Molecular and cellular aspects of insulin-like growth factor action.
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Animals↗
Biomedical subjects
H Werner
Publications and source records attributed to H Werner.
Fibronectin and vitronectin binding of Bacteroides fragilis and eight other species of the genus.
The fibronectin and vitronectin bindings of 152 strains belonging in 9 Bacteroides species of different origins were tested by means of latex agglutination. 23% of the strains isolated from faeces exhibited fibronectin binding, as did 46% of the strains obtained from severe infections. Most of the strains displaying fibronectin binding belonged to the species Bacteroides fragilis or Bacteroides vulgatus. The binding could be inhibited by preincubation of the cells with an excess amount of fibronectin. Vitronectin binding was less common, but was always observed in parallel with fibronectin binding.
Bacteroides↗
Differential accumulation of insulin-like growth factor-I in kidneys of pre- and postpubertal streptozotocin-diabetic rats.
Nephropathy, one of the major complications of diabetes mellitus, is characterized by an early increase in kidney size. In experimental models of diabetes, this event is preceded by a rapid and transient rise in kidney IGF-I levels, at least in adult animals. Since diabetes-associated renal changes are uncommon in young patients, we investigated the early changes in the components of the IGF system following induction of diabetes in prepubertal and postpubertal rats. The rationale for this study was the evaluation of potential differences which could lead to kidney complications only at adult stages. Unlike the situation in the postpubertal kidney, in which there was a transient accumulation of extractable IGF-I 24-48 h after streptozotocin (STZ) administration, there was a decrease of approximately 12-fold in the level of IGF-I in the prepubertal kidney over the same period of time. Paradoxically, kidney IGF-I mRNA levels were reduced by approximately 50% in the postpubertal rat 24 h after STZ treatment, whereas in the prepubertal kidney IGF-I mRNA levels were unaltered. Furthermore, the levels of IGF-I receptor mRNA and 125I-labelled IGF-I binding to kidney membranes of postpubertal diabetic rats were similar to the levels in control kidneys. On the other hand, both the levels of IGF-I receptor mRNA and 125I-labelled IGF-I binding were increased (approximately 2.5-fold (after 24 h) and approximately 3-fold (after 48 h) respectively) in prepubertal animals. In addition, increased expression of IGF-binding protein (IGFBP)-1 mRNA was seen early in diabetes in both pre- and postpubertal rats. The results of this study suggest that the transient accumulation of IGF-I in the kidney of the postpubertal diabetic rat may not be due to an increase in the local synthesis of IGF-I, but rather to an increase in IGF-I uptake from the circulation due to non-membrane-associated IGFBP-1. The lack of accumulation of IGF-I in the prepubertal kidney probably reflects the approximately 10-fold lower levels of circulating IGF-I in young as compared with adult diabetic rats.
Age Factors↗
Secretion of interleukin-6 by human meningioma cells: possible autocrine inhibitory regulation of neoplastic cell growth.
Using cell culture techniques, the authors have previously shown that human meningioma cells secrete an autocrine growth stimulator related to platelet-derived growth factor. Here, they further demonstrate potential autocrine inhibitory regulation of meningioma cell growth by interleukin (IL)-6. Constitutive IL-6 production was detected in all meningiomas studied, in the form of protein as well as IL-6-specific messenger ribonucleic acid. The IL-6 immunoreactivity in conditioned medium from three different meningioma cultures eluted from a Sephadex G-100 column was evidenced by a single peak corresponding to a molecular weight of about 32 kD. Interleukin-6 secretion was remarkably stimulated by tumor necrosis factor-alpha, IL-1 beta, and IL-4, and was also influenced by a combination of epidermal growth factor and bromocriptine. Recombinant IL-6 exhibited a significant dose-dependent inhibitory effect on meningioma cell proliferation. The maximum effect was observed at concentrations of 10 to 100 pg/ml, with the decrease in thymidine incorporation ranging from 21% to 35% versus control. Addition of an anti-IL-6 antibody enhanced the growth-stimulating effect of meningioma-derived conditioned medium. The rate of IL-6 secretion tended to show an inverse correlation with meningioma growth rate. The results presented here and the previous results suggest that the regulation of meningioma cell proliferation is defined by a complex network of autocrine stimulation, autocrine inhibition, and influences from multiple exogenous factors.
Blotting, Northern↗
[Campylobacter fetus subsp. fetus in a patient with liver cirrhosis].
Campylobacter fetus subsp. fetus infections are very rare in adults but can occur in immunocompromised elderly people and in patients with chronic disease. We describe the clinical case of a 52-year-old woman with alcoholic liver cirrhosis, where we isolated C.fetus subsp. fetus from blood culture.
Campylobacter Infections↗
In vitro activity of meropenem compared with imipenem, metronidazole, ampicillin, and ampicillin/sulbactam against anaerobes.
