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Biomedical subjects

R Maas

Publications and source records attributed to R Maas.

At least 19 recordsLinked to original sources
PubMed2005

Determination of a reference value for N(G), N(G)-dimethyl-L-arginine in 500 subjects.

BACKGROUND: Asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of NO-synthase. In the last years ADMA has emerged as a cardiovascular risk factor. The aim of this study was to determine a reference value for ADMA. METHODS: Plasma samples of 500 healthy subjects in the 19-75 year age group were analyzed. Exclusion criteria from this study were smoking, any known significant disease, body-mass-index (BMI) above 30 kg m(-2), elevated plasma lipid levels, impaired renal function, hypertension, and intake of any medication. The ADMA levels were determined by ELISA, (DLD Diagnostics, Hamburg, Germany). RESULTS: Mean ADMA plasma concentration of the total population was 0.69 micromol L(-1) (SD 0.20) and 95% of the measured values were in the range from 0.36 micromol L(-1) to 1.17 micromol L(-1). Women below 50 years of age had lower ADMA levels than men below 50 years of age [0.62 (0.17) micromol L(-1) vs. 0.69 (0.19) micromol L(-1); P = 0.001] and woman above 50 years of age had higher ADMA levels than men above 50 years of age [0.80 (0.22) micromol L(-1) vs. 0.73 (0.20) micromol L(-1); P = 0.036]. A regression analysis of ADMA levels and age was performed for each sex. The regression factor was r = 0.444 for women in a squared regression model (P < 0.001) and r = 0.212 for men in a linear regression model (P < 0.001). CONCLUSION: The study was able to define a reference value for ADMA plasma levels with 0.36-1.17 micromol L(-1) and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause.

Adult↗
PubMed2004

[Biomarkers as prognostic factors in pulmonary arterial hypertension. Rationale and study design].

CURRENT SITUATION: Pulmonary arterial hypertension (PAH) is a serious disease. Its prognostic is based on the functional status quantified by the NYHA class and the 6-min walking test, and the hemodynamic data. The algorithms of treatment are solely based on the hemodynamic data and the functional status. The main objective is to test whether basal concentrations of isoprostanes, Big endotheline 1, ADMA, high sensitivity CRP, NT-Pro-BNP and cardiac troponin T are a 3-year prognostic factor in PAH using a combined criterion: death from any cause and pulmonary or cardiopulmonary transplantation. MATERIALS AND METHODS: This is a multicenter, prospective, prognostic, single blinded study (plasma and urinary samples being blinded). The study started in november 2003, running for 2 years, with a 3 year follow-up for each patient. The main inclusion criterion is PAH. The data analysis will use a multivariable Cox model, taking into account the functional and hemodynamic parameters. EXPECTED RESULTS: This study will determine whether any of the biomarkers tested provides additional prognostic information in PAH in addition to the functional and hemodynamic parameters.

Biomarkers↗
PubMed2004

Validation study to evaluate the reproducibility of a candidate in vitro potency assay of newcastle disease vaccines and to establish the suitability of a candidate biological reference preparation.

A quantification assay for the Haemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (NDV) has been developed at CIDC-Lelystad as a candidate in vitro potency test for inactivated Newcastle disease (ND) vaccines. In studies performed at CIDC-Lelystad, a high correlation was demonstrated between the results of this candidate in vitro potency assay and the results of the serological potency assay (European Pharmacopoeia monograph 0870; test A). Furthermore, a high correlation between the serological data (Haemagglutination Inhibition-antibody titres) and clinical protection after challenge was demonstrated. Correlation between in vivo and in vitro potency assays was confirmed in a collaborative pre-validation study. In the pre-validation study three Official Medicines Control Laboratories (OMCLs) determined both the NDV-HN antigen content and the in vivo potency (vaccination-serology and vaccination-challenge) of 6 vaccine batches. The conclusion of the pre-validation study was that a large-scale collaborative study should be organised to validate the in vitro method and the suitability of the reference preparation. This report describes the outcome of this study. In brief, 14 laboratories (8 OMCLs and 6 vaccine manufacturers) determined the NDV-HN antigen content of 9 different vaccines in 3 independent tests. The vaccine batches were produced by 5 different manufacturers and represent a quantitative range of ND antigen content. One vaccine batch with insufficient potency and one poultry vaccine not containing NDV were included. Statistical evaluation of the results indicated that the antigen content could be determined with high precision. A good repeatability as well as reproducibility was found. Furthermore all laboratories found a similar ranking of the vaccines, based on the antigen content. Comparison of the antigen content and the in vivo potency of a series of vaccines with relatively low potencies indicated that a threshold relative antigen level of 7.0 antigen units per dose would discriminate between vaccine batches with sufficient and insufficient potency. An in vitro assay with this threshold level for antigen content did not result in any false positive results and only a limited number of false negative results in the BSP055 study. We conclude that the in vitro measurement of the antigen content of inactivated ND-vaccines with the proposed method is a reliable alternative potency assay that could be included as a new method in monograph 0870 on ND-vaccines.

