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F Vogel

Publications and source records attributed to F Vogel.

At least 19 recordsLinked to original sources
PubMed2000

Effects of hydrogen peroxide scavenger Catalase on villous microcirculation in the rat small intestine in a model of inflammatory bowel disease.

This study was conducted to quantify the effect of systemic Catalase, a hydrogen peroxide scavenger, on villous microcirculation in the inflamed small intestine of the rat. Intestinal inflammation was induced with s.c. application of Indomethacin. Intravital fluorescence microscopy and FITC-labeled erythrocytes were used to quantify erythrocyte velocity and arteriolar diameter in the main arteriole of the villi in the terminal ileum following i.v. application of Catalase in the inflamed intestine, and the blood flow was calculated. Control groups were formed for Ringer's lactate, Catalase and Indomethacin, respectively. We found that villous blood flow was significantly increased in the in the inflamed intestine. Application of Catalase led to a significant decrease in villous perfusion, but had no effect in the control group. The increase in villous blood flow was accompanied by changes in the diameter of the main arteriole. This effect on arteriolar diameter was reversed by i.v. Catalase. Our results provide evidence that systemic application of Indomethacin leads to vasodilatation of the main arteriole of the villus in the rat ileum and hyperemia in the mucosa. Hyperemia and the vascular diameter of the main arteriole were significantly reduced by H(2)O(2)-scavenger Catalase, suggesting that endogenous H(2)O(2) may be one of the mediators of hyperemia in the mucosa in this animal model of intestinal inflammation.

Animals↗
PubMed2000

Dendritic cells conditionally transformed by v-relER oncogene express lymphoid marker genes.

The initiation of primary immune responses is the key function of specialized antigen presenting cells, the dendritic cells (DC). DC of myeloid origin capture antigens in tissues, migrate to lymphoid organs and stimulate T cell responses. A subset of DC has been described which expresses lymphoid determinants and has potential regulatory functions. Conditional transformation of chicken bone marrow progenitors with v-relER, a v-rel estrogen receptor (ER) fusion gene, allows expansion of progenitors that can be induced to differentiate into DC in vitro. In this paper we describe that v-relER cells exhibit both myeloid and lymphoid surface markers, while B cell, T cell and NK (natural killer)-specific surface markers are absent. v-relER DC express, however, cytoplasmic CD3 protein and mRNA for CD8alpha and the lymphoid transcription factor GATA-3. These data suggest that v-relER DC might be related to the lymphoid subset of DC described in mammals.

Animals↗
PubMed2000

In vivo assessment of villous microcirculation in the rat small intestine in indomethacin-induced inflammation: role of mast-cell stabilizer Ketotifen.

Indomethacin induces an inflammatory reaction in the small intestine in several rat strains. This animal model is widely used to study the implications of intestinal inflammation. Macroscopically, there is evidence that Indomethacin induces a hyperaemic inflammatory reaction in the mucosa, and in our previous studies, we found a significant increase in villous perfusion in the acutely inflamed small intestine. Mast-cell activation was found to take part in inflammatory reactions in several organ systems in various species. However, no data are available about the effect of mast-cell degranulation on the perfusion of the mucosa in Indomethacin-induced intestinal inflammation. Therefore, we used the mast-cell stabilizer Ketotifen to identify if mast-cell activation may contribute to changes in the perfusion of single villi in the rat ileum. We found that Ketotifen significantly reduced the Indomethacin induced increased blood flow in the main arteriole 60 min after i.v. application, indicating that mast-cell degranulation effects microcirculatory disturbances in the mucosa in Indomethacin-induced intestinal inflammation.

Animals↗
PubMed2000

Nup2p, a yeast nucleoporin, functions in bidirectional transport of importin alpha.

