Biomedical subjects

C Wagner

Publications and source records attributed to C Wagner.

At least 37 records · Page 2Linked to original sources

PubMed2005

S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy.

S-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.

Adenosylhomocysteinase↗

PubMed2005

Negative feedback in NO/cGMP signalling.

Most of the effects of the signalling molecule nitric oxide (NO) are mediated by the stimulation of the NO-sensitive GC (guanylate cyclase) and the subsequent increase in cGMP formation. The enzyme contains a prosthetic haem group, which mediates NO stimulation. In addition to the physiological activator NO, NO-sensitizers like the substance YC-1 sensitize the enzyme towards NO and may therefore have important pharmacological implications. Two isoforms of NO-sensitive GC have been identified to date that share regulatory properties, but differ in the subcellular localization. The more ubiquitously expressed alpha1beta1 heterodimer and the alpha2beta1 isoform are mainly expressed in brain. In intact cells, NO-induced cGMP signalling not only depends on cGMP formation, but is also critically determined by the activity of the enzymes responsible for cGMP degradation, e.g. PDE5 (phosphodiesterase 5). Recently, direct activation of PDE5 by cGMP was demonstrated, limiting the cGMP increase and thus functioning as a negative feedback. As the cGMP-induced PDE5 activation turned out to be sustained, in the range of hours, it is probably responsible for the NO-induced desensitization observed within NO/cGMP signalling.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Implant-associated posttraumatic osteomyelitis: collateral damage by local host defense?

Infections following osteosynthesis or total joint replacement, also known as ''implant-associated posttraumatic osteomyelitis'', represent a major complication in orthopedic and trauma surgery. While the formation of bacterial biofilms on the implanted osteosynthesis materials is generally accepted as cause of the persistent infection, the molecular mechanisms leading to the progressive and destructive local inflammatory process and eventually to bone degradation, the osteolysis, have not been delineated. Here we provide evidence supporting the hypothesis that it is not the infection per se that causes tissue degradation and osteolysis, but rather the cytotoxic, proteolytic, and proinflammatory effector functions of cells of the host defense, particularly of the infiltrating polymorphonuclear neutrophils.

Arthroplasty, Replacement↗

PubMed2004

An improved algorithm for stoichiometric network analysis: theory and applications.

MOTIVATION: Genome scale analysis of the metabolic network of a microorganism is a major challenge in bioinformatics. The combinatorial explosion, which occurs during the construction of elementary fluxes (non-redundant pathways) requires sophisticated and efficient algorithms to tackle the problem. RESULTS: Mathematically, the calculation of elementary fluxes amounts to characterizing the space of solutions to a mixed system of linear equalities, given by the stoichiometry matrix, and linear inequalities, arising from the irreversibility of some or all of the reactions in the network. Previous approaches to this problem have iteratively solved for the equalities while satisfying the inequalities throughout the process. In an extension of previous work, here we consider the complementary approach and derive an algorithm which satisfies the inequalities one by one while staying in the space of solution of the equality constraints. Benchmarks on different subnetworks of the central carbon metabolism of Escherichia coli show that this new approach yields a significant reduction in the execution time of the calculation. This reduction arises since the odds that an intermediate elementary flux already fulfills an additional inequality are larger than when having to satisfy an additional equality constraint.

Algorithms↗

PubMed2004

Genetic deficiency of CD16, the low-affinity receptor for immunoglobulin G, has no impact on the functional capacity of polymorphonuclear neutrophils.

