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Biomedical subjects

P Coucke

Publications and source records attributed to P Coucke.

At least 55 records · Page 3Linked to original sources
PubMed1997

Timing effects of combined radioimmunotherapy and radiotherapy on a human solid tumor in nude mice.

Timing effects of radioimmunotherapy (RIT) combined with external-beam radiotherapy (RT) were assessed in human colon carcinoma xenografts. Initially, dose effects of fractionated RT and RIT were evaluated separately. Then, 30 Gy RT (10 fractions over 12 days) were combined with three weekly i.v. injections of 200 microCi of 131I-labeled anti-carcinoembryonic antigen monoclonal antibodies in four different treatment schedules. RIT was given either prior to, concurrently, immediately after, or 2 weeks after RT administration. The longest regrowth delay (RD) of 105 days was observed in mice treated by concurrent administration of RT and RIT, whereas the RDs of RT and RIT alone were 34 and 20 days, respectively. The three sequential combination treatments produced significantly shorter RDs ranging from 62 to 70 days. The tumor response represented by the minimal volume (MV) also showed that concurrent administration of RT and RIT gave the best result, with a mean MV of 4.5% as compared to MVs from 26 to 53% for the three sequential treatments. The results were confirmed in a second experiment, in which a RT of 40 Gy was combined with an identical RIT as above (three injections of 200 microCi of 131I-labeled monoclonal antibodies). At comparable toxicity levels, the maximum tolerated RT or RIT alone gave shorter RDs and less tumor shrinkage compared to simultaneous RT+ RIT. These results may be useful for designing clinical protocols of combined RIT and RT.

Animals↗
PubMed1997

The gene for Pendred syndrome is located between D7S501 and D7S692 in a 1.7-cM region on chromosome 7q.

Pendred syndrome is an autosomal recessive disorder characterized by goiter and congenital deafness. The primary defect is not yet known, although the gene causing Pendred syndrome has been localized very recently on chromosome 7q, a region that also contains a gene responsible for nonsyndromal hearing loss (DFNB4). We confirmed linkage to this chromosome 7 region in five Pendred families originating from different ethnic groups, with a highest cumulative lod score of 8.26 for marker D7S501. In combination with previous reports, our results define a candidate region for the Pendred gene of 1.7 cM flanked by markers D7S501 and D7S692.

Chromosome Mapping↗
PubMed1997

Diazepam-insensitive GABAA receptors on postnatal spiral ganglion neurones in culture.

Using dissociated spiral ganglion cell cultures obtained from 3-day-old rat cochlea, we investigated the response of auditory neurones to gamma-aminobutyric acid (GABA) using patch-clamp techniques. In our recording conditions, GABA elicited inward currents in > 95% of the neurones which reversed around 0 mV. Similar inward currents were measured using isoguvacin, a specific agonist of GABAA receptors. GABA-gated currents were reversibly inhibited by the channel blocker picrotoxin and the GABA competitive antagonist bicuculline. These functional GABAA receptors are characterized by an insensitivity to benzodiazepines and a relatively high sensitivity to beta-carbolines and barbiturates. These results show that the GABAA receptor pharmacological properties of spiral ganglion neurones are close to those of cerebellar granule cells.

Animals↗
PubMed1997

Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2.

OBJECTIVE: To study nonsyndromic progressive sensorineural hearing loss (SNHL) with significant linkage to the DFNA2 locus on chromosome 1p in a Dutch kindred. DESIGN: A 6-generation family with 194 family members was studied. Of the presumably affected persons, 43 were examined in detail to obtain audiograms and 37 underwent vestibulo-ocular examination. RESULTS: Regression analysis showed significant and equal linear progression in SNHL with age (by about 1 dB per year) at all frequencies. Offset values were close to zero at the low frequencies (0.25, 0.5, and 1 kHz) but increased systematically with the frequency. It is likely that they represent congenital high-frequency SNHL: about 15 dB at 2 kHz, 30 dB at 4 kHz, and 50 dB at 8 kHz. Bilateral caloric weakness was not observed. A significant finding was that 25% to 35% (depending on the exclusion criteria) of the patients showed an increased vestibulo-ocular reflex (hyperreactivity) as measured by rotatory responses. Forty-one patients showed significant linkage to the 1p locus. CONCLUSIONS: Including the present family, 4 families have been reported to show linkage to chromosome 1p. Statistical analysis of the audiological data shows a progression of 1 dB per octave per year in this type of progressive SNHL.

Adult↗
PubMed1997

Transfer of information between angiographic films and CT images: a technique to control the drawing of target volumes.