Animals↗
PubMed2003

Feasibility study to evaluate the correlation between results of a candidate in vitro assay and established in vivo assays for potency determination of Newcastle disease vaccines.

A Newcastle disease virus antigen quantification assay has been developed at CIDC-Lelystad as a candidate in vitro potency test for inactivated Newcastle disease vaccines. In studies performed at CIDC-Lelystad, a high correlation was demonstrated between the results of this candidate in vitro potency assay and the results of the serological potency assay (European Pharmacopoeia monograph 0870; test A). Furthermore, a high correlation between the serological data (Haemagglutination Inhibition-antibody titres) and clinical protection after challenge was demonstrated. The aim of the feasibility study was to confirm the correlation between the results obtained using the candidate in vitro potency assay and the results from both the in vivo potency assays currently prescribed in Ph Eur monograph 0870, in different laboratories and to determine whether a large-scale validation study of the in vitro method should ensue. In the feasibility study three Official Medicines Control Laboratories tested the potency of 5 different inactivated Newcastle disease vaccines and one experimental vaccine, using both of the in vivo methods described in the European Pharmacopoeia and the candidate in vitro method. The 6 vaccine batches represented a quantitative range of Newcastle disease virus antigen content and were produced by different manufacturers. Statistical evaluation of all results indicated that a satisfactory correlation was found in all laboratories between the two types of in vivo tests currently in place, and the candidate in vitro test. An excellent reproducibility of the proposed in vitro method was observed with respect to the ranking of the vaccines included in this study. It is concluded that the results of this feasibility study indicate that a large-scale collaborative study can be organised to validate the in vitro method and the suitability of the reference preparation.

Animal Use Alternatives↗
PubMed2002

Validation of a candidate in vitro potency assay for inactivated Newcastle disease vaccines.

An NDV-HN antigen quantification assay has been developed as a candidate in vitro batch potency assay for inactivated vaccines. The assay consists of extraction of the viral antigens from the oil emulsion vaccines and quantification of the NDV-HN in a DAS-EUSA. After optimisation and preliminary validation, large stocks of lyophilised test reagents were prepared. Stability studies showed that there was no decrease in reactivity of the reagents in one year at -20 degrees after lyophilisation. Also in accelerated stability studies no decrease in reactivity was found after storage at higher temperatures. Antigen recovery, accuracy of the assay and specificity of the assay were found to be satisfactory in an in-house validation study. The intermediate precision was good to very good with coefficient of variation (CV) values that were always below 15%. The transferability of the test protocols has been studied in a pre-validation study in which three laboratories from two different countries participated. The protocols and the assay could be transferred to other laboratories without difficulty. Furthermore, vaccines with low and high potency as well as negative controls were identified by all participants. Finally between-assay as well as between-laboratory variation was satisfactory with CV-values of 0 to 30.

Adjuvants, Immunologic↗
PubMed2002

Antigen content of inactivated Newcastle disease oil emulsion vaccines as an in vitro indicator of potency.

The potency of each batch of inactivated Newcastle disease virus (NDV) vaccine is measured in either a vaccination-serology or a vaccination-challenge experiment. We have developed an antigen quantification assay as an in vitro alternative for these currently prescribed in vivo potency assays. The in vitro assay consists of extraction of the viral antigens from the oil emulsion vaccines by isopropylmyristate, followed by quantification of the NDV HN-antigen in an ELISA. The analysis of 20 inactivated vaccines, representing the most common NDV-vaccines in Western Europe, indicated that large differences in antigen content exist between these vaccines. A comparison of the antigen content with the serological response after vaccination with 1/50 vaccine dose demonstrated that a reliable estimate of the potency can be made, based on the HN-antigen content of the vaccine. We therefore present our antigen quantification assay for NDV as a candidate in vitro potency assay. An international feasibility and validation study will be needed to prove the suitability and reliability of this candidate in vitro potency assay for inactivated NDV vaccines.

Animals↗
PubMed2001

Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract.