BACKGROUND: Of the three receptors for immunoglobulin G (IgG), the low-affinity receptor CD16 is constitutively expressed on polymorphonuclear neutrophils (PMNs), monocytes and NK-cells. CD16 participates in various effector functions, notably phagocytosis of opsonized particles or of immune complexes, and in antibody-dependent cellular cytotoxicity (ADCC). In the present study we report a case of total CD16 deficiency on PMNs and monocytes. DESIGN: Polymorphonuclear neutrophils, monocytes and NK-cells were analyzed for surface-receptor expression by cytofluorometry and laser scan microscopy. Moreover, CD16-specific mRNA was assessed by RT-PCR. As functional parameters, phagocytosis of opsonized bacteria was tested, as was superoxide production. RESULTS: Polymorphonuclear neutrophils and monocytes totally deficient in CD16 were detected by chance in an apparently healthy individual. Further analysis revealed that two more members of his family, his father and sister, were also deficient in CD16. All were healthy and there was no evidence of an increased frequency, or of exceptionally severe or persistent infections. Despite the lack of CD16, phagocytosis of antibody-coated bacteria was within the normal range, as was the superoxide production. CONCLUSION: Deficiency of CD16 does not compromise the host defence. Apparently, the other receptors for IgG, CD32 and CD64, can compensate for the lack of CD16.

Adult↗

PubMed2004

Evaluation of the influence of image compression to the automatic discrimination of histological images of skin lesions.

OBJECTIVES: Telemedicine offers the possibility to get the opinion of an expert within a short time. To reduce data transfer via a network image compression is recommended. The disadvantage of error-free compression is a low compression rate. On the other hand an increased compression rate affects the information content of the image. In this study we evaluated the influence of the compression rate on the automatic discrimination of histological skin lesions in dermatopathology. METHODS: To be independent from subjective reviewing by a dermatopathologist we used tissue counter analysis (TCA) for automatic discrimination of skin tissue. TCA is based on the partition of the image into square elements where the features are calculated out of each square element. 40 cases of benign common nevi and 40 cases of malignant melanoma were used as the study set. First TCA was applied to the uncompressed images to check the discrimination power of the method. Then in the next steps the method was applied to the images with successively higher compression rates. For image compression the wavelet compression was used, where the compression rate was determined by neglecting wavelet coefficients with a magnitude below a given threshold. The number of remaining wavelet coefficients was used as criteria for the compression rate. RESULTS: This study shows that TCA allows automated discrimination even at higher compression rates where only 6-18% of the wavelet coefficients are used for image reconstruction. The recognition rate at higher compression is better for malignant melanoma than for benign common nevi. CONCLUSION: The power of automated discrimination is not essential affected by wavelet image compression.

Austria↗

PubMed2003

Pattern formation at the bicritical point of the Faraday instability.

We present measurements on parametrically driven surface waves (Faraday waves) performed in the vicinity of a bicritical point in parameter space, where modes with harmonic and subharmonic time dependence interact. The primary patterns are squares in the subharmonic and hexagons in the harmonic regime. If the primary instability is harmonic we observe a hysteretic secondary transition from hexagons to squares without a perceptible variation of the fundamental wavelength. The transition is understood in terms of a set of coupled Landau equations and related to other canonical examples of phase transitions in nonlinear dissipative systems. Moreover, the subharmonic-harmonic mode competition gives rise to a variety of new superlattice states. These structures are interpreted as mediator modes involved in the transition between patterns of fourfold and sixfold rotational symmetry.

Journal Article↗

PubMed2003

Scaling properties of simple limiter control.

"Simple limiter control" of chaotic systems is analytically and numerically investigated, proceeding from the one-dimensional case to higher dimensions. The properties of the control method are fully described by the one-parameter one-dimensional flat-top map family, implying that orbits are stabilized in exponential time, independent of the periodicity and without the need for targeting. Fine-tuning of the control is limited by superexponential scaling in the control space, where orbits of the uncontrolled system are obtained for a set of zero Lebesgue measure. In higher dimensions, simple limiter control is a highly efficient control method, provided that the proper limiter form and placement are chosen.

Journal Article↗

PubMed2003

Maternal methionine adenosyltransferase I/III deficiency: reproductive outcomes in a woman with four pregnancies.