BACKGROUND AND PURPOSE: This work was undertaken to improve the definition of target volumes for radiosurgery using the angiographic and CT data. MATERIALS AND METHODS: The basis of this new method is to combine both imaging modalities and to compare them in each representation, i.e. to plot the volume obtained by angiography on CT images and also the contours defined by the CT on angiographic films. To obtain the angiographic volume, the radiographs are taken at several incidence angles. The X-ray sources position and the position of the films are determined using rectangular markers, then the intersection of all the loci of the target volume are calculated. RESULTS: Verifications with a phantom show the accuracy of the procedure and the benefit obtained by increasing the number of angles of incidence in the angiographic imaging. The centre of gravity of the experimental target could be localized to an accuracy of better than 0.4 mm. The method was used in 11 clinical cases with excellent clinical results. CONCLUSIONS: The method can be easily applied and improves the delineation of target volumes in radiosurgery. CT data counterbalances the relative weakness of angiography concerning the three-dimensional geometry. Angiography adds useful information on the blood flow that is not shown in CT. Almost all the presented clinical cases benefit from the technique described here.

Angiography↗
PubMed1996

Beta-carbolines induce apoptotic death of cerebellar granule neurones in culture.

Apart from its role in fast inhibitory transmission, only neurotrophic effects have been reported following activation of the GABAA receptor. Here, we show that n-butyl-beta-carboline-3-carboxylate and n-methyl-beta-carboline-3-carboxamide, which are negative allosteric modulators of the GABAA receptor acting at the benzodiazepine site, are neurotoxic for cerebellar granule neurones in culture. The beta-carboline-induced neuronal death is apoptotic since DNA internucleosomal fragmentation was induced and the neurotoxicity could be prevented by inhibitors of mRNA or protein synthesis. As GABA and benzodiazepine ligands (diazepam and Ro 15-1788) protect cerebellar granule cells against beta-carboline-induced toxicity, these data raise the possibility that the interaction between the beta-carbolines and the GABAA receptor is the triggering event leading to neuronal apoptosis.

Animals↗
PubMed1996

Astroglia-released factor with negative allosteric modulatory properties at the GABA A receptor.

We have previously shown, using whole-cell patch-clamp techniques, that astrocytes release a negative allosteric modulator of the gamma-aminobutyric acid type A receptor (GABAA receptor) with beta-carboline-like properties, thus, likely to act at the benzodiazepine site. Here, using patch-clamp and binding techniques, we confirm that the low-molecular-weight fraction of astroglia-conditioned medium (ACM lmf) contains a factor(s) that negatively modulates GABAA-receptor function. This factor, like beta-carbolines, enhances the specific binding of [35S]t-butyl bicyclophosphorothionate (TBPS) to adult rat cortical membranes in the presence of GABA. However, it fails to interact with various ligands of the benzodiazepine (BZD) site of the GABAA receptor ([3H]flunitrazepam, [3H]Ro 15-1788 and [3H]Ro 15-4513). The question of the actual binding site of the astroglia-derived factor on the GABAA receptor, thus, remains open and can be addressed only after the purification of the active molecule(s) of ACM Imf has been completed, and a labeled form of the endogenous ligand becomes available. Taken together, however, the data suggest that type 1 astrocytes are able to modulate the effects of the main inhibitory neurotransmission in the central nervous system.

Allosteric Regulation↗
PubMed1996

Positional cloning of a gene involved in hereditary multiple exostoses.

Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.

Amino Acid Sequence↗
PubMed1996

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase.

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.

Amino Acid Sequence↗
PubMed1995

Combined radioimmunotherapy and radiotherapy of human colon carcinoma grafted in nude mice.

The effect of combined radioimmunotherapy (RIT) and fractionated external beam radiotherapy (RT) was assessed in two human colon cancer xenografts, Co112 and LS174T in nude mice. These tumors were selected for being resistant to RIT alone, as is usually the case in the clinical situation. Tumor-bearing mice were treated with a combination of five X-ray fractions over 5 days followed by RIT with two doses of 1.5 mCi 131I-labeled anticarcinoembryonic antigen monoclonal antibody F(ab')2. In Co112 and LS174T, RIT alone achieved a regrowth delay similar to that of fractionated RT with total doses of 28 and 26 Gy, respectively. In both tumor types, an additive therapeutic effect, measured as increased regrowth delay or local control, was observed when combining RT of different dose levels with RIT. Normal tissue responses were assessed by monitoring acute peak skin reactions and blood cell count. Bone marrow depression for the combination treatment was similar to that of RIT alone; relative to skin, at equitoxic levels, no mice bearing Co112 tumors were locally controlled with a 32 Gy RT dose alone, while this RT combined with RIT gave a local control of 100%. These studies show a therapeutic benefit when external beam RT is combined with RIT.

