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Biomedical subjects

F Raulf

Publications and source records attributed to F Raulf.

At least 37 records · Page 2Linked to original sources
PubMed1995

Characterization of somatostatin receptor subtypes.

Somatostatin regulates endocrine and exocrine secretion, possesses antiproliferative properties and acts as a neurotransmitter/neuromodulator in the central nervous system. These effects are mediated by G protein-coupled receptors, of which at least five types have been cloned (sstr1-5). In radioligand-binding studies we have compared the binding properties of sstr1-5 with their activities as somatostatin receptors. All receptors identified so far bind somatostatin-14 and somatostatin-28 with high affinity. The similarities in receptor sequence and in the binding profiles of short synthetic somatostastin analogues such as octreotide, MK 678 or RC 160 for sstr1-5 indicate the existence of two classes of receptors sstr1/sstr4 with virtually no or very low affinity and sstr2/sstr3/sstr5 with intermediate to high affinity for the short somatostatin analogues. All five receptors mediate inhibition of adenylyl cyclase; this inhibition is sensitive to pertussis toxin. In vitro and in vivo studies suggest the importance of sstr2 and/or sstr5 in the inhibition of growth hormone release. The sstr2 receptor is apparently the predominant subtype expressed in somatostatin receptor-positive tumours. Evidence exists for the importance of sstr5 receptors in insulin secretion and sstr1 receptors in oncology. Somatostatin receptor-selective agonists and antagonists will help to explore new therapeutic opportunities in oncology as well as in endocrine and gastrointestinal disorders and those of the central nervous system.

Animals↗
PubMed1994

Neurotrophin-6 is a new member of the nerve growth factor family.

During vertebrate development, many neurons depend for survival and differentiation on their target cells. The best documented mediator of such a retrograde trophic action is the neurotrophin nerve growth factor (NGF). NGF and the other known members of the neurotrophin family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are conserved as distinct genes over large evolutionary distances. Here we report the cloning of neurotrophin-6 (NT-6), a new member of this family from the teleost fish Xiphophorus. NT-6 distinguishes itself from the other known neurotrophins in that it is not found as a soluble protein in the medium of producing cells. The addition of heparin (but not chondroitin) effects the release of NT-6 from cell surface and extracellular matrix molecules. Recombinant purified NT-6 has a spectrum of actions similar to NGF on chick sympathetic and sensory neurons, albeit with a lower potency. NT-6 is expressed in the embryonic valvulla cerebelli; expression persists in some adult tissues. The interaction of NT-6 with heparin-binding molecules may modulate its action in the nervous system.

Amino Acid Sequence↗
PubMed1994

Differential expression of five somatostatin receptor subtypes, SSTR1-5, in the CNS and peripheral tissue.

Somatostatin regulates endocrine and exocrine secretion, acts as a neurotransmitter/neuro-modulator and possesses antiproliferative properties. These diverse physiological effects are mediated by G-protein coupled receptors of which at least five subtypes have been cloned (SSTR1-5). Here, we have investigated the tissue distribution pattern of mRNAs encoding the five SRIF receptor subtypes in the adult rat by RT-PCR analysis and in situ hybridization histochemistry. All five receptor subtypes were found to be expressed simultaneously in brain and pituitary by RT-PCR. Besides, the in situ hybridization results clearly show a distinct but overlapping expression pattern of SSTR1-5 mRNA in the central nervous system as was found by RT-PCR for the periphery. Such distinct SRIF receptor expression may contribute to the selective biological functions of the receptor subtypes.

Animals↗
PubMed1993

Cloning and characterization of a fourth human somatostatin receptor.

We have isolated a gene coding for a fourth human somatostatin (somatotropin release-inhibiting factor) receptor. This additional somatostatin receptor (hSSTR4) is specifically expressed in human fetal and adult brain and lung tissue. The deduced amino acid sequence of the receptor displays both sequence and structural homology to three cloned somatostatin receptors as well as to other members of the family of GTP-binding-protein-coupled seven-helix transmembrane-spanning receptors. Pharmacological characterization of the expressed receptor reveals specific, high-affinity binding of somatostatin 14 and somatostatin 28. Surprisingly, several well-characterized synthetic somatostatin analogs fail to exhibit high-affinity binding to hSSTR4, indicating the existence of pharmacologically different receptor subtypes. Our data suggest that the diverse biological effects exerted by somatostatin are mediated by a family of receptors with discrete patterns of expression and different pharmacological properties.