Four pregnancies in a women with moderately severe deficiency of methionine adenosyltransferase I/III (MAT I/III) activity are reported. She is an apparent homozygote for a point mutation in MAT1A, the gene that encodes the catalytically active subunit of MAT I/III. This mutation reduces the activity of her expressed enzyme to some 11% of wild-type. She was the first such individual identified in the United States, and these are the first pregnancies known in anyone with this extent of MAT I/III deficiency. No adverse effects were noted in the mother. Three normal babies resulted, but fetal arrest was detected in one embryo at 10-11 weeks gestation. Plasma methionine concentrations remained virtually constant at their elevated levels of 300-350 micromol/L throughout the pregnancies. Plasma free choline was below the reference range. In view of the evidence that maternal choline delivery to the fetus is important for brain development, it was suggested the patient ingest two eggs daily from gestation week 17. Plasma choline and phosphatidylcholine tended to rise during such supplementation. Plasma cystathionine concentrations rose progressively to far above normal during these pregnancies, but not during pregnancies in control women. This may be explained by delivery of excessive methionine to the fetus, with consequent increased cystathionine synthesis by fetal tissues. Because fetal tissues lack gamma-cystathionase, presumably cystathionine accumulated abnormally in the fetus and was transferred in abnormal amounts back to the mother. Plasma and urinary concentrations of methionine transamination metabolites rose during pregnancy for reasons that remain obscure.

Adult↗

PubMed2003

Glycine N -methyltransferase deficiency: a new patient with a novel mutation.

We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 micro mol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT deficiency, strengthening the likelihood of a causative association. Although his deficiency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.

Child, Preschool↗

PubMed2003

CD44 variant isoform v10 is expressed on tumor-infiltrating lymphocytes and mediates hyaluronan-independent heterotypic cell-cell adhesion to melanoma cells.

CD44 is a family of cell-surface receptors on human lymphocytes that act as co-stimulatory molecules leading to the induction of effector functions in T cells. We have analyzed primary cutaneous malignant melanomas with clinical and histologic signs of tumor regression using immunohistochemistry and observed the predominant expression of the CD44 variant isoform v10 on CD3 CD4/CD8 co-expressing tumor-infiltrating lymphocytes (TIL). We further analyzed the role of CD44v10 in adhesion of lymphocytes to human melanoma cells. In contrast to CD44- lymphatic cells, CD44v10+ lymphatic cells strongly bound to cultured human melanoma cells and to frozen tissue samples of melanomas. Antibody blocking studies revealed a hyaluronan-, integrin-, and selectin-independent pathway of adhesion. Furthermore, CD44v10+ lymphatic cells exhibited significantly higher invasiveness in three-dimensional collagen matrices as compared with CD44H+ and CD44-negative lymphocytes. These results indicate that expression of CD44v10 on TIL may mediate adhesion to melanoma cells and result in gain of novel invasive properties.

Cell Adhesion↗

PubMed2003

Cellular mechanisms involved in the stenosis and obliteration of the cerebral aqueduct of hyh mutant mice developing congenital hydrocephalus.

Two phases may be recognized in the development of congenital hydrocephalus in the hyh mutant mouse. During embryonic life the detachment of the ventral ependyma is followed by a moderate hydrocephalus. During the first postnatal week the cerebral aqueduct becomes obliterated and a severe hydrocephalus develops. The aim of the present investigation was to elucidate the cellular phenomena occurring at the site of aqueduct obliteration and the probable participation of the subcommissural organ in this process. Electron microscopy, immunocytochemistry, and lectin histochemistry were used to investigate the aqueduct of normal and hydrocephalic hyh mice from embryonic day 14 (E-14) to postnatal day 7 (PN-7). In the normal hyh mouse, the aqueduct is an irregularly shaped cavity with 3 distinct regions (rostral, middle, and caudal) lined by various types of ependyma. In the hydrocephalic mouse, these 3 regions behave differently; the rostral end becomes stenosed, the middle third dilates, and the caudal end obliterates. The findings indicate that the following sequence of events lead to hydrocephalus: 1) denudation of the ventral ependyma (embryonic life); 2) denudation of dorsal ependyma and failure of the subcommissural organ to form Reissner fiber (first postnatal week); 3) obliteration of distal end of aqueduct; and 4) severe hydrocephalus. No evidence was obtained that NCAM is involved in the detachment of ependymal cells. The process of ependymal denudation would involve alterations of the surface sialoglycoproteins of the ependymal cells and the interaction of the latter with macrophages.

