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Biomedical subjects

J Schwander

Publications and source records attributed to J Schwander.

At least 37 records · Page 2Linked to original sources
PubMed1993

The RIA for IGFBP-2 in man--a meagre catch?

In man IGFBP-2 is by concentration the second most important IGF binding protein in serum, the most abundant carrier protein in milk and CSF. In serum its levels are age dependent. There is no good evidence, to date, for a regulation of its production or degradation by insulin. IGF-I treatment increases serum IGFBP-2 concentration. IGFBP-2 is at least partially metabolized by the kidney, since it accumulates in serum of patients with renal failure and normalizes after renal transplantation. Individuals with neoplastic diseases very often present with elevated serum levels.

Adolescent↗
PubMed1993

Insulin-like growth factor (IGF) I and II and IGF binding protein (IGFBP) 1, 2 and 3 in serum from patients with Cushing's syndrome.

In the present study of twenty-two patients with Cushing's syndrome, serum insulin-like growth factor (IGF)-I concentrations were normal to high with an increased mean IGF-I concentration, 40% above that of healthy subjects of the same age (p < 0.001). Serum IGF-II concentrations were normal. The morning serum IGF binding protein (IGFBP)-1 concentrations were within the range of healthy controls. IGFBP-1 was inversely correlated to the IGF-I concentration (p < 0.001) and to the 24 h urinary cortisol excretion (p < 0.005) with a combined R squared value of 0.58. In contrast to IGFBP-1, serum IGFBP-2 and IGFBP-3 concentrations were elevated by 1.89 +/- 1.78 SD and 0.92 +/- 0.78 SD (mean +/- 2 SD), respectively. Although increased, the serum IGFBP-2 concentration was inversely correlated to the IGF-I concentration (r = -0.67, p < 0.001). Immunoreactive IGFBP-3 was increased in proportion to IGF-I and the molar ratio [IGFBP-3]:[IGF-I] + [IGF-II] was close to unity (1.04 +/- 0.14), as that of healthy subjects. In serum from patients with Cushing's syndrome, with increased immunoreactive IGFBP-3, there was a corresponding increase in intact glycosylated 40-43 kDa IGFBP-3 as determined by Western ligand blotting. Neutral size chromatography of serum from patients with Cushing's syndrome showed that IGF-I and IGFBP-3 immunoreactivity were predominantly found at the elution volume of the ternary 150 kDa IGF-I/IGFBP-3/acid labile subunit complex and a similar pattern was displayed by normal serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Insulin-like growth-factor-binding protein gene expression and protein production by human tumour cell lines.

The secretion of insulin-like growth-factor-binding proteins (IGFBPs) and expression of the genes encoding IGFBP-1, IGFBP-2 and IGFBP-3 have been studied in a panel of cell lines derived from breast carcinomas, Wilms' tumour, neuroblastoma, retinoblastoma, colon carcinoma, liver adenocarcinoma, Burkitt's lymphoma and a non-small-cell lung carcinoma. All cell lines, with the exception of the Burkitt's lymphoma cell line, secreted IGFBPs, as detected by affinity labelling. A 34-kDa BP was present in the conditioned media of all IGFBP-secreting cell lines, whereas BPs ranging from 18 kDa to 53 kDa were variably secreted. All IGFBP-secreting cell lines expressed the IGFBP-2 gene as determined by Northern blot analysis. The Wilms' tumour, the neuroblastoma and the retinoblastoma cell line expressed the IGFBP-2 gene only. All other cell lines, with the exception of the Burkitt's lymphoma, expressed the IGFBP-2 gene and, in addition, either the IGFBP-1 gene and/or the IGFBP-3 gene. IGFBP-1 gene expression could be detected by reverse transcriptase polymerase chain reaction only. IGFBP-3 gene expression was detected by Northern blot analysis, but transcripts were less abundant than IGFBP-2 mRNAs. These findings indicate that the expression of multiple BP genes and the secretion of BPs may be a common property of tumour cells.

Affinity Labels↗
PubMed1992

Differential regulation of insulin-like growth factor binding protein (IGFBP)-2 mRNA in liver and bone cells by insulin and retinoic acid in vitro.