The aim of the present study was to compare the in vitro activity of meropenem (ICI 194660, CAS 96036-03-2) with imipenem, metronidazole, clindamycin, ampicillin and ampicillin/sulbactam against a variety of anaerobic bacteria using an agar dilution method. 423 clinical isolates were tested belonging to 70 species of 15 anaerobic genera. They included Bacteroides fragilis (n = 62), Bacteroides thetaiotaomicron (n = 45), Prevotella bivia (n = 11), Fusobacterium nucleatum (n = 12), Clostridium perfringens (n = 15) and several rarely isolated species and genera, e.g. Selenomonas sputigena and Clostridium symbiosum. Bacteroides species were inhibited by meropenem at < or = 2.0 micrograms/ml, Clostridium species, including C. difficile, at < or = 4.0 micrograms/ml and all the other anaerobes at < or = 0.5 microgram/ml. Meropenem and imipenem were the most active substances, but often equal to, or only slightly better than, metronidazole, clindamycin or ampicillin/sulbactam, dependent on species. Meropenem was especially active against Bacteroides gracilis (MIC90 0.015 microgram/ml), Prevotella disiens (MIC90 0.03 microgram/ml), Fusobacterium nucleatum (MIC90 0.015 microgram/ml), Clostridium perfringens (MIC90 0.015 microgram/ml) and Veillonella parvula (MIC90 0.03 microgram/ml). The results obtained indicate that meropenem might be a useful adjunct to chemotherapy of anaerobic and mixed aerobic and anaerobic infections.
Ampicillin↗
[RU 486 and sulprostone in pregnancy termination in the 2nd and 3rd trimesters].
OBJECTIVE: Describe our experience with the RU 486 (mifepristone) in case of pregnancy termination induced by sulprostone. METHOD: Prospective non controlled study in the department of Fetal Medicine of the "Institut de Puériculture de Paris". 158 women undergoing termination of pregnancy during the second and third trimester received a single dose of 600 mg of RU 486, 36 hours prior to infusion of 100 micrograms/hour of sulprostone. MAIN OUTCOME MEASURES: Delay between sulprostone therapy and diagnosis of labour duration of delivery. Prostaglandin doses used and frequency of secondary effects. RESULTS: The mean time between sulprostone administration and diagnosis of labour (146.5 +/- 106 minutes) as well delay of delivery (592.2 +/- 504 minutes) corresponded to the results reported in the literature. The primigravid women needed higher doses of prostaglandin and consequently experienced more secondary effects. No severe secondary effects were observed in this study. CONCLUSION: RU 486 is a satisfactory treatment for pregnancy termination during the second or third trimester.
Abortifacient Agents, Nonsteroidal↗
Insulin-like growth factor receptors. Implications for nervous system function.
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Animals↗
Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.
Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediated through activation of the IGF-I receptor (IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney and in Wilms tumor samples using solution hybridization/RNase protection assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than in adjacent normal kidney tissue. Among the tumors themselves, the levels of IGF-IR mRNA in those containing heterologous stromal elements were 2-fold higher (P < 0.01) than in tumors without these elements. IGF-IR gene (designated IGF1R) expression in the tumors was inversely correlated with the expression of the Wilms tumor suppressor gene WT1, whose inactivation appears to be a key step in the etiology of Wilms tumor. Cotransfection of Chinese hamster ovary cells with rat and human IGF-IR gene promoter constructs driving luciferase reporter genes and with WT1 expression vectors showed that the active WT1 gene product represses IGF-IR promoter activity in a dose-dependent manner. These results suggest that underexpression, deletion, or mutation of WT1 may result in increased expression of the IGF-IR, whose activation by IGF-II may be an important aspect of the biology of Wilms tumor.
Animals↗
[Characteristics of antibiotic therapy in the elderly].
In the elderly, the morbidity and mortality rates of infections are significantly increased. Atypical or nonspecific symptoms or their absence often delay the diagnosis. When providing treatment, in addition to microbiological specifics of infections in the aged, consideration must also be given to pharmacokinetic aspects when choosing a suitable antibiotic. Furthermore, any existing medication must be taken into account in order to avoid interactions and undesirable drug effects. In view of the elevated mortality and multimorbidity rates, the early use of antibiotics is of considerable importance. If no specific etiological diagnosis is available, a broad-spectrum antibiotic should be administered.
Aged↗
The regulation of IGF-I receptor gene expression by positive and negative zinc-finger transcription factors.
