam group (10 of 24) than in the imipenem-cilastatin group (2 of 22). This study suggests that piperacillin-tazobactam monotherapy is at least as effective and safe as imipenem-cilastatin monotherapy in the treatment of nosocomial pneumonia or peritonitis. In P. aeruginosa pneumonia, piperacillin-tazobactam achieved a better clinical efficacy than imipenem-cilastatin, due to reduced development of microbiological resistance. Tolerance was comparable, with the exception of diarrhea, which was more frequent with piperacillin-tazobactam.

Acute Disease↗
PubMed1997

An alpha-E-catenin gene trap mutation defines its function in preimplantation development.

Catenins are proteins associated with the cytoplasmic domain of cadherins, a family of transmembrane cell adhesion molecules. The cadherin-catenin adhesion system is involved in morphogenesis during development and in the maintenance of the integrity of different tissue types. Using a gene trap strategy, we have isolated a mouse mutation for the gene encoding the alpha-E-catenin. This form of the alpha-catenin appears frequently coexpressed with E-cadherin in epithelial cell types. The mutation obtained eliminates the carboxyl-terminal third of the protein but nevertheless provokes a complete loss-of-function phenotype. Homozygous mutants show disruption of the trophoblast epithelium (the first differentiated embryonic tissue), and development is consequently blocked at the blastocyst stage. This phenotype parallels the defects observed in E-cadherin mutant embryos. Our results show the requirement of the alpha-E-catenin carboxy terminus for its function and represent evidence of the role of the alpha-E-catenin in vivo, identifying this molecule as the natural partner of the E-cadherin in trophoblast epithelium.

Animals↗
PubMed1997

A specific domain in alpha-catenin mediates binding to beta-catenin or plakoglobin.

The E-cadherin-catenin adhesion complex has been the subject of many structural and functional studies because of its importance in development, normal tissue function and carcinogenesis. It is well established that the cytoplasmic domain of E-cadherin binds either beta-catenin or plakoglobin, which both can assemble alpha-catenin into the complex. Recently we have identified an alpha-catenin binding site in beta-catenin and plakoglobin and postulated, based on sequence analysis, that these protein-protein interactions are mediated by a hydrophobic interaction mechanism. Here we have now identified the reciprocal complementary binding site in alpha-catenin which mediates its interaction with beta-catenin and plakoglobin. Using in vitro association assays with C-terminal truncations of alpha-catenin expressed as recombinant fusion proteins, we found that the N-terminal 146 amino acids are required for this interaction. We then identified a peptide of 27 amino acids within this sequence (amino acid positions 117-143) which is necessary and sufficient to bind beta-catenin or plakoglobin. As shown by mutational analysis, hydrophobic amino acids within this binding site are important for the interaction. The results described here, together with our previous work, give strong support for the idea that these proteins associate by hydrophobic interactions of two alpha-helices.

Animals↗
PubMed1997

[Conservative treatment of gastroduodenal peptic ulcer perforations: indications and results].

Surgery is the conventional form of treatment for perforated peptic ulcer. Conservative treatment has however been described, and is still used in rare situations. The present study analyzes the indications and results of conservative therapy in our hospital. Between 1978 and 1995, 332 patients were admitted for perforated peptic ulcer. Twelve (3.5%), with a mean age of 85 (67-93) years, underwent conservative treatment (gastric suction, H2-blockers and broad-spectrum antibiotics). The diagnosis was established on the basis of epigastric pain and the finding of a pleuriperitoneum on the plain film of the abdomen. The indication for conservative treatment was a prohibitive anesthesiological risk in 11 patients and absence of peritoneal sign in one. The evolution was favourable only in 4 patients, who were discharged after a median stay of 18 days. Mortality was 8/12 patients. In one of these, autopsy showed ischemic colonic perforation. Conservative treatment of perforated peptic ulcer is associated with very high mortality. The results suggest that frequent and careful clinical monitoring is essential during the first 24 hours. In the event of deterioration, surgery must be reconsidered. In addition, the diagnosis should be confirmed by ruling out perforation of another abdominal organ.

Aged↗
PubMed1997

[Orthotopic liver transplantation for familial Portuguese amyloidosis].

Type I familial amyloid polyneuropathy (FAP), or Andrade's disease, is an inherited autosomal dominant disease, always fatal, involving mixed progressive polyneuropathy associated with systemic amyloid deposits. The disease is secondary to mutations of a gene (located on chromosome 18) which encodes for a serum protein, transthyretin. This variant protein is essentially (> 90%) produced in the liver and constitutes the biological marker of the disease. Many surgical teams have established a liver transplantation program for this non-cirrhotic pathology. Between January and August 1994, we performed three orthotopic liver transplantations (OLT) in patients with FAP. The patients were men aged between 30 and 33 years and the mean duration of symptoms was 3 years. The diagnosis of FAP was confirmed by rectal biopsy and detection of the genetic mutation (PCR analysis). All patients presented a severe sensory, motor and autonomic neuropathy with major digestive and urologic dysfunction. Two other patients were not accepted for OLT because of advanced disease with ulcerous lesions of the inferior limbs and cardiopathy. All patients survived with excellent post-operative hepatic function. One month after OLT, one patient had hepatocellular rejection which responded favorably to steroids. Another patient developed post-transfusional B hepatitis 10 months after the graft, but without major hepatic lesions. In the three cases, we observed stabilization of the peripheral neuropathy and an objective improvement of the autonomic affection (neurogenic bladder, diarrhea). The patients who did not undergo transplantation died within a year. Thus, in patients suffering from familial amyloid polyneuropathy OLT must be performed, especially in the early stage of the disease and especially in young patients before serious neurological complications set in.

Amyloid Neuropathies↗
PubMed1996

Embryonic heart and skin defects in mice lacking plakoglobin.

Plakoglobin is the only component common to both the desmosomal plaque and the cadherin-catenin cell adhesion complex in the adherens junction. It is highly homologous to vertebrate beta-catenin and to Drosophila armadillo protein and may-like these proteins-be also involved in signaling pathways. To analyze the role of plakoglobin during mouse development we inactivated the plakoglobin gene by homologous recombination in embryonic stem cells and generated transgenic mice. Plakoglobin null-mutant embryos died from Embryonic Day 10.5 onward, due to severe heart defects. Some mutant embryos developed further, especially on a C57BL/6 genetic background, and died around birth, presumably due to cardiac dysfunction, and with skin blistering and subcorneal acantholysis. Ultrastructural analysis revealed that here desmosomes were greatly reduced in number and structurally altered. Thus, using reversed genetics we demonstrate that plakoglobin is an essential structural component for desmosome function. The skin phenotype in plakoglobin-deficient mice is reminiscent of the human blistering disease, epidermolytic hyperkeratosis.

Animals↗