Biomedical subjects

Rolf Fimmers

Publications and source records attributed to Rolf Fimmers.

43 records · Page 3Linked to original sources

PubMed2003

How to model a complex trait. 2. Analysis with two disease loci.

Complex traits are often governed by more than one trait locus. The first step towards an adequate model for such diseases is a linkage analysis with two trait loci. Such an analysis can be expected to have higher power to detect linkage than a standard single-trait-locus linkage analysis. However, it is crucial to accurately specify the parameters of the two-locus model. Here, we recapitulate the general two-locus model with and without genomic imprinting. We relate heterogeneity, multiplicative, and additive two-locus models to biological or pathophysiological mechanisms, and give the corresponding averaged ("best-fitting") single-trait-locus models for each of the two loci. Furthermore, we derive the two-locus penetrances from the averaged single-locus models, under the assumption of one of the three model classes mentioned above. Using these formulae, if the best-fitting single-locus models are available, investigators may perform a two-trait-locus linkage analysis under a realistic model. This procedure will maximize the power to detect linkage for traits which are governed by two or more loci, and lead to more accurate estimates of the disease-locus positions.

Computer Simulation↗

PubMed2002

Differential genetic determination of immune responsiveness to hepatitis B surface antigen and to hepatitis A virus: a vaccination study in twins.

BACKGROUND: The course of viral hepatitis is thought to be affected by genetic host variability and, in particular, by genes of the major histocompatibility locus. Hepatitis A and B vaccination is a useful model to study the effect of host factors on the immune response to viral antigens. We aimed to assess the heritability of the HBsAg (anti-HBs) and anti-hepatitis A virus (anti-HAV) immune response and to estimate the effect of the HLA-DRB1 locus and other genetic loci unlinked to HLA. METHODS: We did an open prospective study and vaccinated 202 twin pairs with a combined recombinant HBsAg/inactivated hepatitis A vaccine. We measured antibodies to HBsAg and HAV and determined HLA-DRB1* alleles. Heritability was calculated based on variance of antibody response within pairs. Model-fitting analyses were done to analyse genetic and environmental components of vaccine responses. FINDINGS: Anti-HBs and anti-HAV showed heritabilities of 0.61 (95% CI 0.41 to 0.81) and 0.36 (-0.02 to 0.73), respectively. For the anti-HBs immune response, 60% of the phenotypic variance was explained by additive genetic and 40% by non-shared environmental effects. The heritability of the HBsAg vaccine response accounted for by the DRB1* locus was estimated to be 0.25, leaving the remaining heritability of 0.36 to other gene loci. INTERPRETATION: Genetic factors have a strong effect on the immune response to HBsAg. Although genes encoded within the MHC are important for this immune response, more than half the heritability is determined outside this complex. Identification of these genes will help us to understand regulation of immune responses to viral proteins.

Adolescent↗

PubMed2002

Three-dimensional sonographic evaluation of the fetal lumbar spinal canal.

In a prospective cross-sectional ultrasound study the size of the fetal lumbar spinal canal was evaluated to determine reference values for the lumbar part of the vertebral canal. One hundred and sixty-seven pregnant women undergoing routine obstetric ultrasound were studied between 16 and 41 weeks of gestation. Exclusion criteria consisted of structural fetal anomalies or growth restriction. Area and volume of the vertebral canal at L1, L3 and L5 were calculated by three-dimensional (3D) ultrasound. Length of the lumbar spine was also determined. The size of the spinal canal and spinal length correlated well with gestational age. No gestational-age-dependent differences in area and volume measurements between upper and lower lumbar spine were found. The results provide an in vivo assessment of the spinal canal by 3D ultrasound over the entire gestation period.

Cross-Sectional Studies↗

PubMed2002

Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis.

Patients with atopic dermatitis display substantial immunologic abnormalities, among which elevated total IgE is considered as a hallmark; however, a subgroup of atopic dermatitis patients exhibits normal IgE levels, but mechanisms contributing to the so-called "intrinsic" or "nonallergic" form of atopic dermatitis are obscure. In order to unravel similarities and differences of both atopic dermatitis subtypes, the phenotype of monocytes, total serum IgE levels, and serum levels of cytokines regulating the IgE production from nonatopic individuals and patients with allergic rhinitis, and extrinsic and intrinsic atopic dermatitis were measured. Concomitantly, genomic DNA probes of all subjects were analyzed for single nucleotide polymorphisms of candidate genes of structures involved in the regulation of the IgE synthesis, such as interleukin-4 and the interleukin-4R/interleukin-13R. Our data show that the surface expression of the high- and low-affinity receptor for IgE (FcepsilonRI and FcepsilonRII/CD23) and the interleukin-4Ralpha chain were significantly elevated in monocytes from patients with extrinsic atopic dermatitis. Furthermore, serum levels of interleukin-13 were significantly increased in patients with intrinsic atopic dermatitis. In addition, the frequency of the interleukin-4Ralpha polymorphism C3223T and the interleukin-4 polymorphism C590T tended to be higher in extrinsic atopic dermatitis than in intrinsic atopic dermatitis. Altogether our findings indicate that intrinsic atopic dermatitis patients exhibit phenotypic and immunologic features, which differ from those of patients with extrinsic atopic dermatitis or other atopic disorders.

Adolescent↗

PubMed2002

Impact of genotype and morphology on the prognosis of glioblastoma.

