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M Mangin

Publications and source records attributed to M Mangin.

At least 19 recordsLinked to original sources
PubMed2006

[Diagnosis of myocarditis: description and assessment of available methods].

Myocarditis is a common disease in all age groups. Correct diagnosis of myocarditis is difficult, but of clinical and scientific importance. It is the aim of this review to describe and evaluate diagnostic possibilities. It is not possible to make a definitive diagnosis of myocarditis by electrocardiography, laboratory tests or echocardiography. Nor can techniques of nuclear medicine or coronary angiography provide an unequivocal diagnosis of myocarditis. Myocarditis can be diagnosed with certainty only by endomyocardial biopsy, which must be examined by histological, immunohistological and molecular techniques to obtain maximal sensitivity. But optimal diagnosis of a biopsy is subject to the problem of sampling error. Furthermore, myocardial biopsy is in practice used only rarely, despite a low complication rate. Thus the diagnosis of myocarditis is often based merely on suspicion. The limitations of standard methods employed so far have made cardiac magnetic resonance imaging (CMR) a valuable new additional test when there is the clinical suspicion of myocarditis. A myocardial biopsy will often reveal myocarditis in patients with cardiac symptoms and CMRI findings typical of myocarditis, especially if the biopsy was obtained near the area of contrast enhancement in the CMRI. CMRI can also be used for noninvasive and low-risk follow-up of functional parameters and tissue damage.

Biopsy↗
PubMed1991

[The association of continuous peridural anesthesia with general anesthesia. Apropos of 2 accidents].

Continuous lumbar epidural anaesthesia combined with light general anaesthesia provides optimal anaesthetic conditions to realize major lower abdominal or pelvic surgical cases. However this technique may cause haemodynamic alterations due to the important vasoplegia and to the potential myocardial toxicity of the local anaesthetics. The authors report two accidents associated with this technique, one of them with lethal outcome.

Aged↗
PubMed1990

Structure of the mouse gene encoding parathyroid hormone-related peptide.

The parathyroid hormone-related peptide (PTHRP) was initially isolated from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene is a complex transcriptional unit which uses multiple promoters and contains alternatively spliced 3' exons that result in mRNAs encoding three different deduced products. We report here the structure of the mouse PTHRP gene. The mouse gene has a considerably simpler organization than its human counterpart. This organization includes a single 3' exon and an apparent single 3' splicing pathway, leading to an mRNA encoding a 139-amino acid mature PTHRP. In addition, the mouse gene appears to be predominantly under the control of a short proximal promoter element. By RNase protection analysis, we identified PTHRP mRNA in specimens prepared from a variety of normal rodent tissues, including a number of tissues not previously recognized as sites of PTHRP gene expression.

Amino Acid Sequence↗
PubMed1990

Regulation of parathyroid hormone-related peptide gene expression by cycloheximide.

A novel parathyroid hormone-related peptide (PTHRP) has been isolated from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene appears to use multiple promoters and contains alternatively spliced 3' exons which give rise to three PTHRP mRNA classes, each bearing multiple copies of an AU motif that has been associated with mRNA instability. We report here that inhibition of protein synthesis leads to the super-induction of PTHRP mRNA expression in a number of human and rat cell lines. This phenomenon was found to reflect both an increase in the rate of PTHRP gene transcription and a stabilization of PTHRP mRNAs. The transcriptional mechanism appears to preferentially involve the activity of a short downstream promoter of the gene, which is presumed to be regulated by a labile repressor protein. Our findings indicate that both transcriptional and posttranscriptional mechanisms may be important control points in the regulation of PTHRP expression in normal and malignant cells.

Actins↗
PubMed1990

Identification of an up-stream promoter of the human parathyroid hormone-related peptide gene.

