BACKGROUND Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disabilit... more BACKGROUND Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy. AIM: To present an overview of the development of targeted treatment for fxs. METHOD: Several important publications were collected and indexed. RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing. CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement...
Introduction of new genetic test technologies in the last decade have accelerated genetic diagnos... more Introduction of new genetic test technologies in the last decade have accelerated genetic diagnosis in many medical specialties and have increased diagnostic yield considerably. SNP-arrays have been established as first tier diagnostic tools, more and more being replaced by next generation sequencing strategies, like targeted genomic panels and whole exome sequencing. We present the diagnostic work-up of a clinical case, a girl with congenital vertebral and rib anomalies. This case illustrates the complexity of genetic tests and the need for knowledge and experience to interpret the results. Intensive collaboration between pediatrician, clinical geneticist and laboratory specialist is mandatory, as is long-term commitment to involve parents in the diagnostic journey .
ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verst... more ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verstandelijke beperking en autismespectrumstoornissen. Een gerichte therapie ontbreekt vooralsnog. De afgelopen decennia brachten een explosie aan kennis over de betrokken moleculaire processen en daarmee potentiele aangrijpingspunten voor gerichte therapie. DOEL Een overzicht geven van de ontwikkeling van gerichte therapie voor fxs. METHODE Een aantal belangrijke publicaties werd verzameld en op een rij gezet. RESULTATEN Preklinische diermodelonderzoeken tonen veelbelovende resultaten van gerichte interventies, maar vertaling naar de kliniek is vooralsnog teleurstellend. CONCLUSIE Een gerichte therapie voor fxs is nodig en zou mogelijk kunnen worden toegepast bij andere oorzaken van autisme en verstandelijke beperking. Aspecten op het gebied van translatie, studieopzet en uitkomstmaten spelen mogelijk een rol bij de teleurstellende resultaten. Voor de klinische implementatie van toekomstige...
Modulators of the 'classical' multidrug resistance (mdr) phenotype have low effic... more Modulators of the 'classical' multidrug resistance (mdr) phenotype have low efficacy in patients with solid tumors. We analyzed BIBW22BS, 4-[N-(2-hydroxy-2-met- hyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-dimethyl-morpho- lino)-6-phenylpteridine, a derivative of dipyridamole, for its higher potential to modulate mdr. Four human malignant cell lines: BRO, A2780, GLC4, SW1573, the Pgp-positive sublines: BRO/mdr1.1, 2780AD and the non-Pgp sublines: GLC4/ADR, SW1573/2R120 were used in vitro to investigate BIBW22BS as a modulator of the antiproliferative effects of vincristine and doxorubicin and to compare the potency of BIBW22BS with that of dipyridamole, verapamil, bepridil and flunarizine. BRO/mdr1.1 s.c. well-established xenografts in nude mice were used to study the modulating properties of BIBW22BS 50 mg/kg i.v. followed after one h by vincristine 1 mg/kg i.p. or doxorubicin 8 mg/kg i.p. weekly x 2. BIBW22BS was 20- to 100-fold more potent than dipyridamole in the reversal of resistance in the Pgp-positive sublines. Reversal of resistance was obtained in a dose-dependent manner and was complete at concentrations of 0.5-2.5 microM. At non-toxic, equimolar concentrations of 1.0 microM BIBW22BS showed higher modulating potency than the calcium-channel blockers. BIBW22BS did not affect resistance in the non-Pgp sublines. BRO/mdr1.1 s.c. xenografts have stable multidrug-resistance characteristics upon serial transplantation. BIBW22BS, vincristine, or doxorubicin as single agents were not effective in vivo, while the addition of BIBW22BS could significantly reduce the tumor growth expressed as the T/C% of vincristine from 109% to 48% and that of doxorubicin from 55% to 32%. However, reversal of vincristine resistance in BRO/mdr1.1 xenografts was not complete when compared to the efficacy of vincristine in BRO xenografts. The results encourage the further preclinical development of BIBW22BS as a modulator of 'classical' multidrug resistance in cancer patients.
ABSTRACT In Nederland is de incidentie van gastro-enteritis bij kinderen tot 5 jaar in de huisart... more ABSTRACT In Nederland is de incidentie van gastro-enteritis bij kinderen tot 5 jaar in de huisartsenpraktijk 90 per 1000 per jaar. Minder dan 1% wordt opgenomen in een ziekenhuis. 1 Van de kinderen die in de tweede lijn worden beoordeeld, wordt 40% opgenomen. De mortaliteit onder kinderen in West-Europa is de laatste decennia sterk gedaald.
