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Biomedical subjects

Christine Fischer

Publications and source records attributed to Christine Fischer.

16 recordsLinked to original sources
PubMed2004

Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous human disorders. Dysfunction of serotonergic neurotransmission is thought to play a major role in the pathophysiology of the fibromyalgia syndrome (FMS) which is characterised by non-restorative sleep and severe pain. In our study, both serotonin receptor subunit genes, HTR3A and HTR3B, have been investigated for sequence variations in FMS patients in order to reveal a possible involvement in the aetiology of FMS. We examined DNA samples from 48 patients with FMS representing sporadic cases by single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (dHPLC) analysis, sequenced samples with conspicuous patterns and performed statistical calculations. HTR3A mutational analysis revealed one novel as well as five known sequence variations. Investigating HTR3B, we detected seven formerly described mutations and one novel sequence variant. Statistical computation rated all variants as probably non-disease-related polymorphisms. Nevertheless, one might speculate about an effect of the respective sequence variants on the severity of the disease. Sequence variants of the serotonin receptor subunit genes HTR3A and HTR3B indicate no obvious significance in the aetiology of fibromyalgia, yet they represent the basis for future studies on their pharmacogenetic relevance.

Chromatography, High Pressure Liquid↗
PubMed2004

Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants.

The thiopurine S-methyltransferase (TPMT) genetic polymorphism has a significant clinical impact on the toxicity of thiopurine drugs. It has been proposed that the identification of patients who are at high risk for developing toxicity on the basis of genotyping could be used to individualize drug treatment. In the present study, phenotype-genotype correlation of 1214 healthy blood donors was investigated to determine the accuracy of genotyping for correct prediction of different TPMT phenotypes. In addition, the influence of gender, age, nicotine and caffeine intake was examined. TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2 and *3. Discordant cases between phenotype and genotype were systematically sequenced. A clearly defined trimodal frequency distribution of TPMT activity was found with 0.6% deficient, 9.9% intermediate and 89.5% normal to high methylators. The frequencies of the mutant alleles were 4.4% (*3A), 0.4% (*3C) and 0.2% (*2). All seven TPMT deficient subjects were homozygous or compound heterozygous carriers for these alleles. In 17 individuals with intermediate TPMT activity discordant to TPMT genotype, four novel variants were identified leading to amino acid changes (K119T, Q42E, R163H, G71R). Taking these new variants into consideration, the overall concordance rate between TPMT genetics and phenotypes was 98.4%. Specificity, sensitivity and the positive and negative predictive power of the genotyping test were estimated to be higher than 90%. Thus, the results of this study provide a solid basis to predict TPMT phenotype in a Northern European Caucasian population by molecular diagnostics.

Adolescent↗
PubMed2004

Early experience alters brain function and structure.

OBJECTIVE: To investigate the effects of early experience on brain function and structure. METHODS: A randomized clinical trial tested the neurodevelopmental effectiveness of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). Thirty preterm infants, 28 to 33 weeks' gestational age (GA) at birth and free of known developmental risk factors, participated in the trial. NIDCAP was initiated within 72 hours of intensive care unit admission and continued to the age of 2 weeks, corrected for prematurity. Control (14) and experimental (16) infants were assessed at 2 weeks' and 9 months' corrected age on health status, growth, and neurobehavior, and at 2 weeks' corrected age additionally on electroencephalogram spectral coherence, magnetic resonance diffusion tensor imaging, and measurements of transverse relaxation time. RESULTS: The groups were medically and demographically comparable before as well as after the treatment. However, the experimental group showed significantly better neurobehavioral functioning, increased coherence between frontal and a broad spectrum of mainly occipital brain regions, and higher relative anisotropy in left internal capsule, with a trend for right internal capsule and frontal white matter. Transverse relaxation time showed no difference. Behavioral function was improved also at 9 months' corrected age. The relationship among the 3 neurodevelopmental domains was significant. The results indicated consistently better function and more mature fiber structure for experimental infants compared with their controls. CONCLUSIONS: This is the first in vivo evidence of enhanced brain function and structure due to the NIDCAP. The study demonstrates that quality of experience before term may influence brain development significantly.

