Biomedical subjects

F Horn

Publications and source records attributed to F Horn.

At least 19 recordsLinked to original sources

PubMed2006

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription.

BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IkappaB family protein that is involved in transcriptional regulation of a number of NF-kappaB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-kappaB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

B-Cell Lymphoma 3 Protein↗

PubMed2006

[Healthy optic discs with large cups--a diagnostic challenge in glaucoma].

BACKGROUND: Healthy optic discs with large cups are often characterised to be glaucomatous in automated, morphometric analysis. The aim of this study was to investigate the variables of laser scanning tomography (LST) and nerve fibre polarimetry of these disks in comparison to small and normal sized disks. METHODS: 117 eyes (age 49.3 +/- 14.6 years) with healthy, non-atrophic disks (md = 0.8 dB, Tensio 14.3 +/- 2.5 mmHg) of the Erlangen Glaucoma Registry were clinically examined. Morphometry was performed both by planimetry and the HRT I (Heidelberg Engineering, Dossenheim, version 2.01) and with the GDx FCC (Laser Diagnostics, San Diego). 63 eyes initially referred for a large cup were compared to 54 normal eyes. All measurements were analysed globally and in four sectors according to Jonas. RESULTS: The disc area of discs with large cups was significantly larger than that for the normals (3.1 +/- 5.3 vs. 2.2 +/- 4.2 mm (2)). Both the multivariate analysis of the HRT and the GDx revealed a significant correlation with total disk area (R = 0.34, p = 0.0001), with a high percentage of false positive glaucoma eyes among large disks. Cup area and volume showed, in contrast to rim volume and rim area, a significant correlation (R = 0.76, p = 0.0001) with the disc size. Thickness of retinal nerve fibre layer measurements both in HRT and GDx showed higher values for larger disc size with steeper cup measurements. The vertical diameter of the cup increased in comparison to the horizontal to a higher extent with increasing disc size. CONCLUSIONS: By the pronounced enlargement of cup measurements, decreasing nerve fibre thickness values and decreasing ratio of temporal-to-inferior width of the neuroretinal rim, large disks may easily be detected as false glaucomatous by morphometric analysis systems. A better presentation of large discs in a normative database and integration of sectors and disc area in a multivariate analysis may improve the diagnostic abilities of automated morphometric disk analysis.

Diagnosis, Differential↗

PubMed2005

STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis.

Classical Hodgkin lymphoma (cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the biology of cHL, the transforming events remain to be elucidated. Recently, we demonstrated that the Janus kinase inhibitor AG490 blocked cellular proliferation and STAT3 phosphorylation in cHL. To explore the potential of constitutively activated STAT3 as a drug target and its role in cHL pathogenesis, different cHL cell lines were analyzed. Treatment of cHL cells by the protein tyrosine kinase inhibitor AG17 was associated with inhibition of cellular proliferation and cell cycle arrest. AG17 treatment was accompanied by decreased levels of STAT3 phosphorylation, whereas NF-kappaB and p38/SAPK2 signaling were not inhibited. Incubation with AG17 or AG490 sensitized cHL cells to CD95/Fas/Apo-1 or staurosporine-mediated apoptosis. Coincubation of tyrphostins with staurosporine was accompanied by rapid complete inhibition of STAT3 phosphorylation. RNA interference directed against STAT3 in L428 and L1236 cHL cells demonstrated that STAT3 is essential for cell proliferation of these cHL cells. In conclusion, these findings support the concept that STAT3 signaling is important in the pathogenesis of cHL and tyrphostins are agents for developing new therapeutic strategies.

Apoptosis↗

PubMed2004

[Exchange amnioinfusion in conceptus with laparoschisis (first experience)].