Adenine Nucleotides in Cellular Energy Transfer and Signal Transduction, 1992
Overexpression of P-glycoprotein genes is one established cause of multidrug resistance in mammal... more Overexpression of P-glycoprotein genes is one established cause of multidrug resistance in mammalian cells. We are studying P-glycoproteins and their genes in man, in the mouse and in the nematode worm Caenorhabditis elegans in order to understand the normal, physiological role of P-glycoproteins, and the mechanistics of P-glycoprotein function. Our data suggest that one common, and evolutionarily well-conserved function of P-glycoproteins is protection of the organism against naturally occurring xenotoxins present in ingested food. We consider it likely, however, that some P-glycoprotein variants perform a more specialized function in the organism.
Nederlands tijdschrift voor geneeskunde, Jan 18, 2006
A newborn girl was seen with one eye closed, which she opened synchronous with suction; this was ... more A newborn girl was seen with one eye closed, which she opened synchronous with suction; this was due to a congenital ptosis, so-called Marcus Gunn jaw-winking ptosis.
We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated f... more We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated from normal human liver into human BRO melanoma cells to study the drug-resistant phenotype produced by the exclusive overexpression of normal human mdr1 P-glycoprotein. The drug resistance pattern of mdr1-transfected clones includes relatively high resistance to gramicidin D (about 300-fold), vincristine (about 100-fold), and actinomycin D (about 100-fold) and a lower degree of resistance to doxorubicin (about 10-fold), VP16-213 (about 10-fold), and colchicine (about 6-fold). The transfectants did not exhibit resistance to trimetrexate, cis-platinum, mitomycin C, 1-beta-D-arabinofuranosylcytosine, bleomycin, G418, or magainin-2-amide; they were slightly more sensitive to verapamil (2-fold) but not to Triton X-100. As in other multidrug-resistant cell lines, resistance to vincristine could be reversed by verapamil and, more effectively, by cyclosporin A. Chloroquine only marginally increa...
Onder ernstige meervoudige beperkingen wordt verstaan: ernstige cognitieve beperking (totaal iq &... more Onder ernstige meervoudige beperkingen wordt verstaan: ernstige cognitieve beperking (totaal iq < 30, ontwikkelingsleeftijd < 2 jaar) en motorisch functioneren op niveau iv of v volgens het Grof Motorisch Functionerings-classificatie Systeem (gmfcs) voor cerebrale parese (cp).
ABSTRACT De behandeling van een aan appendicitisgerelateerd intra-abdominaal abces bij kinderen b... more ABSTRACT De behandeling van een aan appendicitisgerelateerd intra-abdominaal abces bij kinderen bestaat in principe uit chirurgische of radiologische drainage. Dit is echter vaak technisch moeilijk uitvoerbaar en geassocieerd met morbiditeit. Op grond van literatuurgegevens en door de risico&#39;s van drainage af te wegen tegen de voordelen van conservatieve therapie behandelden wij zeven opeenvolgende kinderen met een appendiculair abces succesvol met breedspectrumantibiotica. Individueel zal steeds de keuze gemaakt moeten worden voor conservatieve behandeling dan wel chirurgische drainage, maar er tekent zich een trend af naar een conservatieve benadering. Het adagium ubi pus, ibi evacua kon in de door ons beschreven gevallen van een intra-abdominaal abces bij kinderen worden vervangen door de aanbeveling ubi pus, ibi antibiotica. Summary The treatment of an intra-abdominal abscess related to an appendicitis in children is primarily surgical or radiological drainage. However, this is often technically difficult to perform and associated with morbidity. According to the literature and comparing the risk of drainage against the benefits of conservative therapy we treated seven consecutive children successfully with an appendicular intra-abdominal abscess with broad spectrum antibiotics. Looking at every patient individually a choice must be made for either conservative treatment of surgical drainage, but a trend emerges towards a conservative approach. The maxim ubi pus, ibi evacua could be replaced in the above described cases of intra-abdominal abscesses in children by the recommendation ubi pus, ibi antibiotics.