Previous evidence has suggested that the human PTH-related peptide (PTHRP) gene uses two promoters, one a short down-stream element lying immediately between two 5' exons (1 and 2) and a second lying in an unknown up-stream location. We approached identification of the up-stream element in three steps. First, Northern analysis carried out using progressively 5' fragments of the gene as probes identified a candidate region some 2.5 kilobases up-stream of exon 1. Second, a battery of overlapping 5' cRNA probes was used in RNase protection experiments to identify two previously unrecognized exons, 212 and 93 basepairs in length (termed exons 1A and 1B to distinguish them from the previously designated exon 1, which was termed exon 1C). Third, primer extension experiments were performed with oligonucleotides complementary to each of the 5' exonic sequences. These experiments identified a transcription start site up-stream of exon 1A and also demonstrated that the 5' exons of the PTHRP gene could be spliced together in several combinations. The up-stream promoter element contains a TATA box, but does not otherwise resemble the down-stream PTHRP gene promoter or the PTH gene promoter. We conclude that the human PTHRP gene contains eight exons spanning more than 15 kilobases of genomic DNA, with promoter elements lying immediately up-stream of exons 1A and 2. The identification of these elements will permit functional analysis of their roles in mediating tissue- and tumor-specific PTHRP gene expression.

Base Sequence↗
PubMed1989

Transcriptional regulation of the parathyroid hormone-related peptide gene by glucocorticoids and vitamin D in a human C-cell line.

A parathyroid hormone-related peptide (PTHRP) has been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP and parathyroid hormone (PTH) genes appear to have arisen by duplication and to represent members of a gene family. PTHRP mRNAs have been demonstrated in a number of normal tissues, but little is known concerning the regulation of PTHRP gene expression in any site. We studied PTHRP gene expression in TT cells, a human C-cell line which also produces calcitonin and calcitonin gene-related peptide. We found that both the synthetic glucocorticoid, dexamethasone, and the active vitamin D metabolite, 1,25-dihydroxyvitamin D3, decreased steady-state PTHRP mRNA levels in TT cells in a time- and dose-dependent fashion. The dexamethasone effect was completely blocked by the glucocorticoid antagonist RU-486. 24,25-dihydroxyvitamin D3 was found to be inactive. Neither dexamethasone nor 1,25-dihydroxyvitamin D3 appeared to influence PTHRP mRNA stability in TT cells, and both agents were shown by nuclear transcription run-off assay to decrease PTHRP gene transcription. These findings indicate that the PTHRP gene is under the transcriptional control of glucocorticoids and vitamin D in a cell line with prototypical neuroendocrine features.

Calcitonin↗
PubMed1989

Clonal rat parathyroid cell line expresses a parathyroid hormone-related peptide but not parathyroid hormone itself.

A novel parathyroid hormone-related peptide has been identified in tumors associated with the syndrome of humoral hypercalcemia of malignancy. Subsequently, mRNAs encoding this peptide have been found to be expressed in a number of normal tissues, including the parathyroids. Using Northern blotting, RNase protection, and immunochemical techniques, we examined a clonal rat parathyroid cell line originally developed as a model system for studying parathyroid cell physiology. We found that this line expresses the parathyroid hormone-related peptide but not parathyroid hormone itself. Secretion of the parathyroid hormone-related peptide varied inversely with extracellular calcium concentration, but neither calcium nor 1,25-dihydroxyvitamin D3 appeared to influence steady-state parathyroid hormone-related peptide mRNA levels. This clonal line may prove to be an interesting system for studying the factors responsible for tissue-specific parathyroid hormone and parathyroid hormone-related peptide gene expression.

Animals↗
PubMed1989

Isolation and characterization of the human parathyroid hormone-like peptide gene.