Animals↗
PubMed1995

Nausea and vomiting in fractionated radiotherapy: a prospective on-demand trial of tropisetron rescue for non-responders to metoclopramide.

A prospective trial was performed to better assess the risk of nausea and vomiting and the rescue value of tropisetron (TRO), a 5-HT3 receptor antagonist, in 88 patients undergoing fractionated radiotherapy to the abdomen or to large supradiaphragmatic fields and failing a first anti-emetic trial with metoclopramide (MET). Nausea was graded 0 (absent), 1 (mild), 2 (moderate) and 3 (severe). Nausea requiring anti-emetics (> or = grade 2) was present in 64% of the patients. MET was able to control nausea (< or = grade 1) in 26 of 58 patients (45%) who developed > or = grade 2 nausea during radiation treatment (2 patients vomiting without nausea included). 34 patients required TRO, and 31 experienced immediate relief. However, nausea (> or = grade 2) recurred in 7 patients from 1 to 3 weeks after starting TRO. Sex, age, field type and field size (cm2) did not influence the incidence and severity of nausea and vomiting. Only 24/88 patients vomited after starting radiotherapy. MET helped to eliminate emesis in one third of these patients. TRO helped to control vomiting in 73% of the salvaged patients. Constipation was observed in 8 patients on TRO and was a reason to stop the medication in 4 cases.

Abdominal Neoplasms↗
PubMed1995

Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease.

Phosphorylase kinase (PHK) is a key enzyme in the control of glycogen breakdown. Several types of PHK deficiency have been described of which X-linked liver glycogenosis type I (XLG I) is the most common. Since the XLG I locus and the gene encoding the liver alpha-subunit gene of PHK (PHKA2) have both been localized to Xp22, PHKA2 was a candidate gene for XLG I. In this study we identified four point mutations in four unrelated XLG I patients: three mutations introduce a premature stop codon, whereas the fourth mutation abolishes a splice site consensus sequence leading to exon skipping. These findings indicate that PHKA2 is the XLG I gene.

Base Sequence↗
PubMed1995

Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15.

Progressive hearing loss affects approximately 50% of the elderly by the age of 80, and is most likely caused by an interaction of genetic and environmental factors. Identification of the genes responsible for hereditary hearing loss is therefore important. Families with pure genetic degenerative hearing disorders may be helpful as the same genes may be also involved in age-related hearing loss in general. In this study we have performed a genome search in an extended Dutch family with autosomal dominant progressive hearing loss starting in the high frequencies. The gene causing hearing loss in this family was localized to the short arm of chromosome 7, in a 15 cM interval between markers D7S493 and D7S632.

Chromosome Mapping↗
PubMed1995

Linkage of a gene for dominant non-syndromic deafness to chromosome 19.

Inherited hearing impairment can occur either in the presence of other clinical features (syndromic hearing loss, SHL) or in isolation (non-syndromic hearing loss, NSHL). The latter is more common and is highly heterogeneous. To date, six NSHL loci have been mapped. We report the identification of a seventh locus (DFNA4) on chromosome 19q13 and suggest DM kinase as a possible candidate gene.

Chromosome Mapping↗
PubMed1995

Consanguineous nuclear families used to identify a new locus for recessive non-syndromic hearing loss on 14q.

Hearing impairment is inherited most frequently as an autosomal recessive isolated clinical finding (non-syndromic hearing loss, NSHL). Extreme heterogeneity and phenotypic variability in the audiometric profile preclude pooling of affected families and severely hamper gene mapping by conventional linkage analysis. However, in instances of consanguinity, homozygosity mapping can be used to identify disease loci in small nuclear families. This report demonstrates the power of this technique by identifying a locus for recessive NSHL on 14q (DFNB4).

Chromosome Mapping↗
PubMed1995

An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of congenitally acquired inherited hearing impairment. Although numerous loci are believed to exist, only five have been identified. Using a pooled genomic DNA screening strategy, we have identified a sixth locus, DFNB6, on 3p in the interval bounded by D3S1619 and D3S1766.

Alleles↗
PubMed1995

CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1.

L1 is a neuronal cell adhesion molecule with important functions in the development of the nervous system. The gene encoding L1 is located near the telomere of the long arm of the X chromosome in Xq28. We review here the evidence that several X-linked mental retardation syndromes including X-linked hydrocephalus (HSAS), MASA syndrome, X-linked complicated spastic paraparesis (SP1) and X-linked corpus callosum agenesis (ACC) are all due to mutations in the L1 gene. The inter- and intrafamilial variability in families with an L1 mutation is very wide, and patients with HSAS, MASA, SP1 and ACC can be present within the same family. Therefore, we propose here to refer to this clinical syndrome with the acronym CRASH, for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus.

Abnormalities, Multiple↗