Biomedical subjects

Paul H C Eilers

Publications and source records attributed to Paul H C Eilers.

13 recordsLinked to original sources

PubMed2004

Quantile smoothing of array CGH data.

MOTIVATION: Plots of array Comparative Genomic Hybridization (CGH) data often show special patterns: stretches of constant level (copy number) with sharp jumps between them. There can also be much noise. Classic smoothing algorithms do not work well, because they introduce too much rounding. To remedy this, we introduce a fast and effective smoothing algorithm based on penalized quantile regression. It can compute arbitrary quantile curves, but we concentrate on the median to show the trend and the lower and upper quartile curves showing the spread of the data. Two-fold cross-validation is used for optimizing the weight of the penalties. RESULTS: Simulated data and a published dataset are used to show the capabilities of the method to detect the segments of changed copy numbers in array CGH data.

Algorithms↗

PubMed2004

New background correction method for liquid chromatography with diode array detection, infrared spectroscopic detection and Raman spectroscopic detection.

A new method to eliminate the background spectrum (EBS) during analyte elution in column liquid chromatography (LC) coupled to spectroscopic techniques is proposed. This method takes into account the shape and also intensity differences of the background eluent spectrum. This allows the EBS method to make a better estimation of the background eluent spectrum during analyte elution. This is an advantage for quantification as well as for identification of analytes. The EBS method uses a two-step procedure. First, the baseline spectra are modeled using a limited number of principal components (PCs). Subsequently, an asymmetric least squares (asLS) regression method is applied using these principal components to correct the measured spectra during elution for the background contribution. The asymmetric least squares regression needs one parameter, the asymmetry factor p. This asymmetry factor determines relative weight of positive and negative residuals. Simulations are performed to test the EBS method in well-defined situations. The effect of spectral noise on the performance and the sensitivity of the EBS method for the value of the asymmetry factorp is tested. Two applications of the EBS method are discussed. In the first application, the goal is to extract the analyte spectrum from an LC-Raman analysis. In this case, the EBS method facilitates easy identification of unknown analytes using spectral libraries. In a second application, the EBS method is used for baseline correction in LC-diode array detection (DAD) analysis of polymeric standards during a gradient elution separation. It is shown that the EBS method yields a good baseline correction, without the need to perform a blank chromatographic run.

Spectrophotometry, Infrared↗

PubMed2004

Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features. We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid beta precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

Gene Expression Profiling↗

PubMed2004

Enhancing scatterplots with smoothed densities.

MOTIVATION: Scatterplots of microarray data generally contain a very large number of dots, making it difficult to get a good impression of their distribution in dense areas. RESULTS: We present a fast and simple algorithm for two-dimensional histogram smoothing, to visually enhance scatterplots. AVAILABILITY: Functions for Matlab and R are available from the corresponding author.

Algorithms↗

PubMed2004

Parametric time warping.

A parametric model is proposed for the warping function when aligning chromatograms. A very fast and stable algorithm results that consumes little memory and avoids the artifacts of dynamic time warping. The parameters of the warping function are useful for quality control. They also are easily interpolated, allowing alignment of batches of chromatograms based on warping functions for a limited number of calibration samples.

Journal Article↗

PubMed2004

A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient.

Recently, we documented an increased risk for the occurrence of breast- and cartilaginous tumors in the same patient, statistically pointing towards a potential genetic trait. This trait is most probably not associated with mutations in the two major hereditary breast cancer genes since no cases of enchondroma or chondrosarcoma were found in Dutch BRCA1 and BRCA2 families. We were able to collect and review the tumor tissue samples from 34 patients with both breast- and cartilaginous tumors and compared histopathological and immunohistochemical features of these tumors with controls. Breast cancer controls were available from literature data generated to compare familial breast cancers with nonselected cases. Clinical markers for chondrosarcoma controls were collected from the Netherlands Committee of Bone Tumors. Immunohistochemical data on chondro-tumor controls were available from our own files. Breast tumors of patients with cartilaginous sarcomas showed a significantly higher mitotic count (P=0.001), contained less lymphocyte infiltrate (P=0.025) and less nuclear pleomorphism. Remarkably, all cartilaginous tumors are of one common histological category originating centrally (P=0.014). Estrogen receptor and p53 expression were significantly higher (P<0.001) in breast cancer associated with chondro-tumors. p21 staining was more often negative in chondro-tumors associated with breast cancer. In seven cases of breast cancer, we found a slight decrease in CHEK2 expression. However, we could not identify the CHEK2 1100delC mutation in these cases nor in cases with normal CHEK2 expression. Hierarchical cluster analysis of all parameters within chondro-tumor-associated breast cancer specimens revealed two different subgroups, the largest one associated with estrogen receptor-positive breast cancer, which may distinguish sporadic cases from those belonging to the potential genetic trait. These distinct phenotypic findings support the existence of a new hitherto unrecognized syndrome, characterized by an increased risk to develop both breast cancer and centrally originating cartilaginous tumors.