The IGF-I-R gene promoter is a TATA-less, CAAT-less, GC-rich promoter which contains potential binding sites for the Sp1 and WT1 zinc-finger transcription factors. We have shown that Sp1 positively activates the IGF-I-R promoter. Since both the Sp1 and IGF-I-R genes are widely expressed, it is possible that Sp1 is one of the main regulators of IGF-I-R gene expression. This is supported by the correlation between the distribution and developmental regulation of Sp1 and IGF-I-R gene expression, in that both genes appear to be co-regulated during normal development. In a model of human neoplasm, WT, we have demonstrated increased expression of the IGF-I-R gene, which may result from loss of repression of the IGF-I-R promoter by another Zn(2+)-finger protein, the WT1 tumor suppressor gene product. Future studies will define whether other disease states in which the IGF-I-R gene is highly expressed are also associated with loss of negative regulation of the IGF-I-R promoter by WT1 or other tumor suppressor gene products.
Animals↗
The role of insulin-like growth factors in diabetic kidney disease.
Early renal manifestations of type I diabetes include kidney enlargement, increased glomerular filtration rate, and renal plasma flow. These hemodynamic changes may be caused by a number of factors, including growth hormone and/or insulin-like growth factor-I (IGF-I). Streptozotocin-induced insulinopenic diabetes in rats represents a model of human type I diabetes and is associated with the early hemodynamic changes in the kidney seen in poorly controlled type I diabetic patients. These changes are preceded by an accumulation of IGF-I peptide in the kidney. Insulin-like growth factor-I is not locally produced, but rather accumulates from circulating IGF-I, trapped by increased levels of IGF-binding proteins, particularly IGF-binding protein-1. The hemodynamic effects, reproduced by infusions of recombinant human IGF-I in normal rats, may be blocked by co-infusion of a kinin-receptor antagonist, suggesting that at least one of the mechanisms involved is the kallikrein-kinin system. These studies strongly support the notion that the IGF system may play a role in early hemodynamic manifestations of the diabetic kidney. Whether these effects lead to long-term diabetic renal disease remains to be studied.
Animals↗
Distinct promoters in the rat insulin-like growth factor-I (IGF-I) gene are active in CHO cells.
In mammals, IGF-I mRNAs contain one of two different leader exon sequences that encode different 5'-untranslated regions (UTRs) and signal peptides. The pattern and regulation of expression of these exon 1 and exon 2-derived mRNAs suggests that the expression of each is controlled by a distinct regulatory region. In order to assess this possibility, DNA fragments consisting of sequences flanking and including the exon 1 and exon 2 transcription initiation sites were cloned into a luciferase expression vector and plasmid DNAs were transiently transfected into Chinese hamster ovary (CHO) cells. A fragment containing approximately 1.1 kb of sequence flanking the most upstream exon 1 transcription initiation site and 362 bp of exon 1 sequence did not stimulate luciferase activity. However, fragments containing 133 bp of 5'-flanking sequence and either 362 or 192 bp of exon 1 sequence stimulated luciferase activity significantly above that seen with a promoterless control plasmid. When the -133/+362 fragment was cloned in the opposite orientation with respect to the luciferase cDNA, the same level of promoter activity was observed. Removal of approximately 860 bp from the inactive fragment (i.e., approximately 782 bp of flanking sequence and approximately 74 bp of exon 1 sequence) resulted in promoter activity which was significantly greater than that seen with the promoterless luciferase expression vector, but which was less than that observed with fragments containing the proximal 133 bp of 5'-flanking sequence. Plasmids containing approximately 1.5 kb or 0.5 kb of flanking sequence and 44 bp of exon 2 sequence also significantly stimulated luciferase activity. These results constitute the first demonstration that both exon 1 and exon 2 transcription start sites are associated with distinct and potentially independently regulatable promoters and provide a molecular basis for the differential expression of these leader exons by developmental, tissue-specific and hormonal factors.
Animals↗
Regulation of insulin-like growth factor (IGF) binding protein-5 in the T47D human breast carcinoma cell line by IGF-I and retinoic acid.
The T47D human breast carcinoma cell line has been shown to synthesize insulin-like growth factor-I (IGF-I) binding proteins (IGFBPs) and IGF-I receptors, and to exhibit a mitogenic response to exogenous IGF-I. We have used T47D cells to investigate the regulation of IGFBPs by IGF-I and retinoic acid (RA), agents that affect cell proliferation and have been shown to regulate IGFBP levels in other cell types. Exposure of T47D cells to IGF-I resulted in the appearance of IGFBP-2, -4, and -5 in conditioned medium but had no effect on the levels of IGFBPs in Triton X-100-extracted cells. This effect was most pronounced for IGFBP-5 and was also elicited by an IGF-I analog that retains affinity for IGFBPs but not by insulin or IGF analogs that have decreased affinity for IGFBPs. Additionally, this effect was not associated with a change in IGFBP-5 messenger RNA (mRNA) levels; however, the appearance of IGFBP-5 in the conditioned medium was inhibited by an anti-IGF-I receptor antibody (alpha IR-3). RA decreased IGFBP-5 mRNA levels and cell-associated IGFBP-5 in both the presence and absence of IGF-I and inhibited the IGF-I-stimulated secretion of IGFBP-5 into T47D cell conditioned medium. These results suggest that IGF-I increases IGFBP-5 levels in the T47D cell line both through direct interaction with IGFBP-5 as well as through a receptor-mediated process that does not require direct interaction with IGFBPs. The latter results are consistent with an effect of IGF-I on a factor that may modulate an IGFBP protease activity. The inhibitory effect of RA, on the other hand, appears to be due primarily to regulation of IGFBP-5 mRNA levels. Thus, IGFBP-5 accumulation appears to be positively regulated by IGF-I, potentially at the level of susceptibility to proteolysis, and negatively regulated at the level of gene expression by RA.