Aging↗

PubMed2003

Urban traffic and pollutant exposure related to respiratory outcomes and atopy in a large sample of children.

Conflicting results have been reported for the relationship between traffic exposure and inception of atopy. The effect of traffic on the prevalence of asthma and atopy at school age was investigated in a representative population. Random samples of schoolchildren (n=7,509, response rate 83.7%) were studied using the International Study of Asthma and Allergies in Childhood phase-II protocol with skin-prick tests, measurements of specific immunoglobulin E and lung function. Traffic exposure was assessed via traffic counts and by an emission model which predicted soot, benzene and nitrogen dioxide (NO2). Traffic counts were associated with current asthma, wheeze and cough. In children with tobacco-smoke exposure, traffic volume was additionally associated with a positive skin-prick test. Cough was associated with soot, benzene and NO2, current asthma with soot and benzene, and current wheeze with benzene and NO2. No pollutant was associated with allergic sensitisation. High vehicle traffic was associated with asthma, cough and wheeze, and in children additionally exposed to environmental tobacco smoke, with allergic sensitisation. However, effects of socioeconomic factors associated with living close to busy roads cannot be ruled out.

Asthma↗

PubMed2003

Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3A1 gene cause type I cystinuria, patients with non-type I cystinuria carry mutations in the SLC7A9 gene. Both gene products form the renal amino acid transporter rBAT/b0,+AT affected in cystinuria. In the present study a total of 59 patients with different ethnic background were screened for sequence variations in SLC7A9, out of these 32 were of German origin. For determination of allele frequencies of detected polymorphisms, 58 healthy German controls were investigated. Molecular-genetic analysis was performed using single-strand conformation polymorphism analysis, restriction assays and sequencing. Allele frequencies were analyzed statistically for the detected polymorphisms. In addition to the 6 already known variants we identified 7 new polymorphisms. Statistical analyses showed a significantly different distribution of alleles between German patients and German controls in case of the polymorphisms c. 147C>T (exon 2), c.386C>T (exon 3), IVS3+22T>G, c.584C>T (exon 4), c.610T>C (exon 4), c.692C>T (exon 5), c.852C>A (exon 6) and c.872C>T (exon 6). In summary, our results show that cystinuria is a complex disease which is not only caused by mutations in SLC7A9 and SLC3A1, but also influenced by other modifying factors such as variants in SLC7A9.

Alleles↗

PubMed2002

Phase relaxation of Faraday surface waves.

Surface waves on a liquid-air interface excited by a vertical vibration of a fluid layer (Faraday waves) are employed to investigate the phase relaxation of ideally ordered patterns. By means of a combined frequency-amplitude modulation of the excitation signal a periodic expansion and dilatation of a square wave pattern is generated, the dynamics of which is well described by a Debye relaxator. By comparison with the results of a linear theory, it is shown that the measured relaxation time allows a precise evaluation of the phase diffusion constant.

Journal Article↗

PubMed2002

Up-regulation of the dendritic cell marker CD83 on polymorphonuclear neutrophils (PMN): divergent expression in acute bacterial infections and chronic inflammatory disease.