P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-re... more P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-resistant phenotype to mammalian tumor cells. To obtain more information on their functions in normal cells we have cloned genomic and complementary DNA sequences of four P-glycoprotein gene homologs of the genetically well-characterized nematode Caenorhabditis elegans, termed pgp-1, pgp-2, pgp-3 and pgp-4, respectively. The genes were physically mapped on chromosome IV (pgp-1), I (pgp-2) and X (pgp-3 and pgp-4). Phenotypic mutants corresponding to these loci have not yet been described. Two of the genes, pgp-1 and pgp-3, were analyzed in detail. They are predicted to encode ATP-binding membrane-spanning proteins of 1321 and 1254 amino acid residues, respectively, with the characteristic features shared by most P-glycoproteins described thus far. Intra-species divergence of P-glycoprotein genes is more pronounced in C. elegans than in mammals. Only 40% of the amino acids of pgp-1 and pgp-3 are identical, in contrast to 77% identity between human MDR1 and MDR3. pgp-1 consists of 14 exons, pgp-3 of 13. The two genes share only one intron position, whereas they share four (pgp-1) and five (pgp-3) intron positions with mammalian P-glycoprotein genes. pgp-1, pgp-2, and pgp-3 are transcribed into low abundance mRNAs in wild-type nematodes. pgp-1 and pgp-3 mRNAs have the trans-spliced leader SL1 at their 5&amp;amp;#39; ends. Arsenite, emetine and actinomycin D drugs did not increase the steady state levels of pgp mRNA, unlike in some mammalian cell types. Heat shock disturbed trans as well as cis-splicing of pgp-1 and led to the accumulation of partially processed pgp-1 RNA. Thus, in C. elegans these genes are not induced in the context of a general stress response, as has been proposed for mammalian P-glycoprotein genes in certain tissues.
Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than... more Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples. We have investigated the blood cells of 2 patients (1a and 1b) in a previously described family suffering from favism and cataract and of a novel patient (2) presenting with severe neonatal jaundice. Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting. Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme. The red blood cells from patient 2 did not exhibit GR activity either, but the patient's leukocytes contained some residual activity that correlated with a weak protein expression. Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the super...
BACKGROUND Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disabilit... more BACKGROUND Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy. AIM: To present an overview of the development of targeted treatment for fxs. METHOD: Several important publications were collected and indexed. RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing. CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement...
Introduction of new genetic test technologies in the last decade have accelerated genetic diagnos... more Introduction of new genetic test technologies in the last decade have accelerated genetic diagnosis in many medical specialties and have increased diagnostic yield considerably. SNP-arrays have been established as first tier diagnostic tools, more and more being replaced by next generation sequencing strategies, like targeted genomic panels and whole exome sequencing. We present the diagnostic work-up of a clinical case, a girl with congenital vertebral and rib anomalies. This case illustrates the complexity of genetic tests and the need for knowledge and experience to interpret the results. Intensive collaboration between pediatrician, clinical geneticist and laboratory specialist is mandatory, as is long-term commitment to involve parents in the diagnostic journey .
ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verst... more ACHTERGROND Het fragiele-X-syndroom (fxs) is de meest voorkomende erfelijke oorzaak van een verstandelijke beperking en autismespectrumstoornissen. Een gerichte therapie ontbreekt vooralsnog. De afgelopen decennia brachten een explosie aan kennis over de betrokken moleculaire processen en daarmee potentiele aangrijpingspunten voor gerichte therapie. DOEL Een overzicht geven van de ontwikkeling van gerichte therapie voor fxs. METHODE Een aantal belangrijke publicaties werd verzameld en op een rij gezet. RESULTATEN Preklinische diermodelonderzoeken tonen veelbelovende resultaten van gerichte interventies, maar vertaling naar de kliniek is vooralsnog teleurstellend. CONCLUSIE Een gerichte therapie voor fxs is nodig en zou mogelijk kunnen worden toegepast bij andere oorzaken van autisme en verstandelijke beperking. Aspecten op het gebied van translatie, studieopzet en uitkomstmaten spelen mogelijk een rol bij de teleurstellende resultaten. Voor de klinische implementatie van toekomstige...