OBJECTIVE: During amnioinfusion exchange (AE) a certain amount of amniotic fluid is repeatedly extracted and the same amount of physiological solution is consequently instilled into the amniotic fetal cavity. The aim of this procedure is to dilute the amniotic fluid that surrounds the eviscerated organs of fetuses with laparoschisis so as to avoid the genesis of fibrous coating on these organs. DESIGN: Prospective study. SETTING: Gynekologicko-pôrodnícka klinika SZU, FNsP akad. L. Dérera, Bratislava, Slovakia. METHODS: We have executed AE in five fetuses with laparoschisis since June 2002. Two patients underwent the treatment 2 times during the 32nd and 36th weeks of gestation. Two other patients were treated once during the 32nd week and one patient once during the 36th week. Under ultrasound control we used a spinal needle to extract 120-180 ml of dense, cloudy amniotic fluid. Consequently, we instilled the same amount of physiological solution warmed up to the temperature of 37 degrees C into the amniotic cavity through antibacterial filter. The fetuses were monitored cardiotocographically and with the help of ultrasound flowmetry in umbilical vessels, before and after the treatment. RESULTS: The AE were successful and without complications in all five cases. All patients delivered via elective caesarean section during the 36th - 37th gestation week. One patient delivered 24 hours after second AE due to the danger of intrauterine fetal hypoxia that was verified cardiotocographically. The other patients delivered 1-4 weeks after AE. CONCLUSION: The significance of AE lies primarily in the reduction of the occurrence of fibrous coating on eviscerated organs. It enables postnatal primary surgical closure of the defect in the front abdominal wall, an earlier onset of intestine peristalsis, transition from parenteral to peroral nutrition and shorter hospitalization.

Amniotic Fluid↗

PubMed2003

A Boophilus microplus vitellin-degrading cysteine endopeptidase.

Here we describe the purification and characterization of a vitellin (VT) degrading cysteine endopeptidase (VTDCE) from eggs of the hard tick Boophilus microplus. A homogeneous enzyme preparation was obtained by chromatographic fractionation on ion-exchange and gel filtration columns and an autolysis step. This step consisted of incubation of a semipurified enzyme (after the first ion-exchange chromatography) at pH 4.0 that dissociated the enzyme from VT, to which VTDCE is naturally tightly associated. The enzyme purity was confirmed by capillary and native gel electrophoresis, and SDS-PAGE suggested the enzyme is a dimer of 17 and 22 kDa. VTDCE was active upon several synthetic substrates, with a preference for a hydrophobic or a basic residue in P1, and a hydrophobic residue in P2. VTDCE also hydrolysed haemoglobin, albumin, gelatin and vitellin. VTDCE is inactive in the absence of DTT and was totally inhibited by E-64, indicating it is a cysteine endopeptidase. Our results suggest that VTDCE is a major enzyme involved in yolk processing during B. microplus embryogenesis.

Animals↗

PubMed2003

IGFs, basic FGF, and glucose modulate proliferation and apoptosis induced by IFNgamma but not by IL-1beta in rat INS-1E beta-cells.

We investigated the effects of glucose and beta-cell growth factors (IGF-I, IGF-II, bFGF) on growth and apoptosis in the presence and absence of apoptosis inducing cytokines (IFNgamma, Il-1beta, TNFalpha). Rat INS-1E beta-cell viability was measured by WST-1 viability assay and cell counting, apoptosis by FACS analysis of annexin-V-FITC and fluorescein-dUTP (TUNEL-staining)-positive cells. Glucose alone maintained INS-1E beta-cell viability at high physiological concentrations (6.2-12.5 mmol/l), addition of IGF-II alone or in combination with bFGF further increased these glucose effects. The cytokines IFNg and IL-1beta, but not TNFalpha strongly induced INS-1E beta-cell apoptosis. Interestingly, glucose alone induced apoptosis at extremely low or very high concentrations. In combination with IFNg, low glucose (1.6 mmol/l) increased apoptosis by 25.6% (1SD 5.0%) and high glucose (50 mmol/l) by 22.8% (1SD 2.8%) compared to 12.5 mmol/l glucose. In contrast, glucose failed to modulate IL-1beta-induced apoptosis. Most importantly, IGF-II and bFGF inhibited apoptosis induced by IFNg, but not by IL-1beta. Therefore, IGF signaling, supported by bFGF and optimal glucose levels, maintains beta-cell viability in vitro. Cytokines IFNg and IL-1beta differentially interfere with intracellular signaling cascades stimulated by IGFs and bFGF or glucose, respectively.