Adenocarcinoma↗

PubMed2004

Transposition rates of Mycobacterium tuberculosis IS6110 restriction fragment length polymorphism patterns.

To determine the rate at which IS6110 restriction fragment length polymorphism (RFLP) patterns in Mycobacterium tuberculosis change over time, we applied a smooth nonparametric survival model to several data sets, including data from previous publications on the rate of change. The results strongly suggest a simple parametric model, with an instantaneous change at time zero and essentially a zero rate of change thereafter. Our interpretation of the results is that at the time of collection of the first isolate, more than one strain is present. We speculate that the selection of mutant strains is most likely during rapid growth, revival of the dormant bacteria, and/or adaptation to a new host. The parameter most accurately describing changing RFLP patterns is the proportion of isolates with band changes, rather than the half-life or the rate of change.

DNA Transposable Elements↗

PubMed2004

Leptin and the proinflammatory state associated with human obesity.

It has been suggested that elevated leptin levels underlie the low grade proinflammatory state in human obesity. We reasoned that if elevated leptin levels are an important factor in the proinflammatory state in obesity, then exogenous leptin administration during weight loss should counteract the concurrent beneficial effects of weight loss on the proinflammatory state. We therefore determined whether long-acting pegylated recombinant leptin (PEG-OB) prevents the decrease in cellular and humoral inflammation parameters during a very low calorie diet in healthy overweight young men. Except for B cells, PEG-OB treatment did not influence the decline in total leukocyte count and mononuclear subfractions during the diet. Weight loss decreased the humoral inflammation parameters TNFalpha, tissue plasminogen activator, and von Willebrand factor (P < 0.05), but in combination with PEG-OB treatment, a significant decrease was shown for inflammation markers as a whole (P < 0.014) and that of the individual parameters tissue plasminogen activator, von Willebrand factor, plasminogen activator inhibitor type 1, and intercellular adhesion molecule-1 (P < 0.05). The increase in C-reactive protein levels (P < 0.05) was the sole indication for a humoral proinflammatory action of leptin. Although PEG-OB treatment significantly increased weight loss (P < 0.03), the data do not support a proinflammatory role of leptin in human obesity.

Adult↗

PubMed2003

Heterogeneity of rhythmic suprachiasmatic nucleus neurons: Implications for circadian waveform and photoperiodic encoding.

Circadian rhythms in neuronal ensemble, subpopulations, and single unit activity were recorded in the suprachiasmatic nuclei (SCN) of rat hypothalamic slices. Decomposition of the ensemble pattern revealed that neuronal subpopulations and single units within the SCN show surprisingly short periods of enhanced electrical activity of approximately 5 h and show maximal activity at different phases of the circadian cycle. The summed activity accounts for the neuronal ensemble pattern of the SCN, indicating that circadian waveform of electrical activity is a composed tissue property. The recorded single unit activity pattern was used to simulate the responsiveness of SCN neurons to different photoperiods. We inferred predictions on changes in peak width, amplitude, and peak time in the multiunit activity pattern and confirmed these predictions with hypothalamic slices from animals that had been kept in a short or long photoperiod. We propose that the animals' ability to code for day length derives from plasticity in the neuronal network of oscillating SCN neurons.

Animals↗

PubMed2003

A perfect smoother.

The well-known and popular Savitzky-Golay filter has several disadvantages. A very attractive alternative is a smoother based on penalized least squares, extending ideas presented by Whittaker 80 years ago. This smoother is extremely fast, gives continuous control over smoothness, interpolates automatically, and allows fast leave-one-out cross-validation. It can be programmed in a few lines of Matlab code. Theory, implementation, and applications are presented.