A parathyroid hormone-like peptide (PTH-LP) has recently been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The peptide appears to be encoded by a single-copy gene that gives rise to multiple mRNAs that are heterogeneous at both their 5' and their 3' ends. Alternative RNA splicing is responsible for the 3' heterogeneity and results in mRNAs encoding three different peptides, each with a unique C terminus. We have isolated and characterized the human PTHLP gene. The gene is a complex transcriptional unit spanning more than 12 kilobases of DNA and containing six exons. Two 5' exons encode distinct 5' untranslated regions and are separated by a putative promoter element, indicating that the gene either has two promoter or is alternatively spliced from a single promoter upstream of the first exon. The middle portion of the PTHLP gene, comprising exons 2-4, has an organizational pattern of introns and exons identical to that of the parathyroid hormone gene, consistent with a common ancestral origin of these two genes. Exon 4 of the PTHLP gene encodes the region common to all three peptides and the C terminus of the shortest peptide, and exons 5 and 6 encode the unique C termini of the other two peptides. Northern analysis of mRNAs from four human tumors of different histological types reveals the preferential use of 3' splicing patterns by individual tumors.

Amino Acid Sequence↗
PubMed1989

Expression of transcripts encoding a parathyroid hormone-related peptide in abnormal human parathyroid tissues.

A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene has been recently isolated and found to be a complex transcriptional unit using multiple promoters and containing alternatively spliced 3' exons which result in three mRNA classes, each class encoding a PTHRP with a unique carboxy-terminus. The PTHRP gene appears to be expressed in a number of normal tissues, and PTHRP transcripts have been previously reported to be overexpressed in a small sample of human parathyroid adenomas. In the present study we surveyed RNA prepared from a total of 60 abnormal human parathyroid glands for PTHRP gene expression using a combination of Northern blotting and RNase protection techniques. Apparent overexpression of PTHRP mRNA was observed in two thirds of parathyroid adenomas, whereas no overexpression was found in 7 examples of sporadic primary hyperplasia, 5 examples of secondary hyperplasia, and 3 examples of parathyroid carcinoma. Apparent overexpression was also observed in 1 of 4 cases of multiple endocrine neoplasia type 1, 1 of 2 examples of multiple endocrine neoplasia type 2, and 1 gland considered to represent tertiary hyperparathyroidism. Northern analysis of poly(A)+ RNA prepared from three representative adenomas using region-specific probes indicated that two putative promoters are used and revealed a pattern of preferential splicing of transcripts to include the most distal 3' exon. These findings suggest that the PTHRP gene is commonly overexpressed in adenomatous parathyroid glands, but not in sporadic primary hyperplasia, that this overexpression does not seem to be dependent on the use of a single specific promoter, and that adenomatous parathyroid cells appear to preferentially use one of several alternative splicing pathways. It is presently not known whether PTHRP is secreted by abnormal parathyroid tissues and, if so, in what form.

Adenoma↗
PubMed1989

Glucocorticoid regulation of parathyroid hormone-related peptide gene transcription in a human neuroendocrine cell line.

A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP and PTH genes appear to represent members of a gene family. Whereas the PTH gene is expressed exclusively in the parathyroids, the PTHRP gene appears to be widely expressed, but little is known concerning the regulation of its expression in any site. We studied the regulation of PTHRP gene expression in a human carcinoid cell line (NCI-H727) which has neuroendocrine features and also produces calcitonin, calcitonin gene-related peptide, and chromogranin-A. We found that the synthetic glucocorticoid triamcinolone produced time- and dose-dependent decreases in steady state PTHRP and calcitonin mRNA levels in NCI-H727 cells. This effect was blocked by the competitive glucocorticoid inhibitor RU-486. Messenger RNA stability and transcription run-off experiments revealed that triamcinolone decreased PTHRP and calcitonin expression by repressing the transcription rates of both genes.

Calcitonin↗
PubMed1988

Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy.

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome that appears to be mediated in many instances by a parathyroid hormone-like peptide. Poly(A)+ RNA from a human renal carcinoma associated with this syndrome was enriched by preparative electrophoresis and used to construct an enriched cDNA library in phage lambda gt10. The library was screened with a codon-preference oligonucleotide synthesized on the basis of a partial N-terminal amino acid sequence from a human tumor-derived peptide, and a 2.0-kilobase cDNA was identified. The cDNA encodes a 177 amino acid protein consisting of a 36 amino acid leader sequence and a 141 amino acid mature peptide. The first 13 amino acids of the deduced sequence of the mature peptide display strong homology to human PTH, with complete divergence thereafter. RNA blot-hybridization analysis revealed multiple transcripts in mRNA from tumors associated with the humoral syndrome and also in mRNA from normal human keratinocytes. Southern blot analysis of genomic DNA from humans and rodents revealed a simple pattern compatible with a single-copy gene. The gene has been mapped to chromosome 12.