Isolated cells produce insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Two distinct cell types were studied with regard to IGFBP-2 expression: (i) rat hepatocytes, which produce IGF I at a high rate and thus regulate its plasma concentration; and (ii) rat osteoblasts, which are targets of IGF I action. IGFBP-2 expression is low in hepatocytes prepared from normal adult rats and high in calvaria cells from newborn rats. Retinoic acid stimulates IGFBP-2 production by liver cells. Insulin suppresses both basal and retinoic acid-induced IGFBP-2 mRNA expression in hepatocytes and has no such effect on osteoblasts. Retinoic acid and insulin regulate IGFBP-2 expression in a tissue-specific manner.

Animals↗
PubMed1992

Expression of insulinlike growth factor (IGF) and IGF-binding protein genes in human lung tumor cell lines.

BACKGROUND: The presence of multiple, low-molecular-weight, insulinlike growth factor (IGF)-binding proteins in lung tumor cell-conditioned medium and lung cancer patient serum has been recently reported. PURPOSE: To begin to elucidate the genetic basis for these observations, the present study examines the expression by lung tumor cell lines of three IGF-binding protein genes, namely, IGFBP-1, IGFBP-2, and IGFBP-3. Since IGF-binding proteins are thought to modulate the biologic action of the IGFs, the relationship between the expression of IGF-binding protein genes and the genes encoding IGF-I and IGF-II also has been investigated. METHODS: Gene expression was studied in four small-cell lung cancer (SCLC) and three non-small-cell lung cancer (NSCLC) cell lines using Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR) for IGFBP-1. RESULTS: IGFBP-1 gene expression was detected by Northern blot analysis in one NSCLC cell line only. However, RT-PCR revealed that the IGFBP-1 gene was expressed in all four SCLC cell lines and in two of the three NSCLC lines. Northern blot analysis of IGFBP-2 gene expression demonstrated that all lung tumor cell lines expressed this gene. A low level of IGFBP-3 gene expression was detected in one SCLC cell line and in all three NSCLC cell lines. All lung tumor cell lines expressed the IGF-II gene as determined by Northern blot analysis. In marked contrast, none of the lines showed evidence of IGF-I gene expression using this method. However, RT-PCR revealed a low level of IGF-I gene expression in one SCLC and one NSCLC cell line only. CONCLUSIONS: These observations indicate 1) that IGF-binding proteins secreted by lung tumors are encoded by at least three different genes; 2) that there may be a close association between IGF-II and IGFBP-2 gene expression, such that, where there is production of IGF-II, IGFBP-2 is the principal BP; and 3) that the IGF-II gene is more widely expressed than the IGF-I gene in human lung tumor cell lines.

Base Sequence↗
PubMed1992

Structure of the human insulin-like growth factor binding protein-2 gene.

Insulin-like growth factors (IGFs) are polypeptide hormones with structural homology to proinsulin. IGFs circulate in blood bound to specific IGF binding proteins (IGFBPs). cDNA sequences of six members of a family of human and rat IGFBPs have been published. Here we present a partial characterization of the human IGFBP-2 gene. This single copy gene is located on chromosome 2 and spans a total of more than 32 kilobases (kb) of genomic sequence. It is organized in four exons with sizes of more than 568, 220, 141, and 496 nucleotides. The intron between exon one and exon two contributes 27 kb to the size of the IGFBP-2 gene. The second and the third introns comprise 1.1 kb and 1.95 kb, respectively. When the structure of the IGFBP-2 gene is compared to that of the IGFBP-1 and IGFBP-3 genes, the exon boundaries are found to be conserved in these three genes. A single transcriptional start site was localized to 113 +/- 2 nucleotides 5' of the ATG start codon of IGFBP-2 translation. Furthermore, the region between nucleotides -635 and -2 upstream of the ATG was demonstrated to exhibit promoter activity in human Jurkat K16 cells. This region is devoid of TATA or CAAT consensus sequence motifs and has a high content of dC and dG nucleotides. In this respect the putative IGFBP-2 promoter region resembles the promoters which are often associated with housekeeping genes.

Amino Acid Sequence↗
PubMed1992

Triiodothyronine (T3) stimulates insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-2 production by rat osteoblasts in vitro.