Modulators of the &#39;classical&#39; multidrug resistance (mdr) phenotype have low effic... more Modulators of the &#39;classical&#39; multidrug resistance (mdr) phenotype have low efficacy in patients with solid tumors. We analyzed BIBW22BS, 4-[N-(2-hydroxy-2-met- hyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-dimethyl-morpho- lino)-6-phenylpteridine, a derivative of dipyridamole, for its higher potential to modulate mdr. Four human malignant cell lines: BRO, A2780, GLC4, SW1573, the Pgp-positive sublines: BRO/mdr1.1, 2780AD and the non-Pgp sublines: GLC4/ADR, SW1573/2R120 were used in vitro to investigate BIBW22BS as a modulator of the antiproliferative effects of vincristine and doxorubicin and to compare the potency of BIBW22BS with that of dipyridamole, verapamil, bepridil and flunarizine. BRO/mdr1.1 s.c. well-established xenografts in nude mice were used to study the modulating properties of BIBW22BS 50 mg/kg i.v. followed after one h by vincristine 1 mg/kg i.p. or doxorubicin 8 mg/kg i.p. weekly x 2. BIBW22BS was 20- to 100-fold more potent than dipyridamole in the reversal of resistance in the Pgp-positive sublines. Reversal of resistance was obtained in a dose-dependent manner and was complete at concentrations of 0.5-2.5 microM. At non-toxic, equimolar concentrations of 1.0 microM BIBW22BS showed higher modulating potency than the calcium-channel blockers. BIBW22BS did not affect resistance in the non-Pgp sublines. BRO/mdr1.1 s.c. xenografts have stable multidrug-resistance characteristics upon serial transplantation. BIBW22BS, vincristine, or doxorubicin as single agents were not effective in vivo, while the addition of BIBW22BS could significantly reduce the tumor growth expressed as the T/C% of vincristine from 109% to 48% and that of doxorubicin from 55% to 32%. However, reversal of vincristine resistance in BRO/mdr1.1 xenografts was not complete when compared to the efficacy of vincristine in BRO xenografts. The results encourage the further preclinical development of BIBW22BS as a modulator of &#39;classical&#39; multidrug resistance in cancer patients.
ABSTRACT In Nederland is de incidentie van gastro-enteritis bij kinderen tot 5 jaar in de huisart... more ABSTRACT In Nederland is de incidentie van gastro-enteritis bij kinderen tot 5 jaar in de huisartsenpraktijk 90 per 1000 per jaar. Minder dan 1% wordt opgenomen in een ziekenhuis. 1 Van de kinderen die in de tweede lijn worden beoordeeld, wordt 40% opgenomen. De mortaliteit onder kinderen in West-Europa is de laatste decennia sterk gedaald.
Adenine Nucleotides in Cellular Energy Transfer and Signal Transduction, 1992
Overexpression of P-glycoprotein genes is one established cause of multidrug resistance in mammal... more Overexpression of P-glycoprotein genes is one established cause of multidrug resistance in mammalian cells. We are studying P-glycoproteins and their genes in man, in the mouse and in the nematode worm Caenorhabditis elegans in order to understand the normal, physiological role of P-glycoproteins, and the mechanistics of P-glycoprotein function. Our data suggest that one common, and evolutionarily well-conserved function of P-glycoproteins is protection of the organism against naturally occurring xenotoxins present in ingested food. We consider it likely, however, that some P-glycoprotein variants perform a more specialized function in the organism.
Nederlands tijdschrift voor geneeskunde, Jan 18, 2006
A newborn girl was seen with one eye closed, which she opened synchronous with suction; this was ... more A newborn girl was seen with one eye closed, which she opened synchronous with suction; this was due to a congenital ptosis, so-called Marcus Gunn jaw-winking ptosis.
We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated f... more We have transfected a eukaryotic expression vector containing a mdr1 complementary DNA isolated from normal human liver into human BRO melanoma cells to study the drug-resistant phenotype produced by the exclusive overexpression of normal human mdr1 P-glycoprotein. The drug resistance pattern of mdr1-transfected clones includes relatively high resistance to gramicidin D (about 300-fold), vincristine (about 100-fold), and actinomycin D (about 100-fold) and a lower degree of resistance to doxorubicin (about 10-fold), VP16-213 (about 10-fold), and colchicine (about 6-fold). The transfectants did not exhibit resistance to trimetrexate, cis-platinum, mitomycin C, 1-beta-D-arabinofuranosylcytosine, bleomycin, G418, or magainin-2-amide; they were slightly more sensitive to verapamil (2-fold) but not to Triton X-100. As in other multidrug-resistant cell lines, resistance to vincristine could be reversed by verapamil and, more effectively, by cyclosporin A. Chloroquine only marginally increa...