Data indicate that estrogen-dependent and -independent pathways are involved in the teratogenic/carcinogenic syndrome that follows developmental exposure to 17beta-estradiol or diethylstilbestrol (DES), a synthetic estrogen. However, the exact role and extent to which each pathway contributes to the resulting pathology remain unknown. We employed the alphaERKO mouse, which lacks estrogen receptor-alpha (ERalpha), to discern the role of ERalpha and estrogen signaling in mediating the effects of neonatal DES exposure. The alphaERKO provides the potential to expose DES actions mediated by the second known ER, ERbeta, and those that are ER-independent. Wild-type and alphaERKO females were treated with vehicle or DES (2 microg/pup/day for Days 1-5) and terminated after 5 days and 2, 4, 8, 12, and 20 months for biochemical and histomorphological analyses. Assays for uterine expression of the genes Hoxa10, Hoxa11, and Wnt7a shortly after treatment indicated significant decreases in DES-treated wild-type but no effect in the alphaERKO. In contrast, the DES effect on uterine expression of Wnt4 and Wnt5a was preserved in both genotypes, suggesting a developmental role for ERbeta. Adult alphaERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure exhibited in treated wild-type animals, including atrophy, decreased weight, smooth muscle disorganization, and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent vaginal cornification. Therefore, the lack of DES effects on gene expression and tissue differentiation in the alphaERKO provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract.

Abnormalities, Drug-Induced↗
PubMed2001

Expression, cellular distribution and protein binding of the glioma amplified sequence (GAS41), a highly conserved putative transcription factor.

The glioma amplified sequence 41 (GAS41) was previously isolated by microdissection mediated cDNA capture from the glioblastoma multiforme cell line TX3868 and shown to be frequently amplified in human gliomas. We determined the complete cDNA sequence of the GAS41 gene, demonstrated that the GAS41 protein is evolutionarily conserved, specifically at the N-terminus, and identified the yeast transcription factor tf2f domain within the GAS41 sequence. A human multiple-tissue Northern blot revealed ubiquitous expression of GAS41 with the highest expression in human brain. After generating polyclonal antibodies we found GAS41 protein expression in the nucleus of the TX3868 cell line by Western blot analysis and immunofluorescence microscopy. The nuclear localization was confirmed for several human tumors including gliomas of different grades of malignancy. In neuroblastoma however, GAS41 was found in the nucleoli but not in the nucleoplasm. Yeast two-hybrid screening of the TX3868 cell line identified the nuclear mitotic apparatus protein (NuMA), the KIAA1009 protein, and prefoldin subunit 1 (PFDN1) as potential interacting partners of GAS41. We generated a polyclonal antibody against the KIAA1009 protein and we demonstrated that the KIAA1009 protein is a nuclear protein, which appears to be co-localized with the GAS41 protein and NuMA.

Amino Acid Sequence↗
PubMed2001

Change of plasmid DNA structure, hypermethylation, and Lon-proteolysis as steps in a replicative cascade.

I have defined conditions under which RepFIC plasmid DNA can be maintained in a state of lowered helical density. In exponentially growing cultures, the DNA of lowered helical density is present in small amounts but never totally absent, suggesting that it is a normal variant of plasmid maintenance. It is fully methylated at frequent sites by dam-methyltransferase, some not previously recognized, further suggesting that the variant is a precursor of replication. The low-helical density plasmid is present in dam hosts, indicating that methylation is not essential for the change in helical density. The lowered helical density is stabilized in lon hosts, suggesting that Lon-protease may remove both the protein(s) that lower the helical density and the dam-methyltransferase after each round of replication.

ATP-Dependent Proteases↗
PubMed2001

A nonsense mutation in MSX1 causes Witkop syndrome.

Witkop syndrome, also known as tooth and nail syndrome (TNS), is a rare autosomal dominant disorder. Affected individuals have nail dysplasia and several congenitally missing teeth. To identify the gene responsible for TNS, we used candidate-gene linkage analysis in a three-generation family affected by the disorder. We found linkage between TNS and polymorphic markers surrounding the MSX1 locus. Direct sequencing and restriction-enzyme analysis revealed that a heterozygous stop mutation in the homeodomain of MSX1 cosegregated with the phenotype. In addition, histological analysis of Msx1-knockout mice, combined with a finding of Msx1 expression in mesenchyme of developing nail beds, revealed that not only was tooth development disrupted in these mice, but nail development was affected as well. Nail plates in Msx1-null mice were defective and were thinner than those of their wild-type littermates. The resemblance between the tooth and nail phenotype in the human family and that of Msx1-knockout mice strongly supports the conclusions that a nonsense mutation in MSX1 causes TNS and that Msx1 is critical for both tooth and nail development.

Adult↗
PubMed2001

Psychiatric conditions in patients with recurrent unexplained syncope.