Import of proteins containing a classical nuclear localization signal (NLS) into the nucleus is mediated by importin alpha and importin beta. Srp1p, the Saccharomyces cerevisiae homologue of importin alpha, returns from the nucleus in a complex with its export factor Cse1p and with Gsp1p (yeast Ran) in its GTP-bound state. We studied the role of the nucleoporin Nup2p in the transport cycle of Srp1p. Cells lacking NUP2 show a specific defect in both NLS import and Srp1p export, indicating that Nup2p is required for efficient bidirectional transport of Srp1p across the nuclear pore complex (NPC). Nup2p is located at the nuclear side of the central gated channel of the NPC and provides a binding site for Srp1p via its amino-terminal domain. We show that Nup2p effectively releases the NLS protein from importin alpha-importin and beta and strongly binds to the importin heterodimer via Srp1p. Kap95p (importin beta) is released from this complex by a direct interaction with Gsp1p-GTP. These data suggest that besides Gsp1p, which disassembles the NLS-importin alpha-importin beta complex upon binding to Kap95p in the nucleus, Nup2p can also dissociate the import complex by binding to Srp1p. We also show data indicating that Nup1p, a relative of Nup2p, plays a similar role in termination of NLS import. Cse1p and Gsp1p-GTP release Srp1p from Nup2p, which suggests that the Srp1p export complex can be formed directly at the NPC. The changed distribution of Cse1p at the NPC in nup2 mutants also supports a role for Nup2p in Srp1p export from the nucleus.

Active Transport, Cell Nucleus↗
PubMed2000

Some problems in the genetics of X-linked mental retardation.

X-linked mental retardation has recently become one of the most interesting genetic anomalies. Studying this group of conditions has led to many insights into the mechanisms involved in normal and abnormal gene actions in humans. Since the early 1980s, the number of disease entities for which the responsible genes could be localized on the X chromosome has increased from year to year; at the Ninth International Workshop on Fragile-X-Syndrome and X-linked Mental Retardation, 199 such disease units were counted (Hamel, 1999). Conventionally, these units were subdivided into two groups: syndromal and non-syndromal types. The syndro- mal types are characterized by external features, neurological signs, and/or metabolic anomalies. The non-syndromal types do not show such specific features; here, the X-linked mode of inheritance is the only indicator. Due to the reduced reproduction of mentally severely retarded males, a relatively high fraction of new mutants among cases of a specific type must be expected. It cannot be the purpose of the present short article to review sufficiently well the entire field; this would require a complete book. Rather, it is our intention to point to some open problems and possible ways for their solution.

Fragile X Syndrome↗
PubMed1999

[Linkage studies of a familial spastic paraplegia pedigree from Tibet].

OBJECTIVE: To study the location of disease-related gene in a hereditary spastic paraplegia family with autosomal dominant inheritance in Tibet. METHODS: The AD-HSP family in Tibet was analyzed by linkage studies using 9 highly polymorphic microsatellite DNA markers at three chromosomal regions. RESULTS: The maxium Lod- Score of D14S264 was 0.5163(theta=0.05); of D14S75, 2. 1072 (theta=0);+D14S69, 0.2840 (theta=0.10); of D14S266, 0.9311 (theta=0);of D14S66, 0.7991(theta=0);OF GABRB3, 0(theta =0.40);of D15S128, 0(theta=0.40); of D2S2255, 0 (theta=0.40);and of D2S2347,0(theta=0.40). CONCLUSION: In this Tibetian family, the disease-related gene is linked to D14S75 locus of SPG3 region.

Female↗
PubMed1999

Indomethacin-induced disturbances in villous microcirculation in the rat ileum.

Indomethacin is a widely used nonsteroidal antiphlogistic compound used-among others-for the treatment of rheumatoid arthritis in humans. Common side effects of indomethacin in the gastrointestinal tract include ulcerative lesions and petechial bleeding in the mucosa. In the rat, oral intake of indomethacin induces ulcerations in the mucosa of the stomach and, if administered systemically, edema, petechial bleeding, and ulcerations in the small intestine. In order to determine if systemic administration of indomethacin may induce changes in villous perfusion, we assessed the effect of indomethacin on erythrocyte velocity and the diameter of the main arteriole in the villi of the rat ileum. We found that indomethacin led to a significant decrease in mean arteriolar blood flow (6.3 +/- 0.8 vs 5.0 +/- 1.2 nl/min, means +/- SD) 7 days after administration. Mean diameter of the main arteriole remained unchanged (control, 7. 8 +/- 0.8 vs indomethacin, 7.0 +/- 0.9 microm). In conclusion, systemic application of indomethacin leads to a decrease in blood supply to the mucosa. We previously found an increase in villous perfusion when assessed 24 h after administration of indomethacin, accompanied by an increase in arteriolar diameter of the main arteriole. In summary, different regimens of application of indomethacin lead to varying observations in microcirculatory parameters in single villi. Further studies are required to identify the underlying mechanisms.