Brain↗
PubMed2003

Facile and racemization-free conversion of chiral nitriles into pyridine derivatives.

The results described herein demonstrate how the very mild reaction conditions of the Co(I)-catalyzed photochemical [2 + 2 + 2] cyclocotrimerization are suited to prepare chiral compounds containing unsubstituted and polysubstituted 2-pyridyl moieties starting from chiral nitriles without any detectable loss of enantiomerical purity. This further increases the already very broad synthetic scope of this particular reaction.

Journal Article↗
PubMed2003

Synthesis of a new chiral bisphospholane ligand for the Rh(I)-catalyzed enantioselective hydrogenation of isomeric beta-acylamido acrylates.

The highly stereoselective synthesis of a chiral silylphospholane has been described, which can be advantageously used as a building block under base-free conditions for the construction of diphosphines related to DuPHOS. The utility of silylphospholane is shown in the synthesis of a new bisphospholane ligand 1 (MalPHOS), which is characterized by a maleic anhydride backbone. The ligand forms with Rh(I) a complex with a larger bite angle P-Rh-P than the analogue Me-DuPHOS complex. Both complexes have been tested in the asymmetric hydrogenation of unsaturated alpha- and beta-amino acid precursors of pharmaceutical relevance. In several cases, the new catalyst was superior in comparison to the Me-DuPHOS complex, in particular when (Z)-configured beta-acylamido acrylates were used as substrates.

Journal Article↗
PubMed2003

Haplotype sharing analysis with SNPs in candidate genes: the Genetic Analysis Workshop 12 example.

Haplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct influence on affection and harbors more than 70 SNPs. Haplotype sharing analysis depends heavily on previous haplotype estimation. Using GENEHUNTER haplotypes, strong evidence was found for most SNPs in the isolated population sample, thus providing evidence for an involvement of this gene, but the maximum -log(10)(p) values for the haplotype sharing statistics (HSS) test statistic did not correspond to the location of the true variant in either population. In comparison, transmission disequilibrium test (TDT) analysis showed the strongest results at the disease-causing variant in both populations, and these were outstanding in the general population. In this example, TDT analysis appears to perform better than HSS in identifying the disease-causing variant, using SNPs within a candidate gene in an outbred population. Simulations showed that the performance of HSS is hampered by closely spaced SNPs in strong linkage disequilibrium with the functional variant and by ambiguous haplotypes.

Chromosome Mapping↗
PubMed2002

Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation.

Patients with abnormal accumulations of desmin have been described in myopathies with or without cardiac involvement. Desmin deposits were sometimes associated with abnormal aggregates of other cytoskeletal proteins. In the present study we present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin, plectin and alphaB-crystallin is altered in skeletal muscles from a patient with a L345P mutation in the desmin gene. In general, accumulations of desmin together with synemin, nestin, plectin and alphaB-crystallin were present between myofibrils and beneath the sarcolemma. However, as the biopsy samples were very myopathic, large variability in fibre size and fibre maturation was seen, thus the myofibrillar content and the cytoskeletal organisation varied considerably. In cultured satellite cells from the patient, desmin aggregates were not observed in initial passages, but occurred over time in culture in the form of perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin was only present in cells with a disrupted desmin network. Plectin was altered in a subset of cells with a disrupted desmin network, whereas synemin and paranemin were not detected. We conclude that the L345P desmin mutation has a profound influence on the cytoskeletal organisation both in vivo and in vitro, which reflects the pathogenesis of the desmin myopathy.

Cells, Cultured↗
PubMed2002

Exclusion mapping of the genetic predisposition for cervical artery dissections by linkage analysis.