Osteoblast-like cells prepared from neonatal rat calvariae and grown under serum-free conditions produce IGF-1 and IGFBPs. In contrast to growth hormone, T3 and PTH increased both IGF-1 mRNA expression and net IGF-1 release in calvaria cells. In addition, they stimulated net production of IGFBP-3 and of an IGFBP with an apparent molecular weight of 32 kDa which was recognized by an antiserum against rat IGFBP-2. Bone cells expressed remarkably high levels of mRNA for IGFBP-2, the predominant IGFBP in serum of newborn rats. T3 at low physiological concentrations but not growth hormone stimulated IGFBP-2 mRNA expression and IGFBP-2 production in bone cells in vitro. Thus, IGFBPs are differentially regulated by these hormones and may play an autocrine/paracrine regulatory role in bone.

Animals↗
PubMed1991

The ovarian expression of the antigonadotropic insulin-like growth factor binding protein-2 is theca-interstitial cell-selective: evidence for hormonal regulation.

To begin the process of identification and charactization of rat ovarian insulin-like growth factor binding proteins, we have undertaken to explore the ovarian expression, cellular localization, and hormonal regulation of the insulin-like growth factor binding protein-2 (IGFBP-2) gene for which an antigonadotropic potential has recently been demonstrated. To this end, a solution hybridization/RNase protection assay was employed wherein total ovarian RNA (20 micrograms) from immature (21-23 days old) female rats was hybridized with a [32P]-labeled IGFBP-2 riboprobe. As in liver, a single protected fragment (550 bases long) corresponding to IGFBP-2 transcripts was identified in whole ovarian material. Cellular localization studies revealed the IGFBP-2 gene to be exclusively expressed in the theca-interstitial rather than the granulosa cell compartment. To confirm the cellular distribution of the IGFBP-2 protein, media conditioned by cultured granulosa or theca-interstitial cells were subjected to immunoprecipitation using two IGFBP-2-directed polyclonal antisera. Expectedly, both antibodies (but not non-immune rabbit serum) readily immunoprecipitated the 28 kDa rat IGFBP-2 species generated by hepatic BRL-3A cells. Similarly, both antibodies effectively immunoprecipitated an IGFBP the size of rat IGFBP-2 elaborated by theca-interstitial cells. In contrast, neither antibody immunoprecipitated the 28-29 kDa IGFBP species elaborated by granulosa cells otherwise readily apparent in conventional Western ligand blots. Hypophysectomy resulted in a 3-fold decrease (P less than 0.05) in the relative (densitometrically-quantified) abundance of ovarian IGFBP-2 transcripts, a diametrically opposed effect (P less than 0.05) being noted at the level of the liver. In contrast, treatment of immature hypophysectomized rats with a diethylstilbestrol-containing subcutaneous silastic implant for a total of 5 days resulted in a concordant 3-fold increase (P less than 0.05) in the relative abundance of IGFBP-2 transcripts in both ovary and liver when compared with untreated hypophysectomized controls. Taken together, these findings document rat ovarian IGFPB-2 gene expression to be theca-interstitial (rather than granulosa) cell-selective, and subject to upregulatory control by pituitary principle(s) and/or by estrogens. Although equally estrogen-dependent, hepatic IGFBP-2 gene expression proved constitutive in nature and subject to (diametrically opposed) inhibitory control by (potentially distinct) pituitary principle(s).

Animals↗
PubMed1991

Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity.

Ether link cleavage (ELC) of T4 yielding diiodotyrosine (DIT) has recently been shown in vitro to be the major pathway of T4 metabolism in phagocytosing leukocytes. To evaluate this pathway in vivo and the possible clinical relevance of DIT measurements in diseases with increased leukocyte activity, radioimmunological studies on serum levels of DIT and other thyroid parameters were performed in 125 critically ill patients classified into 3 groups with bacterial infections according to the severity of infection and 1 group without infections. While the pattern of iodothyronine and TSH levels typical for severe nonthyroidal disorders, i.e. decreased total T3 and elevated rT3, normal or decreased total T4 and TSH, and normal free T4, was found in all four groups of intensive care patients studied, elevated serum DIT was observed only in those patients whose clinical course was complicated by severe bacterial infections. Serial measurements revealed a close temporal connection between the infection phase and increased DIT levels. Median values and 16th to 84th percentile ranges (in parentheses) of serum DIT (normal range, 0.02-0.55 nmol/L) were as follows: sepsis, 1.38 (0.32-5.14); severe nonsystemic infections such as peritonitis and abscesses, 3.84 (0.24-17.2); moderate infections such as pneumonia and tracheobronchitis, 0.44 (0.18-1.16); and critical illness without infections, 0.14 (0.08-0.30) nmol/L. These elevations of circulating DIT could neither be correlated with changes in renal function nor attributed to drug effects. The results of the present study do not allow any definitive conclusions to be made about the mechanisms underlying the phenomenon of increased serum DIT levels in infections. Apart from this open question, DIT appears to be a relatively specific serum parameter for the presence and course of severe bacterial inflammations. Its measurement could provide useful clinical information, particularly for monitoring the time course of deep-seated infections.