Amino Acid Sequence↗
PubMed1993

Somatostatin analogs for diagnosis and treatment of cancer.

Somatostatin (SRIF) is a cyclic tetradecapeptide hormone initially isolated from ovine hypothalami. It inhibits endocrine and exocrine secretion, as well as tumor cell growth, by binding to specific cell surface receptors. Its potent inhibitory activity, however, is limited by its rapid enzymatic degradation and the consequent short plasma half-life. Octreotide is a short SRIF analog with increased duration of action compared to SRIF. Octreotide is approved for the treatment of acromegaly, amine precursor uptake and decarboxylation-omas, complications of pancreatic surgery and severe forms of diarrhea. Preclinical studies have focussed on the anticancer effects of octreotide and the related SRIF analogs BIM 23014 and RC-160. In vitro at nanomolar concentrations, these analogs inhibit the growth of tumor cells that express high affinity SRIF receptors. Accordingly, SRIF analogs, such as octreotide, potently inhibit the growth of SRIF receptor-positive tumors in various rodent models, and, in particular, xenotransplanted human tumors in nude mice. The range of cancers susceptible to octreotide and related SRIF analogs includes mammary, pancreatic, colorectal and lung malignancies. Moreover, an indirect antiproliferative effect of SRIF analogs is achievable in SRIF receptor-negative tumors, whose growth is driven by factors (gastrin, insulin-like growth factor-1, etc.) that are downregulated by SRIF. The use of radiolabeled somatostatin analogs represents a new diagnostic approach. [111In-DTPA]octreotide was developed for gamma camera imaging of SRIF receptor-positive malignancies, such as gasteroenteropancreatic tumors. Visualization of SRIF receptor-positive tumors in humans is emerging as an important methodology, both in tumor staging and predicting therapeutic response to octreotide. Recently, five SRIF receptor subtypes (SSTR1-5) have been cloned, all of which bind SRIF with high affinity. In contrast, SRIF receptor subtypes 1-5 have different binding profiles for short SRIF analogs. Octreotide, SSTR5, show moderate affinity for SSTR3 and fail to bind with high affinity to the other subtypes (SSTR1 and 4). Accordingly, the oncological profile of these three analogs is apparently similar. In conclusion, somatostatin analogs are a promising class of compounds for diagnosis and treatment of cancer. Current work is focussed on the identification of further SRIF receptor subtype-selective analogs with potential in oncology.

Amino Acid Sequence↗
PubMed1992

Brain-derived neurotrophic factor is more highly conserved in structure and function than nerve growth factor during vertebrate evolution.

Mammalian nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are members of a protein family with perfectly conserved domains arranged around the cysteine residues thought to stabilize an invariant three-dimensional scaffold in addition to distinct sequence motifs that convey different neuronal functions. To study their structural and functional conservation during evolution, we have compared NGF and BDNF from a lower vertebrate, the teleost fish Xiphophorus, with the mammalian homologues. Genomic clones encoding fish NGF and BDNF were isolated by cross-hybridization using probes from the cloned mammalian factors. Fish NGF and BDNF were expressed by means of recombinant vaccinia viruses, purified, and their neuronal survival specificities for different classes of neurons were found to mirror those of the mammalian factors. The half-maximal survival concentration for chick sensory neurons was 60 pg/ml for both fish and mammalian purified recombinant BDNF. However, the activity of recombinant fish NGF on both chick sensory and sympathetic neurons was 6 ng/ml, 75-fold lower than that of mouse NGF. The different functional conservation of NGF and BDNF is also reflected in their structures. The DNA-deduced amino acid sequences of processed mature fish NGF and BDNF showed, compared to mouse, 63% and 90% identity, respectively, indicating that NGF had reached an optimized structure later than BDNF. The retrograde extrapolation of these data indicates that NGF and BDNF evolved at strikingly different rates from a common ancestral gene about 600 million years ago. By RNA gel blot analysis NGF mRNA was detected during late embryonic development; BDNF was present in adult brain.