Animals↗
PubMed1999

Grepafloxacin: a review of its safety profile based on clinical trials and postmarketing surveillance.

The safety profile of grepafloxacin has been characterized in a number of preclinical and clinical studies. Preclinical investigations have shown that its toxicologic profile is similar to that of other fluoroquinolones, and phase I studies in humans have confirmed these data. A photosensitivity study demonstrated equivalence with ciprofloxacin, and a study in elderly patients taking the highest clinical dose of grepafloxacin indicated that prolongation of the QTc interval by grepafloxacin was less than 2 ms, 15 times less than that observed in a study of erythromycin. In phase II and III clinical investigations conducted in the United States and the United Kingdom, safety data have been gathered from more than 3000 patients with either community-acquired pneumonia or acute bacterial exacerbations of chronic bronchitis. The most common adverse events with grepafloxacin 400 or 600 mg were gastrointestinal, such as nausea, vomiting, and diarrhea. The frequency of these adverse events was similar to that seen with ciprofloxacin. Significantly more patients reported a mild, unpleasant metallic taste with grepafloxacin than with ciprofloxacin, but <1% of patients withdrew from therapy because of this. Headache was observed significantly more often in ciprofloxacin-treated patients than in grepafloxacin-treated patients. Recent postmarketing data confirm the good tolerability and safety profile of grepafloxacin. These data, from a case-report study of more than 9000 patients in Germany, demonstrated that only 2.3% of patients reported adverse events when grepafloxacin was used in routine clinical practice. The most frequently reported events were nausea (0.8%) and gastrointestinal symptoms (0.4%). Dizziness was reported by only 0.3% of patients, and only 4 patients (0.04%) reported photosensitization. Adverse events did not appear to be either dose dependent or related to diagnosis. More than 400,000 patients world-wide have received grepafloxacin treatment. No new safety issues have arisen from the spontaneous-report data and, with the exception of rare reports of an unpleasant taste, the most commonly reported events have been the same as those seen in clinical studies. These data support grepafloxacin as a well-tolerated fluoroquinolone suitable for the treatment of community-acquired respiratory tract infections.

Animals↗
PubMed1999

Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis.

The efficacy and safety of grepafloxacin were compared with clarithromycin in a randomized, double-blind, multicentre clinical trial of 805 patients with acute bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized to receive grepafloxacin 400 mg od for either 5 (n = 273) or 10 days (n = 268) or clarithromycin 250 mg bd for 10 days (n = 261). Patients were assessed pre-treatment, 3-5 days during treatment, 1-3 days post-treatment and at follow-up (21-28 days post-treatment). The clinical success rates for the evaluable patients were 91% in the 5 day grepafloxacin group, 95% in the 10 day grepafloxacin group and 86% in the clarithromycin group. At follow-up, respective rates were 72%, 81% and 73%. A total of 513 pathogens were isolated from the pre-treatment sputum specimens of 400 (49%) patients. The primary pathogens were Haemophilus influenzae (36% of isolates), Haemophilus parainfluenzae (27%), Moraxella catarrhalis (12%), Streptococcus pneumoniae (11%) and Staphylococcus aureus (3%). Pathogens were eradicated or presumed eradicated at post-treatment in 85%, 91% and 58% of evaluable patients treated with grepafloxacin for 5 days, grepafloxacin 10 days and clarithromycin 10 days, respectively. The eradication rates in both grepafloxacin groups were significantly greater than the clarithromycin group (P<0.001). All treatments were well tolerated and incidence of drug-related adverse events in each group was comparable. This study demonstrates that both a 5 and a 10 day regimen of grepafloxacin 400 mg od are as clinically and bacteriologically effective as in the treatment of ABECB clarithromycin 250 mg bd. for 10 days.

Acute Disease↗
PubMed1999

Yeast cells allow high-level expression and formation of polyomavirus-like particles.