Journal Article↗

PubMed2003

Prognostic value of the disodium phosphate 32P uptake test in uveal melanoma: a long-term study.

OBJECTIVE: To evaluate whether nuclear activity as measured by the disodium phosphate 32P (32P) uptake test for uveal melanoma is of prognostic value and corresponds to known prognostic factors. METHODS: A retrospective analysis of 121 patients with choroidal and/or ciliary body melanoma, tested with the 32P uptake test before enucleation between January 1, 1973, and December 31, 1976, at the Leiden University Medical Center. We obtained the 25-year follow-up information of this group of patients and compared the 32P test results and histopathological variables with the long-term survival rates. RESULTS: The cumulative 5-, 10-, and 20-year survival for melanoma-related death was 81.4%, 73.3%, and 63.9%, respectively. The results of the 32P uptake test were not significantly correlated with survival (P =.35). Of all prognostic factors under study, tumor diameter, cell type, and mitotic count were identified as the most important prognostic markers for uveal melanoma in this group. CONCLUSIONS: The 32P isotope uptake test has no prognostic value for uveal melanoma. Moreover, the results of this study indicate that it is unlikely that cell activity as determined by 32P uptake involves mitotic activity of the tumor.

Adolescent↗

PubMed2003

Renal mRNA levels as prognostic tools in kidney diseases.

Molecular biologic techniques are currently considered as new diagnostic and prognostic parameters with a sensitivity and specificity exceeding those of histologic and functional data currently used in clinical practice. The results in various clinical settings have been of limited value up to now. This study is an investigation of the use of tissue levels of RNA determined in routine clinical kidney biopsies as prognostic tools. The focus was on RNA encoding for molecules known to be involved in the pathogenesis of renal disorders. Fresh kidney biopsy tissue was obtained from 52 patients with various renal diseases. The GFR was followed for 12 mo. The extent of glomerulosclerosis and interstitial fibrosis in the biopsies was determined with quantitative digital image analysis. Glomerular and tubulointerstitial compartments from each biopsy specimen were separated, and mRNA levels of TGF-beta, collagen I, collagen IV, and fibronectin were quantitated by real-time PCR. Correlations, along with 95% confidence intervals (CI), between all variables tested at time biopsy were determined. To assess their prognostic value, these variables were correlated with the slope of GFR within several time intervals after biopsy. In addition, to evaluate the predictive value of the variables for outcome in individual patients, differences for each variable were tested between patients showing progressive decline in renal function (slope GFR < 0) and patients showing stable or improving renal function over time (slope GFR >or= 0). In chronic renal diseases, the extent of histologic damage correlated with the GFR at the time of biopsy (r = -0.44; CI -0.68 to -0.11), but it did not correlate with the slope expressing a change in GFR after the biopsy. Tubulointerstitial TGF-beta mRNA levels correlated with the rate of change in GFR between time of biopsy and 1 mo later (r = 0.41; CI, 0.07 to 0.67). The GFR at the time of biopsy correlated with the slope of change in GFR between time of biopsy and 12 mo later (r = -0.50; CI, -0.73 to -0.18). In chronic renal diseases, glomerular fibronectin mRNA levels, in comparison with the GFR at time of biopsy, correlated relatively strongly with the slope of change in GFR between 3 and 12 mo (r = 0.50; CI, 0.16 to 0.74). Patients with favorable renal outcome after 12 mo showed significantly higher TGF-beta mRNA levels and lower proteinuria levels at time of biopsy (P < 0.05) than patients with a progressive decline in renal function. This study shows that mRNA levels measured in kidney biopsies can function as prognostic tools in human renal diseases. In particular, relatively high levels of tubulointerstitial TGF-beta mRNA and glomerular fibronectin mRNA are associated with less deterioration in renal function.

Adult↗

PubMed2002

Gastric motility: comparison of assessment with real-time MR imaging or barostat measurement initial experience.

Measurements of gastric volume and motility with magnetic resonance (MR) imaging were compared with simultaneously performed measurements with a barostat in six healthy volunteers. Three-dimensional volume and two-dimensional dynamic MR images and barostat measurements were obtained at rest. Alterations in gastric volume and motility were induced by means of infusion of glucagon and erythromycin, respectively. There is strong evidence to have the opinion that MR imaging is as accurate as barostat measurement in determining changes in gastric volume, and it yields additional information about gastric contractions.

Adult↗