Animals↗

PubMed2002

[Maffucci's syndrome--case report of a 5-year-old female patient].

Maffucci's syndrome is a congenital non-hereditary syndrome characterized by a combination of dyschondroplasia (enchondromatosis) and haemangiomatosis. It is a rare disease. During the last 140 years only 200 cases were described [5]. 109 cases are described in the literature by other authors [21]. This disease is associated with a high risk of development of neoplastic processes, in particular sarcomatous transformation of enchondromatoses as well as other mesodermal and non-mesodermal malignities [13]. Based on the incidence of spinocellular haemangioendothelioma with other congenital syndromes, the presence at a young age of patients and the multicentric incidence support the assumption that spinocellular haemangioendothelioma may be the manifestation of genetically based mesodermal disease which may be associated with the picture of Maffucci's syndrome [6]. In their case-history the authors present a 5-year-old patient. They describe the clinical course and findings taking into account possible manifestations and risks associated with the disease. With regard to the low incidence of the disease and its interdisciplinary character the authors pen the question of possible causal, symptomatic or palliative treatment.

Child, Preschool↗

PubMed2002

[A pediatrician's views on the treatment of extensive hemangiomas in childhood].

Haemangiomas are the most frequent tumours of child age. They are found in 10-12% of infants. The authors summarize contemporary knowledge of the treatment of haemangiomas as well as their own experience with their treatment. They follow-up 18 children with haemangiomas at different sites, incl. ten with extensive haemangiomas. The latter were treated conservatively with prednisone and interferon alpha.

Angiogenesis Inhibitors↗

PubMed2001

A completely foreign receptor can mediate an interferon-gamma-like response.

A tripartite receptor comprising the external region of the erythropoietin (Epo) receptor, the transmembrane and JAK-binding domains of the gp130 subunit of the interleukin-6 (IL-6) receptor, and a seven amino acid STAT1 recruitment motif (Y440) from the interferon (IFN)-gamma receptor, efficiently mediates an IFN-gamma-like response. An analogous completely foreign chimeric receptor in which the Y440 motif is replaced with the Y905 motif from gp130 also mediates an IFN-gamma-like response, but less efficiently. The IFNGR1 signal-transducing subunit of the IFN-gamma receptor is tyrosine phosphorylated through the chimeric receptors and the endogenous IL-6 and OSM receptors. Cross phosphorylation of IFNGR1 is not, however, required for the IFN-gamma-like response through the chimeric receptors, nor does it mediate an IFN-gamma-like response to IL-6 or OSM. The data argue strongly for modular JAK/STAT signalling and against any rigid structural organization for the "pathways" involved. They emphasize the likely high degree of overlap between the signals generated from disparate JAK-receptor complexes and show that relatively minor changes in such complexes can profoundly affect the response.

DNA-Binding Proteins↗

PubMed2001

Collecting and harvesting biological data: the GPCRDB and NucleaRDB information systems.

The amount of genomic and proteomic data that is entered each day into databases and the experimental literature is outstripping the ability of experimental scientists to keep pace. While generic databases derived from automated curation efforts are useful, most biological scientists tend to focus on a class or family of molecules and their biological impact. Consequently, there is a need for molecular class-specific or other specialized databases. Such databases collect and organize data around a single topic or class of molecules. If curated well, such systems are extremely useful as they allow experimental scientists to obtain a large portion of the available data most relevant to their needs from a single source. We are involved in the development of two such databases with substantial pharmacological relevance. These are the GPCRDB and NucleaRDB information systems, which collect and disseminate data related to G protein-coupled receptors and intra-nuclear hormone receptors, respectively. The GPCRDB was a pilot project aimed at building a generic molecular class-specific database capable of dealing with highly heterogeneous data. A first version of the GPCRDB project has been completed and it is routinely used by thousands of scientists. The NucleaRDB was started recently as an application of the concept for the generalization of this technology. The GPCRDB is available via the WWW at http://www.gpcr.org/7tm/ and the NucleaRDB at http://www.receptors.org/NR/.