Breast Neoplasms↗
Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels.
We have analysed the expression of the IGF-I receptor gene in lymphocytes of patients with low levels of circulating IGF-I (four patients with isolated GH deficiency (IGHD) and one Laron-type dwarf (LTD)) in comparison with a control group exhibiting normal serum IGF-I levels and endocrine profiles. 125I-Labelled IGF-I binding assays were performed on erythrocytes to determine the number of IGF-I binding sites per cell and their dissociation constants. Erythrocytes from patients with IGHD or LTD contained significantly (P = 0.002) more receptors per cell (10.9 +/- 3.1 binding sites/cell), with a reduced affinity (Kd = 0.49 +/- 0.05 nM), than erythrocytes from controls (2.0 +/- 0.4 sites/cell; Kd = 0.14 nM). The levels of IGF-I receptor mRNA in circulating lymphocytes were determined by an RNA template-specific reverse transcription/polymerase chain reaction method. There was a statistically significant increase in IGF-I receptor mRNA levels in lymphocytes from patients with LTD or IGHD when compared with controls (3108.1 +/- 775.9 vs 576.0 +/- 465.7 arbitrary units, P = 0.006). The increased level of IGF-I binding due to increased IGF-I receptor gene expression may represent a compensatory up-regulation process activated in response to the low levels of IGF-I in the circulation of patients with LTD or IGHD.
Base Sequence↗
[Employment of cross-border workers in the Federal Republic of Germany].
The author analyzes the cross-border movement of labor migrants in Germany. The impact of increased integration among European Community countries is considered, and the pressure of migration from neighboring Eastern European countries is discussed. "Employment of workers from border regions [provides the] possibility of meeting the labour demand in the region, of alleviating the pressure to migrate by legalizing inflows and of balancing the interests of employers and cross-border workers, thus avoiding some of the negative side-effects or social costs of traditional labour migration." (SUMMARY IN ENG AND FRE AND RUS)
Demography↗
[Superselective intra-arterial chemotherapy in breast cancer].
Forty-two patients with locally advanced breast cancer (n = 8) or recurrent breast cancer (n = 34) received regional chemotherapy (mitoxantrone 25 mg/m2 per 24 h) via the internal mammary artery or other vessels of the subclavian artery. To prevent artery thrombosis 500-1000 U heparin per hour were administered i.v. Tumour perfusion was monitored by intra-arterial angio-CT. Remission rates (CR + PR) were 100% (primary breast cancer) and 89% (recurrent tumours), respectively. Intra-arterial chemotherapy was well tolerated. No complications were noted.
Adult↗
RNA polymerase III catalysed transcription can be regulated in Saccharomyces cerevisiae by the bacterial tetracycline repressor-operator system.
We have investigated whether the RNA polymerase III-driven transcription of eukaryotic tRNA genes can be regulated by the prokaryotic tetracycline operator-repressor system. The bacterial tet operator (tetO) was inserted at two different positions (-7 and -46) upstream of a tRNA(Glu) (amber) suppressor gene. Both constructs are transcribed in Saccharomyces cerevisiae and yield functional tRNAs as scored by suppression of an amber nonsense mutation in the met8-1 allele. Controlled expression of Tet repressor was achieved by fusing the bacterial tetR gene to the yeast gal1 promoter. This leads to expression of Tet repressor in yeast on galactose--but not on glucose--containing media. Regulation of the su-tRNA gene with the tetO fragment inserted at position -7 has been demonstrated. Under conditions which allow tetR expression, cells exhibit a met- phenotype. This methionine auxotrophy can be conditionally reverted to prototrophy by adding tetracycline. However, a su-tRNA gene with the tetO fragment inserted at position -46 cannot be repressed. Our results demonstrate clearly that the bacterial repressor protein binds to its operator in the yeast genome. Formation of this complex in the vicinity of the pol III transcription initiation site reduces the level of su-tRNA at least 50-fold as concluded from quantitative primer extension analyses. This indicates for the first time that class III gene expression can be regulated by a DNA binding protein with its target site in the 5'-flanking region and that a prokaryotic repressor can confer regulation of a suitably engineered tRNA gene.
Alleles↗