Polyomavirus-derived virus-like particles (VLPs) have been described as potential carriers for encapsidation of nucleic acids in gene therapy. Although VLPs can be generated in E. coli or insect cells, the yeast expression system should be advantageous as it is well established for the biotechnological generation of products for human use, especially because they are free of toxins hazardous for humans. We selected the yeast Saccharomyces cerevisiae for expression of the major capsid protein VP1 of a non-human polyomavirus, the hamster polyomavirus (HaPV). Two entire HaPV VP1-coding sequences, starting with the authentic and a second upstream ATG, respectively, were subcloned and expressed to high levels in Saccharomyces cerevisiae. The expressed VP1 assembled spontaneously into VLPs with a structure resembling that of the native HaPV capsid. Determination of the subcellular localization revealed a nuclear localization of some particles formed by the N-terminally extended VP1, whereas particles formed by the authentic VP1 were found mainly in the cytoplasmic compartment.

Animals↗
PubMed1999

Lack of effects of recombinant human GH on spermatogenesis in the adult cynomolgus monkey (Macaca fascicularis).

OBJECTIVE: The effects on male reproductive parameters after 1 year of treatment with recombinant human GH to the cynomolgus monkey were investigated. DESIGN: Twenty-four male cynomolgus monkeys were given daily subcutaneous doses of 0 (vehicle) (n=7), 0.4 (n=5), 2.0 (n=5) and 10.0 (n=7) IU/kg bodyweight for 52 weeks. At completion of the treatment period two control and two high-dose animals were left for a 12-week treatment-free period. METHODS: Before and during the treatment period and during the recovery period, sperm analyses, testicular volume measurements and hormone analyses of prolactin (PRL), LH, FSH, testosterone and IGF-I in serum, and analysis of serum antibodies against human GH were performed. Testicular morphology was monitored by biopsies, predose and on day 15 of the study, and with light microscopy on organ samples collected at time of death, at the end of the treatment, and during recovery periods respectively. RESULTS: Of all studied parameters, alterations were observed only in serum levels of IGF-I and PRL. IGF-I showed a dose-dependent increase throughout the treatment, with a normalisation during the treatment-free period. PRL decreased significantly in animals given 10.0IU/kg per day from week 14 of treatment and throughout the study but with a normalisation upon cessation of treatment. Spermatogenesis, as judged from semen analysis, testicular volume measurements and testicular morphology was not affected. CONCLUSION: This controlled preclinical study demonstrates that high doses of human GH do not alter male reproductive parameters in a non-human primate model.

Animals↗
PubMed1998

Interplay between humans and infective agents: a population genetic study.

The genetic composition of present day human populations is determined largely by the interaction between the human host and infective agents. Therefore, theoretical analysis of the host-infective-agent system is required in order for us to be able to understand human evolution. Classical population genetics has been confined largely to analysing the interplay of various mechanisms, such as selection, mutation and drift, in one species at a time. Unfortunately, there have been few studies of such interactive systems. In the present investigation, these studies have been enlarged, with problems of human genetics in mind, by mathematical examination of a model in which a diploid host with three alleles interacts with a haploid infective agent with two alleles. The results are compared with those obtained from simpler models analysed in the past. The assumptions inherent in such "gene for gene" models and our results are discussed. An increase in the number of alleles appears to enhance the chances for the establishment of permanent genetic polymorphisms, improving genetic "elasticity" of a population for coping with changing challenges by various infective agents. Interaction between two haploid species leads to a loss of polymorphism in both of them and, hence, to a severe loss of evolutionary elasticity. The hypothesis that the evolution of diploidy might have been favoured by a selective advantage of diploid organisms interacting with environmental challenges, such as infective agents, is supported.

ABO Blood-Group System↗
PubMed1997

Introduction of plasmid DNA into isolated mitochondria by electroporation. A novel approach toward gene correction for mitochondrial disorders.

Mitochondrial disorders are a large group of phenotypically heterogeneous diseases. An understanding of their molecular basis would benefit greatly from the ability to manipulate the mitochondrial genome and/or to introduce functional exogenous DNA into mitochondria. As a first step toward this approach, we have used electroporation to introduce a 7.2-kilobase plasmid DNA into isolated functional mitochondria. Transfer of the DNA at field strengths between 8 and 20 kV/cm was investigated by Southern blot analysis. Maximal plasmid internalization was achieved at a field strength of 14 kV/cm. The functional integrity of the mitochondria after electroporation was verified by enzymatic assays of specific mitochondrial marker enzymes and by measuring respiratory control. At field strengths above 12 kV/cm, an increasing mitochondrial destruction was observed. 12 kV/cm was found to be optimal for the most efficient plasmid internalization while still retaining the functional integrity of the mitochondria. At this field strength, about half of the internalized plasmid was found in the inner membrane or mitochondrial matrix, as determined by immunoelectron microscopy and Southern blot analysis of electroporated mitochondria treated with digitonin. We estimate that on average one plasmid molecule/mitochondrion reaches the matrix or inner membrane.