Amino Acid Sequence↗
PubMed1988

Synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats.

Parathyroid hormone-like adenylate cyclase-stimulating proteins (hACSPs) have been implicated as one of the calcemic, bone-resorbing agents in patients with humoral hypercalcemia of malignancy. We report the synthesis of an amino-terminal hACSP fragment, Tyr36 hACSP (1-36) amide. The synthetic hACSP is a potent agonist of renal membrane adenylate cyclase (Km, 1.7 X 10(-10)) and of bone cell adenylate cyclase (Km 1 X 10(-9)M). It is a potent bone-resorbing agent in vitro, stimulating 45Ca release from fetal rat long bones at a concentration of 10(-9) M. When infused via osmotic minipumps into rats, it is also a potent calcemic factor in vivo, inducing a rise in serum calcium from (mean +/- SD) 10.6 +/- 0.6 to 19.7 +/- 3.2 mg/dl when infused at 1.4 micrograms/h and from 9.9 +/- 0.7 to 11.4 +/- 1.2 mg/dl when infused at 0.14 micrograms/h. These findings indicate that biologically active hACSP fragments can be synthesized. One such synthetic peptide possesses the in vitro and in vivo bioactivities demonstrated in native, tumor-derived hACSPs. It is also a potent calcemic, bone-resorbing agent.

Adenylyl Cyclases↗
PubMed1988

Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy.

The syndrome of humoral hypercalcemia of malignancy (HHM) appears to be mediated in many instances by a parathyroid hormone-like peptide, which has recently been purified, sequenced, and cloned. Using a probe representing the coding region of the human PTH-like peptide, we examined by Northern analysis poly (A)+ RNA from a variety of human and animal tumors associated with HHM. Hybridizing transcripts were identified in mRNA from each of 12 human and each of four animal HHM-associated tumors, with a complex hybridization pattern observed in the human mRNAs and a relatively simple pattern observed in the animal mRNAs. Poly (A)+ RNA prepared from tumors of similar histological types unassociated with HHM failed to hybridize with the probe. Messenger RNA-dependent biological activity from the animal tumors was entirely eliminated in a hybridization-arrest experiment using a complementary oligonucleotide spanning the region of homology between human PTH and the PTH-like peptide. These findings indicate that the PTH-like peptide is associated with the syndrome of HHM in a wide spectrum of tumor types from a variety of mammalian species and that the PTH-like sequence in the proximal amino terminus of the peptide is highly conserved.

Amino Acid Sequence↗
PubMed1988

Synthetic and partially-purified adenylate cyclase-stimulating proteins from tumors associated with humoral hypercalcemia of malignancy inhibit phosphate transport in a PTH-responsive renal cell line.

Hypophosphatemia and hyperphosphaturia characteristically occur in patients with humoral hypercalcemia of malignancy (HHM). To determine if a tumor product causes these abnormalities in phosphate metabolism, rather than, for example, hypercalcemia, we investigated the effect of partially-purified adenylate cyclase-stimulating activity (ACSA) from human and animal HHM-associated tumors on sodium-dependent phosphate transport (Na PiT) in a PTH-responsive renal epithelial cell line. Thirty minute exposure to 7 X 10(-10) MbPTH (1-34) equivalents of ACSA from the human and animal tumors, reduced NaPiT by 20% and 14%, respectively. We also recently isolated an adenylate cyclase-stimulating protein (hACSP) from two human tumors associated with HHM and identified a cDNA clone for this protein which encodes a 141 amino-acid peptide. Based on the deduced amino-acid sequence, we synthesized tyr36 (1-36) hACSP. This synthetic peptide induced a 22% decrease in the initial rate of NaPiT by the epithelial monolayer. Its inhibitory activity was roughly equipotent to that of bPTH (1-34). We conclude that the ACSP derived from HHM-associated tumors decreases phosphate transport in renal epithelial cells. This peptide appears to play a key role in mediating the changes in phosphate metabolism in this syndrome.