Onder ernstige meervoudige beperkingen wordt verstaan: ernstige cognitieve beperking (totaal iq &... more Onder ernstige meervoudige beperkingen wordt verstaan: ernstige cognitieve beperking (totaal iq < 30, ontwikkelingsleeftijd < 2 jaar) en motorisch functioneren op niveau iv of v volgens het Grof Motorisch Functionerings-classificatie Systeem (gmfcs) voor cerebrale parese (cp).
ABSTRACT De behandeling van een aan appendicitisgerelateerd intra-abdominaal abces bij kinderen b... more ABSTRACT De behandeling van een aan appendicitisgerelateerd intra-abdominaal abces bij kinderen bestaat in principe uit chirurgische of radiologische drainage. Dit is echter vaak technisch moeilijk uitvoerbaar en geassocieerd met morbiditeit. Op grond van literatuurgegevens en door de risico&#39;s van drainage af te wegen tegen de voordelen van conservatieve therapie behandelden wij zeven opeenvolgende kinderen met een appendiculair abces succesvol met breedspectrumantibiotica. Individueel zal steeds de keuze gemaakt moeten worden voor conservatieve behandeling dan wel chirurgische drainage, maar er tekent zich een trend af naar een conservatieve benadering. Het adagium ubi pus, ibi evacua kon in de door ons beschreven gevallen van een intra-abdominaal abces bij kinderen worden vervangen door de aanbeveling ubi pus, ibi antibiotica. Summary The treatment of an intra-abdominal abscess related to an appendicitis in children is primarily surgical or radiological drainage. However, this is often technically difficult to perform and associated with morbidity. According to the literature and comparing the risk of drainage against the benefits of conservative therapy we treated seven consecutive children successfully with an appendicular intra-abdominal abscess with broad spectrum antibiotics. Looking at every patient individually a choice must be made for either conservative treatment of surgical drainage, but a trend emerges towards a conservative approach. The maxim ubi pus, ibi evacua could be replaced in the above described cases of intra-abdominal abscesses in children by the recommendation ubi pus, ibi antibiotics.
P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-re... more P-glycoproteins, encoded by families of evolutionarily conserved genes, can confer a multidrug-resistant phenotype to mammalian tumor cells. To obtain more information on their functions in normal cells we have cloned genomic and complementary DNA sequences of four P-glycoprotein gene homologs of the genetically well-characterized nematode Caenorhabditis elegans, termed pgp-1, pgp-2, pgp-3 and pgp-4, respectively. The genes were physically mapped on chromosome IV (pgp-1), I (pgp-2) and X (pgp-3 and pgp-4). Phenotypic mutants corresponding to these loci have not yet been described. Two of the genes, pgp-1 and pgp-3, were analyzed in detail. They are predicted to encode ATP-binding membrane-spanning proteins of 1321 and 1254 amino acid residues, respectively, with the characteristic features shared by most P-glycoproteins described thus far. Intra-species divergence of P-glycoprotein genes is more pronounced in C. elegans than in mammals. Only 40% of the amino acids of pgp-1 and pgp-3 are identical, in contrast to 77% identity between human MDR1 and MDR3. pgp-1 consists of 14 exons, pgp-3 of 13. The two genes share only one intron position, whereas they share four (pgp-1) and five (pgp-3) intron positions with mammalian P-glycoprotein genes. pgp-1, pgp-2, and pgp-3 are transcribed into low abundance mRNAs in wild-type nematodes. pgp-1 and pgp-3 mRNAs have the trans-spliced leader SL1 at their 5&amp;amp;#39; ends. Arsenite, emetine and actinomycin D drugs did not increase the steady state levels of pgp mRNA, unlike in some mammalian cell types. Heat shock disturbed trans as well as cis-splicing of pgp-1 and led to the accumulation of partially processed pgp-1 RNA. Thus, in C. elegans these genes are not induced in the context of a general stress response, as has been proposed for mammalian P-glycoprotein genes in certain tissues.
Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than... more Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples. We have investigated the blood cells of 2 patients (1a and 1b) in a previously described family suffering from favism and cataract and of a novel patient (2) presenting with severe neonatal jaundice. Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting. Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme. The red blood cells from patient 2 did not exhibit GR activity either, but the patient's leukocytes contained some residual activity that correlated with a weak protein expression. Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the super...
Uploads
Papers by C. Lincke