Amino Acid Sequence↗
PubMed1992

[Rational neurologic diagnosis in fecal incontinence].

The effective therapy of a disturbance of anal continence requires an adequate preoperative diagnostics. In most cases this includes some kind of neurophysiological investigation. Close cooperation between the internist, the surgeon and the neurologist is advantageous. The initial history, clinical examination and electromyography of the pelvic floor will usually be enough to differentiate between aetiologies. In the first phase it is necessary to decide whether the problem is neurogenic or muscular, and then to see localising signs for a nerve defect (central or peripheral) or, respectively, signs of a defect in the skeletal musculature. It must be said that a peripheral nerve lesion (eg. a stretching injury of branches of the pudendal nerve) and a muscular defect may be combined. At the end of the diagnostic process the surgeon or internist and neurologist must decide together whether the diagnosis is appropriate, and then whether an operative or non-operative approach to treatment is fitting. In the second phase of diagnosis are further neurophysiological investigations, which are only indicated in more special circumstances. These investigations include: nerve conduction velocities, reflex latencies (anal-, bulbocavernosus-, and pudendoanal reflexes), evoked potentials, and the single fibre EMG to determine fibre density. These neurophysiological investigation in proctology allows the clinician a wider scope of diagnostic possibilities, which should lead to more sensible therapeutic options being taken.

Electromyography↗
PubMed1992

Multiple src-related kinase genes, srk1-4, in the fresh water sponge Spongilla lacustris.

In one of the simplest metazoan organisms, the sponge Spongilla lacustris, at least four different src-related kinase genes (srk1-4) are expressed, all of which show a high degree of similarity to the c-src genes of vertebrates. Whereas srk2 and srk3 are clearly unrelated at the nucleic acid level, srk1 and srk4 share identical sequences in the 5' parts of their cDNAs. The cloning of several primer extension clones and genomic polymerase chain reaction experiments confirmed the hypothesis of an alternative splicing of tandemly arranged carboxy-terminal parts of srk1 and srk4. The genomic sequence encoding both proteins was found to be interrupted at the splice point by an intron which is located in the same position as one of the introns in the chicken src gene, which is the only gene conserved in invertebrates and vertebrates. All four srk genes are expressed in adult sponges as mRNA transcripts of about 2.2 kb. Tyrosine kinase activity of a src-related kinase could be detected in adult sponges but not in their resting form (gemmulae), and may reflect the activity of the srk protein products. Spongilla lacustris is the simplest organism from which a protein tyrosine kinase gene has been isolated. The presence of at least four such genes in the evolutionary ancient and primitive phylum Porifera suggests that tyrosine kinase genes arose concomitantly with or shortly after the appearance of multicellular organisms and that their activity may be involved in aggregation and cell-cell recognition.

Amino Acid Sequence↗
PubMed1991

Anorectal ergotism. Induced by migraine therapy.

The current report describes 15 patients, 14 women and one man, in whom anorectal ulceration appeared after use of ergotamine suppositories. In seven cases there was only ulceration to be seen, whereas in eight anovaginal or rectovaginal fistulae were visible. Symptoms are not specific. In the majority of situations, ulceration can usually be treated successfully by immediate withdrawal alone. In one case a stenosis of the anal canal remained. Fistulae need surgical intervention. Two fistulae could be treated sufficiently by the local flap technique. In six cases a colostomy was needed, which was transient in five and permanent in one patient. One recurrence was seen after continued ergot-abuse. Dosage is not in direct correlation to ulceration.

Adult↗
PubMed1989

Novel putative receptor tyrosine kinase encoded by the melanoma-inducing Tu locus in Xiphophorus.

Malignant melanoma in Xiphophorus fish hybrids is caused by the activity of a dominant oncogene Tu. By combining genetic and molecular approaches, we have isolated the melanoma oncogene. We show that its level of expression correlates with the degree of malignancy of the tumour. The corresponding proto-oncogene is developmentally regulated. The Tu gene codes for a novel receptor tyrosine kinase which is closely related to the receptor for epidermal growth factor.

Amino Acid Sequence↗
PubMed1989

Evolution of the neuron-specific alternative splicing product of the c-src proto-oncogene.