The recognition of molecular subsets among glioblastomas has raised the question whether distinct mutations in glioblastoma-associated genes may serve as prognostic markers. The present study on glioblastomas (GBM) from 97 consecutively sampled adult patients is based on a clinical, histopathological, immunohistochemical, and molecular genetic analysis. Parameters assessed were age at diagnosis, survival, cell type, proliferation, necrosis, microvascular proliferation, sarcomatous growth, lymphocytic infiltration, thromboses, calcifications, GFAP expression, MIB-1 index, loss of heterozygosity (LOH) of the chromosomal arms 1p, 10p, 10q, 17p, 19q and structural alterations in the TP53, EGFR and PTEN genes. As in previous studies, younger age was significantly associated with better survival. Among the molecular parameters, TP53 mutations and LOH10q emerged as favorable and poor prognostic factors, respectively. TP53 mutations were a favorable prognostic factor independent of whether glioblastomas were primary or secondary. LOH1p or 19q, lesions suspected to be over-represented in long term survivors with malignant glioma, were not associated with better survival. However, the combination of LOH1p and LOH19q defined GBM patients with a significantly better survival. Notably, these patients did not exhibit morphological features reminiscent of oligodendroglioma. These findings indicate that genotyping of glioblastoma may provide clinical information of prognostic importance.

Adult↗

PubMed2002

Prognostic factors and outcome after different types of resection for temporal lobe epilepsy.

OBJECT: It is unknown whether different resection strategies for temporal lobe epilepsy (TLE) produce alterations in seizure control or neuropsychological performance. METHODS: A series of 321 patients who underwent surgery for TLE between 1989 and 1997 was submitted to a uni- and multifactorial analysis of clinical, electrophysiological, neuroimaging, neuropsychological, and surgical factors to determine independent predictors of outcome. Until 1993, most patients with TLE underwent standard anterior temporal lobectomy (ATL); beginning in 1993, surgical procedures were increasingly restricted to lesions detected on magnetic resonance (MR) imaging and the presumed epileptogenic foci: for example, amygdalohippocampectomy (AH) or lesionectomy/corticectomy began to be used more often. The mean follow-up duration in this study was 38 months. Two hundred twenty-seven patients were classified as seizure free (70.7%), and 36 patients had rare and nondisabling seizures (11.2%); these groups were summarized as having good seizure control (81.9%). Twenty-four patients attained more than 75% improvement (7.5%), and no worthwhile improvement was seen in 34 cases (10.6%); these groups were summarized as having unsatisfactory seizure control (18.1%). On unifactorial analysis the following preoperative factors were associated with good seizure control (p < 0.05): single and concordant lateralizing focus on electroencephalography studies, low seizure frequency, absence of status epilepticus, concordant lateralizing memory deficit, clear abnormality on MR images, suspected ganglioglioma or dysembryoplastic neuroepithelial tumor (DNT), and absence of dysplasia on MR images. Stepwise logistic regression revealed a model containing five factors that were predictive for good seizure control (p < 0.1): 1) clear abnormality on MR images; 2) absence of status epilepticus; 3) MR imaging-confirmed ganglioglioma or DNT; 4) concordant lateralizing memory deficit; and 5) absence of dysplasia on MR images. Seizure outcome was mainly correlated with diagnosis and clinical factors. No significant differences were found regarding different resection types performed for comparable tumors. Neuropsychological testing revealed better postoperative results after limited resections compared with standard ATL, especially with regard to attention level, verbal memory, and calculated total neuropsychological performance. CONCLUSIONS: Different strategies for surgical approaches in TLE result in equally good outcomes. Seizure outcome is mainly dependent on the diagnosis and clinical factors, whereas the neuropsychological results are more beneficial after resections limited to an epileptogenic lesion and focus.

Adolescent↗

PubMedDate not supplied

Preclinical evaluation of gemcitabine/paclitaxel-interactions in human bladder cancer lines.

BACKGROUND: Gemcitabine and paclitaxel are currently co-administered in clinical studies for bladder cancer as this drug combination may offer better tumor responses. However, the drugs may antagonize the cytotoxic capacity of each other due to cell cycle perturbations. In this study, we evaluated different application schedules to determine the efficacy of the combination and its potential interactions. MATERIALS AND METHODS: Bladder cancer cell lines were exposed to either gemcitabine or paclitaxel, in concentrations ranging from 1-1000 nM. The inhibition concentrations (IC) 20, 50 and 70 were assessed by MTT assay after 24, 48 and 72 hours. Then, the cytotoxic activity and apoptosis induction abilities of the combined agents using the IC20 concentration were analyzed by MTT and Annexin-V/PI staining, respectively. The effects on the cell cycle were assessed by flow cytometry of bromodeoxyuridine (BrdU) and propidium iodide (PI). RESULTS: Gemcitabine and paclitaxel dose-dependently inhibited cell proliferation. Simultaneous application of gemcitabine/paclitaxel yielded superior cytotoxicity rates after 48 and 72 hours. Sequential treatment of cells showed similar results when gemcitabine was given 24 hours before paclitaxel. However, when paclitaxel was given before gemcitabine, the cell kill was less. Gemcitabine as well as paclitaxel have potent apoptosis inducing abilities. Cell cycle evaluation demonstrated a shift towards the S-phase after gemcitabine and a progressive G2/M block after paclitaxel treatment. CONCLUSION: The combination of gemcitabine and paclitaxel in vitro yields superior cytotoxic efficacy, if given simultaneously or with gemcitabine first. While in vitro cell models may not necessarily predict clinical outcome, they do provide a basis for rational scheduling of drugs in clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