Skin biopsies from a patient with a dissection of the left internal carotid artery and from four of his children were analyzed by electron microscopy. The index patient and three children showed mild but regular electron microscopic connective tissue aberrations. They were considered as carriers of an unknown autosomal dominant mutation. Thirty-four candidate genes involved in the biosynthesis of the extracellular matrix were excluded by genetic linkage analysis as possible sites of a disease-causing mutation in this family (logarithm of odds [LOD]-score less than -2.0).

Biopsy↗
PubMed2002

The human SHOX mutation database.

The human SHOX database has recently been established to provide clinicians and scientists access to a central source of information about all known SHOX mutations associated with short stature phenotypes such as idiopathic short stature, Lèri-Weill dyschondrosteosis, Langer syndrome, and Turner syndrome. So far, the database contains 29 unique intragenic mutations of the SHOX gene. These mutations were detected in a total of 39 patients from different families. Fourteen of these mutations have been found from the SHOX research group at the Institute of Human Genetics in Heidelberg, Germany; 25 mutations are from data reported in the literature. Not included in this database are complete SHOX gene deletions which represent the majority of all detectable SHOX mutations [Rappold et al., 2002]. The database is accessible via the website www.shox.uni-hd.de. It contains general information about the SHOX gene, and allows remote users to search the data and to submit new mutations to the database.

Base Sequence↗
PubMed2002

Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23.

BACKGROUND: Diabetic nephropathy is the major cause of end-stage renal failure in patients with diabetes mellitus types 1 and 2. Epidemiological studies have suggested a genetic susceptibility to diabetic nephropathy. The aim of this study was to localize the gene(s) responsible for susceptibility to diabetic nephropathy. METHODS: A genetic linkage analysis was performed in 18 large Turkish families with type 2 diabetes mellitus and diabetic nephropathy. The result was checked in 101 affected sibling pairs of Pima Indians. RESULTS: A highly significant LOD score of 6.1 on chromosome 18q22.3-23 between the markers D18S469 and D18S58 was obtained in multipoint analysis. There was no indication for locus heterogeneity. In Pima Indians, linkage to the markers D18S469 and D18S58 was confirmed (P = 0.033), using the affected sib-pair method. The genetic model that fit best was a dominant mode of inheritance with an almost complete penetration in the Turkish population. CONCLUSIONS: There is strong evidence for the localization of a gene responsible for diabetic nephropathy in Turkish type 2 diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between D18S43 and D18S50, an interval of 8.5 cM.

Adult↗
PubMed2002

Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22-q24.

PURPOSE: To describe the phenotypic expression of a new family with familial lateral temporal lobe epilepsy with aphasic seizures, and to compare the findings with the clinical features of previously reported families linked to chromosome 10q22-q24. METHODS: Medical records were collected from 12 living affected members. The patients underwent a personal interview and a clinical neurologic examination. Results from interictal scalp EEGs and neuroimaging examinations were obtained. RESULTS: The cardinal ictal symptom was a brief sensory aphasia in eight of the patients. In four, this was accompanied by auditory symptoms, usually in the form of monotonous unformed sounds. Simple partial seizures with psychic or somatosensory seizures also were present. Visual ictal symptoms and complex partial seizures were absent. All patients had generalized tonic-clonic seizures. Magnetic resonance imaging (MRI) or computed tomography (CT) did not reveal morphologic correlates. Improvement with age seemed to occur in many patients. Significant linkage to chromosome 10q22-q24 was established by testing 17 polymorphic microsatellite markers. CONCLUSIONS: The epilepsy of this family appears to represent a variety of autosomal dominant lateral temporal lobe epilepsy. Aphasic seizures and a peculiar seizure-precipitating effect of the activation of speech (initiation or perception) may serve as markers for identifying further families with this phenotype.

Adolescent↗
PubMed2002

Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism.

The efficacy of the immunosuppressants azathioprine and 6-mercaptopurine has been well established in the therapy of inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious adverse drug reactions such as hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal disturbances. Whereas azathioprine-related pancytopenia has been clearly linked to thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving azathioprine therapy and had never experienced side effects. Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3; pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type. TPMT deficiency in one patient had led to pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT.

Adult↗