The observation of a slower migrating form of pp60c-src in neural tissue of chicken and mouse has recently been shown to be due to an alternative transcript form of the c-src gene (Martinez et al.: Science 237:411-415, 1987; Levy et al.: Mol Cell Biol 7:4142-4145, 1987). An insertion of 18 basepairs between exons 3 and 4, presumed to be due to alternative splicing of a mini-exon, gives rise to six amino acid residues not found in the non-neuronal (termed fibroblastic) form of pp60c-src. We have addressed the question of the evolutionary origin of the c-src neuronal insert and its functional significance regarding neural-specific expression of the c-src gene. To this end we have investigated whether the c-src gene of a lower vertebrate (the teleost fish Xiphophorus) gives rise to a neural-specific transcript in an analogous manner. We could show that the fish c-src gene does encode for a "fibroblastic" and a "neuronal" form of transcript and that the neuronal transcript does indeed arise by way of alternative splicing of a mini-exon. The mini-exon is also 18 basepairs long and we could demonstrate directly that this exon lies within the intron separating exons 3 and 4. For comparative purposes we have examined whether the fish c-yes gene, the member of the src gene family most closely related to c-src, also encodes a neural tissue-specific transcript. No evidence for a second transcript form in brain was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Localization of cellular src mRNA during development and in the differentiated bipolar neurons of the adult neural retina in Xiphophorus.

The expression of the c-src gene in embryonic and adult tissue of the teleost fish Xiphophorus helleri was analyzed by in-situ hybridization. The highly conserved fish c-src gene was found to be expressed at high levels in midterm embryos, where c-src mRNA was localized in developing neurons of the sensory layer of the differentiating retina and in the developing brain. In adult tissues the expression of c-src was found to persist in certain cell types of the brain and the neural retina, especially in the bipolar cells of the inner nuclear layer, which are postmitotic, fully differentiated mature neurons. Thus c-src in Xiphophorus appears to be a developmentally regulated proto-oncogene which is important for neuronal differentiation during organogenesis, but whose persistence of expression in certain terminally differentiated neurons strongly suggests a particular maintenance function for c-src in these cells as well.

Animals↗
PubMed1988

Expression of proto-oncogenes in embryonic, adult, and transformed tissue of Xiphophorus (Teleostei: Poeciliidae).

In Xiphophorus the causative, primary cellular oncogene for melanoma formation has been assigned by classical genetics to a sex-chromosomal locus, designated Tu. Activation of Tu was proposed to be the result of the elimination of Tu-specific regulatory genes which normally suppress the transforming function in the non-tumorous state. In order to understand the role which known proto-oncogenes might play in this process, we have analysed the expression of src, erb A, erb B, ras, abl, sis and mil related genes from Xiphophorus during embryogenesis, in non-tumorous organs and in melanoma cells. For src, ras, erb B and sis a differential expression during embryogenesis and/or in normal organs was detected, with preferential expression of src in neural tissues, a high abundance of sis transcripts in an embryonal epitheloid cell line and of erbB transcripts in the head nephros. In melanoma cells ras, src and a v-erb B related gene were found to be expressed. The src gene most likely is more involved in secondary processes during tumor progression, while the expression of the v-erb B related gene might be transformation-specific because recently such a sequence was found to map to the close vicinity of the Tu-locus.

Animals↗
PubMed1982

[Massive retroperitoneal haemorrhage in the Bourneville-Pringle syndrome (author's transl)].

Case-report of a 54 year-old patient who was admitted with the clinical picture of an acute abdomen on the basis of intraabdominal haemorrhage. X-ray investigation discounted the diagnosis of ruptured aortic aneurysm, the CAT scan showed a suspected acute haemorrhagic necrotising pancreatitis. At laparotomy, a fatty, bleeding kidney tumour was found growing into the retroperitoneal tissue. The histological frozen-section showed a leimyo liposarcoma of the kidney. Bourneville-Pringle's disease was only afterwards known to be the basic illness of the patient, as was verified at postmortem examination. From the knowledge of these new facts, both the CAT-scan and the intra-operative and histological findings could be correctly interpreted.

Acute Disease↗