Bacterial Infections↗
PubMed1990

Insulin regulates the expression of the insulin-like growth factor binding protein 2 mRNA in rat hepatocytes.

The goal of this study was to find out whether GH or insulin regulate the mRNA expression of the fetal binding protein of insulin-like growth factor (IGFBP-2). Primary hepatocytes from adult rats were used as a test system. IGFBP-2 mRNA was abundant in cells cultured in the absence of hormones and markedly reduced in cultures containing insulin. Addition of GH had no effect on IGFBP-2 mRNA levels although the cells are responsive to GH as demonstrated by a GH mediated elevation of IGF l mRNA levels. Half-maximal down-regulation of IGFBP-2 mRNA levels occurred at an insulin concentration of 1 to 2 x 10(-10) M. The finding that insulin is a potent negative regulator of hepatic IGFBP-2 mRNA levels suggests a physiologically important regulatory link between the two hormones insulin and IGF l.

Animals↗
PubMed1989

Regulation of hepatic expression of IGF I and fetal IGF binding protein mRNA in streptozotocin-diabetic rats.

Hepatic mRNA levels of insulin-like growth factor I (IGF I) and of the fetal, nonglycosylated 32 kDa IGF-binding protein (BP) were analysed in diabetic, diabetic insulin- and IGF I-treated rats as well as in age-matched, healthy control animals. IGF ImRNA levels are reduced in diabetic rats and increased by insulin treatment. In contrast, the infusion of IGF I does not significantly upregulate IGF I mRNA levels. Fetal IGF BP mRNA expression is very low in healthy control animals, but high levels are found in diabetic rats. Insulin therapy lowers fetal IGF BP mRNA levels, whereas IGF I has no effect. We propose that insulin is a major regulator of the 32 kDa IGF BP levels in adult rats.

Animals↗
PubMed1989

Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2).

Insulin-like growth factors bind with high affinity to specific binding proteins in extracellular fluids. To identify structural characteristics of IGF-binding proteins that might define their physiological roles, we determined the complete primary structure of a novel human IGF-binding protein (IGFBP-2) from a cloned cDNA. The cDNA encodes a 328 amino acid IGF-binding protein precursor which contains a 39-residue signal peptide. The mature 289 amino acid IGFBP-2 has a predicted Mr of 31,325. Chinese hamster ovary (CHO) cells stably transformed with the IGFBP-2 cDNA secreted a 36 kd protein which bound, with different affinities, IGFII and IGFI, but did not bind insulin. The predicted protein sequence of this IGF-binding protein shares extensive amino acid homology (greater than 85%) with the IGF-binding protein secreted by rat BRL-3A cells, but less than 40% homology with human IGFBP-1. Therefore IGFBP-2, and not IGFBP-1 as previously suggested, represents the human homologue of the rat BRL-BP (alpha IGFBP-2). Moreover, from alignment of the predicted protein sequences of IGFBP-1 and IGFBP-2, extensive conservation of the distribution of cysteine residues is observed. Although the overall amino acid homology shared by these proteins is not high, we suggest that they represent a family of structurally related human IGFBPs. Southern blot analysis of human DNA demonstrates that IGFBP-2 is encoded by a single-copy gene, different from that of IGFBP-1.

Amino Acid Sequence↗
PubMed1989

Expression of the BRL-3A insulin-like growth factor binding protein (rBP-30) in the rat central nervous system.