Binding, Competitive↗

PubMed2001

The adenovirus type 5 E1B-55K oncoprotein actively shuttles in virus-infected cells, whereas transport of E4orf6 is mediated by a CRM1-independent mechanism.

The E1B-55K and E4orf6 proteins of adenovirus type 5 are involved in viral mRNA export. Here we demonstrate that adenovirus infection does not inhibit the function of the E1B-55K nuclear export signal and that E1B-55K also shuttles in infected cells. Even during virus infection, E1B-55K was exported by the leptomycin B-sensitive CRM1 pathway, whereas E4orf6 transport appeared to be mediated by an alternative mechanism. Our results strengthen the potential role of E1B-55K as the "driving force" for adenoviral late mRNA export.

Adenovirus E1B Proteins↗

PubMed2001

[Diastematomyelia and the tethered spinal cord syndrome. Case report].

The authors present a patient with diastematomyelia and associated congenital malformations of the spinal cord. They caused tethering of the spinal cord. Patient had cutaneous marks of malformation from birth. The congenital malformation was operated at the age 5 years. MRI and surgical findings confirm the existence of diastematomyelia together with thick tethered filum terminale and lipoma of filum terminale. On surgery the bony septum was removed, the filum terminale was resected and the lipoma was excised. Each of the anomalies caused the tethering of the spinal cord and restricted its physiological ascent. Only careful surgical revision with subsequent removal of all causes of the tethering of the spinal cord produced good result. Diastematomyelia is a congenital malformation with some morphological variations and coexistence of other malformations. The presented case is a typical example of malformations associated with diastematomyelia.

Cauda Equina↗

PubMed2001

[Supracondylar fractures of the humerus and disorders of circulation].

Supracondylar fractures (SF) of the humerus are the third most common type of fractures in childhood. The highest rate of pulselessness fracture of the distal humerus is the extension-type. The aim of our treatment is to minimize potential complications. Our management of pulselessness supracondylar fracture is more aggressive compared with other dpts. 223 (100%) patients with SF were treated at the dpt. of Paediatric Surgery, University Children's Hospital in Bratislava, in the 5-year period of (1995-1999). 11 (4.93%) patients remained pulseless after reposition of bone fragments. These patients underwent surgical revision of the brachial artery. Spasms of the brachial artery (BA) occurred in six patients, a lesion of BA in three patients and thrombosis of BA in two patients. We performed revision of the brachial artery by a Fogarthy catheter in six patients--in four cases with thrombectomy. In two cases we released the vessel from bone fragments. In two patients was replaced the injured segment of the brachial artery by a venous allotransplant. Peroperative angiography was performed in six patients. We reoperated three patients with early postoperative complications. We did not record any case of Volkmann's contracture.

Brachial Artery↗

PubMed2000

Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.

LAP/C/EBPbeta is a member of the C/EBP family of transcription factors and contributes to the regulation of the acute phase response in hepatocytes. Here we show that IL-6 controls LAP/C/EBPbeta gene transcription and identify an IL-6 responsive element in the LAP/C/EBPbeta promoter, which contains no STAT3 DNA binding motif. However, luciferase reporter gene assays showed that STAT3 activation through the gp130 signal transducer molecule is involved in mediating IL-6-dependent LAP/C/EBPbeta transcription. Southwestern analysis indicated that IL-6 induces binding of a 68-kDa protein to the recently characterized CRE-like elements in the LAP/C/EBPbeta promoter. Transfection experiments using promoter constructs with mutated CRE-like elements revealed that these sites confer IL-6 responsiveness. Further analysis using STAT1/STAT3 chimeras identified specific domains of the protein that are required for the IL-6-dependent increase in LAP/C/EBPbeta gene transcription. Overexpression of the amino-terminal domain of STAT3 blocked the IL-6-mediated response, suggesting that the STAT3 amino terminus has an important function in IL-6-mediated transcription of the LAP/C/EBPbeta gene. These data lead to a model of how tethering STAT3 to a DNA-bound complex contributes to IL-6-dependent LAP/C/EBPbeta gene transcription. Our analysis describes a new mechanism by which STAT3 controls gene transcription and which has direct implication for the acute phase response in liver cells.