AIMS: The relationship between syncope and psychiatric disorders is little investigated. This study evaluated the prevalence of psychiatric diseases and prognostic outcome in patients with recurrent unexplained syncope. METHODS AND RESULTS: After an inconclusive standard diagnostic work-up for syncope, including head-up tilt testing, a psychiatric evaluation was offered to 50 consecutive patients with recurrent syncope. The evaluation was accepted by 26 patients (77% females, 36 +/- 16 years) and refused by 24 (63% females, 50 +/- 19 years). A psychiatric disorder was diagnosed in 21 (81%) patients: 12 had depression, four panic attacks, two general anxiety, and three a somatization disorder. Only five patients showed normal psychosocial function. Of the patients with psychiatric disorders four accepted psychiatric care, such as psychotherapy and/or pharmacotherapy; 17 patients refused treatment. During 6 months of follow-up no patient under psychiatric care had syncope, while all patients without psycho- or pharmacotherapy had recurrent syncopal events. In these patients the median of syncopal episodes was three in a 6 months interval before and after clinical assessment. Patients who refused both psychiatric evaluation and therapy continued to experience syncope as before. CONCLUSIONS: In patients with recurrent unexplained syncope psychiatric alteration is common. However, patients seldom accepted a psychiatric evaluation and treatment.

Adolescent↗
PubMed2001

Dach1 mutant mice bear no gross abnormalities in eye, limb, and brain development and exhibit postnatal lethality.

Drosophila dachshund is necessary and sufficient for compound eye development and is required for normal leg and brain development. A mouse homologue of dachshund, Dach1, is expressed in the developing retina and limbs, suggesting functional conservation of this gene. We have generated a loss-of-function mutation in Dach1 that results in the abrogation of the wild-type RNA and protein expression pattern in embryos. Homozygous mutants survive to birth but exhibit postnatal lethality associated with a failure to suckle, cyanosis, and respiratory distress. The heart, lungs, kidneys, liver, and skeleton were examined to identify factors involved in postnatal lethality, but these organs appeared to be normal. In addition, blood chemistry tests failed to reveal differences that might explain the lethal phenotype. Gross examination and histological analyses of newborn eyes, limbs, and brains revealed no detectable abnormalities. Since Dach1 mutants die shortly after birth, it remains possible that Dach1 is required for postnatal development of these structures. Alternatively, an additional Dach homologue may functionally compensate for Dach1 loss of function.

Alleles↗
PubMed2000

Conservation of early odontogenic signaling pathways in Aves.

Teeth have been missing from birds (Aves) for at least 60 million years. However, in the chick oral cavity a rudiment forms that resembles the lamina stage of the mammalian molar tooth germ. We have addressed the molecular basis for this secondary loss of tooth formation in Aves by analyzing in chick embryos the status of molecular pathways known to regulate mouse tooth development. Similar to the mouse dental lamina, expression of Fgf8, Pitx2, Barx1, and Pax9 defines a potential chick odontogenic region. However, the expression of three molecules involved in tooth initiation, Bmp4, Msx1, and Msx2, are absent from the presumptive chick dental lamina. In chick mandibles, exogenous bone morphogenetic protein (BMP) induces Msx expression and together with fibroblast growth factor promotes the development of Sonic hedgehog expressing epithelial structures. Distinct epithelial appendages also were induced when chick mandibular epithelium was recombined with a tissue source of BMPs and fibroblast growth factors, chick skin mesenchyme. These results show that, although latent, the early signaling pathways involved in odontogenesis remain inducible in Aves and suggest that loss of odontogenic Bmp4 expression may be responsible for the early arrest of tooth development in living birds.

Animals↗
PubMed2000

The polyurethane nasolacrimal duct stent for lower tear duct obstruction: long-term success rate and complications.

BACKGROUND: The polyurethane nasolacrimal duct stent is used as an alternative to conventional techniques for treatment of lower tear duct obstruction. The aim of this study was to evaluate the clinical success rate after a follow-up of 2 years. METHODS: Nasolacrimal duct stent implantation was attempted in 19 patients with nasolacrimal duct obstruction proven by digital substraction dacryocystography. The median age of the patients was 50 years, and the minimum duration of symptoms was 3 months. Patients were followed up 1 week, 6 months, 1 year and 2 years after the procedure. RESULTS: Eighteen stents were implanted in 17 patients without surgical complications. All stents were proven to be patent at the end of the procedure. Success rate, defined as proportion of patients free of symptoms, was 66.6%, 55.5% and 50% after 1 week, 6 months and I year, respectively, and remained unchanged thereafter. Three stents had to be removed between 6 months and 2 years after implantation. Histological examination showed granulation tissue growing into the opening and obstructing the stent in one case. CONCLUSION: Implantation of a polyurethane nasolacrimal duct stent is an alternative to conventional techniques in lower tear duct obstruction. Its overall success rate is lower than that reported after conventional dacryocystorhinostomy, but the procedure is fast, safe and reversible. Refinement of the surface and stent design may improve results in the future.

Adult↗
PubMed2000

Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation.

The composite structure of the mammalian skull, which forms predominantly via intramembranous ossification, requires precise pre- and post-natal growth regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA binding by a mutant MSX2 homeodomain results in a gain of function and produces craniosynostosis in humans. Here we show that Msx2-deficient mice have defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina (PFM). Msx2-/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that Msx2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis.

Abnormalities, Multiple↗