Upon cultivation with interferon-gamma (IFN-gamma ) and granulocyte/macrophage-colony stimulating factor (GM-CSF) polymorphonuclear neutrophils (PMN) acquire characteristics of dendritic cells, including expression of major histocompatibility complex (MHC) class II antigens, of the co-stimulatory antigens CD80, CD86 and of CD83, the latter considered to be specific for dendritic cells. Dendritic-like PMN were also able to present to T cells antigens in a MHC class II-restricted manner. To assess whether dendritic-like PMN are also generated in vivo, cells of patients with acute bacterial infections and of patients with chronic inflammatory diseases (primary vasculitis) were tested. During acute infection up to 80% of PMN acquired CD83, but remained negative for MHC class II, CD80 or CD86. PMN of patients with primary vasculitis expressed MHC class II antigens, CD80 and CD86, but not CD83, indicating that up-regulation of MHC class II and of CD83 are not necessarily linked to each other. Indeed, parallel studies with PMN of healthy donors showed that while IFN-gamma and granulocyte/macrophage colony stimulating factor (GM-CSF) induced both, MHC class II and CD83, tumour necrosis factor (TNF)-alpha selectively induced de novo synthesis of CD83. The function of CD83 on PMN is still elusive. A participation in the MHC class II-restricted antigen presentation could be ruled out, consistent with the segregation of MHC class II and CD83 expression. Regardless, however, of its function, CD83 expression could serve as a marker to differentiate between acute and chronic inflammation.

Acute Disease↗

PubMed2002

Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease.

Cystinuria is a common inherited disorder of defective renal reabsorption of cystine and dibasic amino acids. Recently, 2 responsible genes have been identified: mutations in the SLC3AI gene encoding the glycoprotein rBAT cause cystinuria type I, while variants in the SLC7A9 gene have been demonstrated in non-type I cystinuria; its gene product b(0)+AT is the light chain of the renal cystine transport system rBAT/b(0),+-AT. To estimate the role of both genes in the etiology of cystinuria, we searched for sequence alterations in SLC7A9 and SLC3AI: 30 unclassified cystinurics were investigated. In 50% of patients (15/30), point mutations in SLC3A1 were detected. Screening of the SLC7A9 gene revealed 10 mutations in 8 patients corresponding to a frequency of 27%. In addition to previously published mutations in the SLC7A9 gene, we detected 2 new mutations (F 140S, c747delG). An overall detection rate of 73% (22/30) in unclassified patients is delineated for mutations in both genes. In 33% (10/30), 2 mutations were detected, in 40% (12/30) 1 mutation. Furthermore, 5 new polymorphic sites were identified in SLC7A9. While the base pair variation in intron 9 is homogeneously distributed in patients and control individuals, the allelic and genotypic distributions of the polymorphisms in 3 exons of SLC7A9--exons 2, 5 and 6--and intron 3 differ significantly between both groups. Our results suggest that some haplotypes defined through the exons 2, 5 and 6 and intron 3 might be markers of a functional variant in the SLC7A9 gene. Evidently, since the mutation detection rates in the 2 so far known cystinuria genes never reach 100%, further genes and modulating factors should influence the phenotype in a subset of patients. However, the presented data show that testing for mutations in the 2 currently known cystinuria genes is already a meaningful approach to the molecular diagnostics of the disease.

Amino Acid Transport Systems, Basic↗

PubMed2002

[Dentists and peer review: results of a descriptive study on perceived effects of peer review].

In the Netherlands over 20% of dentists participate in peer review groups. The peer review method is highly structured and consists of: setting standards for good dental care, measuring and evaluating performances against the standards and making improvements if necessary. An independent research institute (Nivel) investigated the perceived effects and advantages of and barriers to peer review. A postal questionnaire was sent tot 278 dentists who participate in peer review (response 60%). The results showed many effects of peer review. The most frequently reported effects were: more insight into the performances of colleagues, increased inter-professional contacts, a more critical attitude to performances, increased professional expertise and new inspiration and motivation. The respondents reported improvements in practice-organisation as well as in technical aspects of dental care. However, many dentists also mentioned some barriers to peer review. The method was evaluated as rather complex and it appeared to be difficult to reach consensus about standards for good dental care. In general, respondents perceived a positive balance between advantages and disadvantages of peer review, however many dentists were dissatisfied with the lack of financial compensation for participation in peer review.

Adult↗