Animals↗
PubMed1997

Inducible membranes in yeast: relation to the unfolded-protein-response pathway.

Overproduction of an endoplasmic reticulum (ER)-resident membrane protein (cytochrome P450 52A3) and of a secretory protein (invertase) was used to study the regulation of the luminal ER protein Kar2p under conditions that lead to ER proliferation and secretory overload, respectively. In both cases we found (i) a significant increase of Kar2 protein and mRNA levels, (ii) a transcriptional regulation based on the the function of the 22 bp unfolded-protein-response element of the KAR2 promoter and (iii) an essential role of the transmembrane kinase Ire1p for upregulation of KAR2 gene expression. These results show that the same mechanism operates when KAR2 induction is triggered by overproduction of cytochrome P450 or invertase and that this mechanism shares the known features of the unfolded-protein-response pathway. Disruption of the IRE1 gene resulted in a marked decrease of the invertase protein levels produced. In contrast, a functional IRE1 gene was not required to reach high-level production of the integral membrane protein cytochrome P450 52A3, Moreover, IRE1 gene disruption did not prevent P450-induced ER proliferation. We suggest that Ire1p-mediated KAR2 induction is, in the case of cytochrome P450 52A3 overproduction, a process which follows on ER proliferation, thereby monitoring the increase of ER size and adjusting the level of Kar2p accordingly.

Cytochrome P-450 Enzyme System↗
PubMed1997

Another pedigree with pure autosomal dominant spastic paraplegia (AD-FSP) from Tibet mapping to 14q11.2-q24.3.

The mutant in a family with autosomal-dominant spastic paresis in Northern Tibet was mapped by linkage analysis with several microsatellite markers to a gene locus at 14q11.2-q24.3, an area to which a few mutants leading to a condition with similar clinical signs have previously been mapped. The mutant observed in this pedigree probably arose de novo. Gene loci at 2p21-p24 and 15q, which have been found for other pedigrees with dominant spastic paresis, were excluded. The data in this pedigree do not contradict the hypothesis proposed by another group that there might be anticipation.

Adult↗
PubMed1997

Protein quality--a determinant of the intracellular fate of membrane-bound cytochromes P450 in yeast.

To elucidate mechanisms determining the intracellular localization of cytochromes P450, authentic and mutant cytochromes P450 52A4 (P450Cm2) and P450 52A5 (P450Alk2A) were heterologously expressed in Saccharomyces cerevisiae and the ultrastructure of the respective transformants was investigated by means of immunoelectron microscopy. As a result, overproduction of both wild-type P450 forms resulted in a massive proliferation of tubular membrane structures distributed over the whole cytoplasm. In contrast, all mutant P450Cm2 and Alk2A forms tested were mainly localized within stacks of paired membranes which often occurred in close vicinity to the nucleus. As found by serial sectioning of a single cell, these stacked membranes bearing the mutant P450 actually represented plates of consecutive membranes arranged one upon the other. A tubular network of endoplasmic reticulum membranes as observed after expression of the wild-type proteins could not be detected. Generally, the kind of mutation introduced into the P450 forms did not influence the morphology of the induced membranes. Even single amino acid exchanges in the cytosolic domain caused the formation of membrane stacks. The common feature of all mutant P450 forms causing the formation of stacked membranes was, however, their lower protein stability after heterologous expression in the S. cerevisiae host cells, compared to the stability of the authentic cytochromes P450. Furthermore, the proliferated membranes containing the different P450 forms were characterized by means of subcellular fractionation experiments. Using this approach, clear differences in the distribution of spectrally active and inactive P450 molecules were found. The results obtained suggest the presence of an intracellular sorting mechanism based on the protein quality, which finally leads to the differences in the intracellular distribution of wild-type and mutant cytochromes P450.

Candida↗