Adenylyl Cyclases↗
PubMed1988

Two distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing.

A novel PTH-like peptide has recently been isolated and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The deduced product of the initial clones to be reported is a 177 amino-acid protein, consisting of a 36 amino-acid precursor sequence followed by a 141 amino-acid mature peptide. Southern analysis of genomic DNA is compatible with a single-copy gene, but Northern analysis of mRNAs from both tumors and normal tissues consistently reveals multiple hybridizing transcripts, suggesting the possibility of alternative RNA splicing. We provide here direct evidence of alternative RNA splicing by the identification of a second cDNA clone in a human renal carcinoma cDNA library. As compared to the initial clone, this cDNA contains a foreshortened 5'-untranslated region but is otherwise identical until the distal portion of the coding region, at which point it diverges completely to encode a 166 amino-acid mature peptide with 27 amino acids of unique C-terminal sequence. The relative lengths of the primary translation products encoded by these two cDNAs were confirmed by transcription and translation in vitro, and both products were shown to be processed by added microsomes. The unique 3'-ends of these two cDNAs, as well as that of a third cDNA isolated by another laboratory, were used to identify one or more hybridizing transcripts corresponding to each cDNA in mRNA from a human renal carcinoma as well as in mRNA from normal human keratinocytes. We conclude that alternative RNA splicing results in mRNAs which encode multiple PTH-like peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1988

Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas.

A novel PTH-like peptide has recently been purified and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. We surveyed the expression of mRNAs encoding this peptide in normal tissues by Northern analysis. One or more low abundance hybridizing transcripts was identified in poly(A)+ RNA prepared from human keratinocytes, thyroid, bone marrow, and fibroblasts, from bovine hypothalamus, pituitary, parathyroid, adrenal cortex, and adrenal medulla, and from rat brain, stomach mucosa, and fetal but not adult liver. One or more hybridizing transcripts was also identified in poly(A)+ RNA prepared from a number of established lines, including rat pituitary (GH4), rat pheochromocytoma (PC 12), human osteosarcoma (TE-85), and human medullary carcinoma (TT) cells. Northern analysis of mRNAs from abnormal human parathyroid tissue revealed an overexpression of transcripts for the PTH-like peptide which appeared to be specific for adenomatous or autonomous glands. These findings suggest that the PTH-like peptide is expressed in a number of endocrine and nonendocrine tissues, that it is developmentally expressed in at least one tissue (fetal liver), and that the regulation of its expression is abnormal in human parathyroid adenomas.

Adenoma↗
PubMed1986

Human U2 small nuclear RNA genes contain an upstream enhancer.

The human U1 and U2 snRNA genes lack an obvious TATA box, but are extremely powerful RNA polymerase II transcription units capable of accurately initiating at least one transcript per gene every 2-4 s. We have investigated the location of cis-acting regulatory elements within the flanking sequences of human U2 and U1 genes. By introducing marked human U2 genes into HeLa cells on SV40- and pUC13-based vectors, we found that transient expression of the marked U2 gene did not require the SV40 enhancer. The U2 promoter element responsible for SV40 enhancer-independent U2 expression was localized within the 5'-flanking sequence of the gene, and shown to stimulate transcription from the U2 basal promoter in an orientation- and position-independent fashion. In addition, the U2 element could be functionally replaced by either the SV40 enhancer or by distal sequences from the human U1 promoter. We conclude that the human U2 and U1 genes contain functionally equivalent enhancer elements. Moreover, since the human U2 enhancer sequences resemble the Xenopus U2 enhancer-like element, enhancers appear to be a general feature of vertebrate snRNA promoter structure.

Base Sequence↗