Animals↗

PubMed2000

Receptors coupling to G proteins: is there a signal behind the sequence?

Upon the binding of their ligands, G protein-coupled receptors couple to the heterotrimeric G proteins to transduce a signal. One receptor family may couple to a single G protein subtype and another family to several ones. Is there a signal in the receptor sequence that can give an indication of the G protein subtype selectivity? We used a sequence analysis method on biogenic amine and adenosine receptors and concluded that a weak signal can be detected in receptor families where specialization for coupling to a given G protein occurred during a recent divergent evolutionary process. Proteins 2000;41:448-459.

Algorithms↗

PubMed2000

Boophilus microplus anticoagulant protein: an antithrombin inhibitor isolated from the cattle tick saliva.

An anticoagulant was isolated from saliva of the cattle tick Boophilus microplus. Crude saliva prolonged both recalcification time and prothrombin time in assays with bovine plasma. It also inhibited thrombin, but not fXa, amidolytic activity. We purified the antithrombin activity by a combination of gel filtration, anion exchange, and affinity chromatography. The purified inhibitor has a molecular weight of 60,000 Da, determined by SDS-PAGE. The anticoagulant IC50 varied from 100 nM to 1.1 microM, depending on the thrombin concentration and substrate used (fibrinogen or platelet receptor). The excess of inhibitor in relation to thrombin indicates that it is not a tight-binding inhibitor. Chromogenic assays using a panel of five serine-proteinases suggest that the inhibitor is specific against thrombin.

Acari↗

PubMed2000

Interleukin-6 signal transduction and lymphocyte function.

Interleukin-6 (IL-6) is a pleiotropic cytokine that acts on a wide variety of cell types. It has important regulatory functions in the immune system, is a mediator of the acute-phase response, and is involved in the regulation of differentiation, proliferation, and survival of target cells. A major signal transduction pathway for IL-6 involves activation of JAK kinases and the transcription factor Stat3. In addition, a great many of other signalling pathways are induced. Stat3 has been shown to be a central player of IL-6 signalling in many systems whereas the functions of most other IL-6-activated pathways are not yet understood. In this review, we discuss the current knowledge on IL-6 functions in the immune system, IL-6 signal transduction, and its significance for lymphocyte function.

Animals↗

PubMed2000

[Monitoring of morphometric changes of optic discs with morphologic progression of glaucomatous optic atrophy by means of laser scanner tomography].

AIM: Aim of this study was to measure morphometric changes in optic discs with laser-scanning tomography (HRT, Heidelberg-Retina-Tomograph, Heidelberg) in eyes with early glaucomatous morphologic progression. PATIENTS AND METHODS: 61 eyes of 36 patients with marked neuroretinal rim loss or its early morphologic signs (1. optic disc hemorrhages, 2. reduced visibility of the retinal nerve fiber layer (RNF), 3. appearance of narrowing of retinal vessels, 4. enlargement of the choroidal, parapapillary atrophy) were compared to 74 normal eyes of 39 probands. 15 degrees stereographs of the optic discs were evaluated for morphologic changes. The morphometric variables of the neuroretinal rim and excavation measured by the HRT were examined in the course of the disease. RESULTS: In the group of normals no significant changes of the neuroretinal rim in the course of 2.0 +/- 1.2 years were found. In the group of glaucomatous eyes (3.0 +/- 1.5 years follow-up) 34 eyes showed marked neuroretinal rim loss, 17 disc hemorrhages, 4 vessel narrowing, 3 an increased chorioidal atrophy, 3 a decreased visibility of the retinal nerve fiber layer. In these eyes a significant loss of rim area (p = 0.01) and an increase of excavation area (p = 0.0001) and volume (p = 0.003) was measured by the HRT. Only three eyes showed a perimetric loss of sensitivity (0.8-3.4 db) in Octopus static perimetry. CONCLUSIONS: Laser-scanning tomography of the optic disc seems to be able to measure morphometric changes in eyes with morphologic progression of glaucomatous optic atrophy, even before perimetric changes occur.

Adult↗