The expression of the BRL 3A insulin-like growth factor binding protein (rBP-30) was characterized in rat brain, hypothalamus, and pituitary tissue and cultured neuronal and astroglial cells. The 27K BP expressed by BRL 3A cells (rBP-30) was found to also be expressed in conditioned media from newborn rat astrocytes and fetal neurons, but not in the medium from the neuroblastoma cell line, B104. Moreover, a polyclonal antibody, anti HEC1, specifically immunoprecipitated the BRL 3A BP from the same conditioned media, as well as from rat cerebrospinal and amniotic fluid and from conditioned medium of cells isolated from the neurointermediate lobe of adult rat pituitary. The same antibody also immunoprecipitated hBP-31 from human CSF. Northern blot analyses showed that rBP-30 mRNA was expressed in adult rat brain and pituitary, fetal brain and liver, and in fetal neurons and newborn astrocytes maintained in culture. We conclude that the BRL 3A BP (rBP-30) is the major insulin-like growth factor binding protein in the rat CNS and may be the rat analog of hBP-31, the predominant BP in human CSF.

Animals↗
PubMed1989

A low molecular weight insulin-like growth factor binding protein from rat: cDNA cloning and tissue distribution of its messenger RNA.

Rat serum contains two major forms of insulin-like growth factor (IGF) binding proteins (BPs) that have apparent mol wts of about 35,000 and 150,000. We have isolated a cDNA clone encoding an IGF-BP whose N-terminal sequence is completely homologous to the NH2-terminal of the Buffalo rat liver cells-3A BP. The 270 amino acid mature protein has a predicted mol wt of 29,500. It contains a cysteine rich domain at each end of the molecule and an Arg-Gly-Asp (RGD) tripeptide motif near its C-terminus which suggests that this BP might associate with integrin cell surface receptors. The mature protein shares only partial homology with two published human IGF-BPs. Northern blot analysis shows that its mRNA is abundant in several fetal tissues, in adult brain, testes, ovaries, and kidney. Expression in the liver is high in fetal life but decreases to a barely detectable level in adulthood. However, upon hypophysectomy, the mRNA level increases at least 20-fold which suggests a hormonal regulation for the hepatic production of this small IGF-BP.

Amino Acid Sequence↗
PubMed1989

Prospective multicentre study on the prediction of relapse after antithyroid drug treatment in patients with Graves' disease.

Graves' disease is an autoimmune disease characterized by a course of remission and relapse. Since the introduction of antithyroid drug treatment, various parameters have been tested for their ability to predict the clinical course of a patient with Graves' disease after drug withdrawal. Nearly all these studies were retrospective [corrected] and often yielded conflicting results. In a prospective multicentre study with a total of 451 patients, we investigated the significance of a variety of routine laboratory and clinical parameters for predicting a patient's clinical course. Patients who had positive TSH receptor antibodies activity at the end of therapy showed a significantly higher relapse rate than those without (P less than 0.001). However, the individual clinical course cannot be predicted exactly (sensitivity 0.49, specificity 0.73, N = 391). The measurement of microsomal (P = 0.99, sensitivity 0.37, specificity 0.63, N = 275) or thyroglobulin antibodies (P = 0.76, sensitivity 0.18, specificity 0.84, N = 304) at the end of antithyroid drug therapy did not show a statistically significant difference in the antibody titre between the patients of the relapse and those of the remission group. Additionally, HLA-DR typing (HLA-DR3: P = 0.37, sensitivity 0.36, specificity 0.58, N = 253) was proven to be unsuitable for predicting a patient's clinical course. Patients with abnormal suppression or an abnormal TRH test at the end of antithyroid drug therapy relapse significantly more often (P less than 0.001) than patients with normal suppression or normal TRH test. Patients with a large goitre also have a significantly (P less than 0.001) higher relapse rate than those with only a small enlargement. The sensitivity and specificity values of all these parameters, however, were too low to be useful for daily clinical decisions in the treatment of an individual patient. This is also true for the combinations of different parameters. Though the highest sensitivity value (0.94) was found for a combination of the suppression and the TRH test at the end of therapy, the very low specificity value (0.13) for this combination reduced its clinical usefulness.

Follow-Up Studies↗