PubMed Health⌕ Search

Biomedical subjects

Jens Timmer

Publications and source records attributed to Jens Timmer.

At least 19 recordsLinked to original sources
PubMed2006

Seizure prediction: the impact of long prediction horizons.

Several procedures have been proposed to be capable of predicting the occurrence of epileptic seizures. Up to now, all proposed algorithms are far from being sufficient for a clinical application. This is, however, often not obvious when results of seizure prediction performance are reported. Here, we discuss impacts of long prediction horizons with respect to clinical needs and the strain on patients by analyzing long-term continuous intracranial electroencephalography data.

Adolescent↗
PubMed2006

WNT and DKK determine hair follicle spacing through a reaction-diffusion mechanism.

Mathematical reaction-diffusion models have been suggested to describe formation of animal pigmentation patterns and distribution of epidermal appendages. However, the crucial signals and in vivo mechanisms are still elusive. Here we identify WNT and its inhibitor DKK as primary determinants of murine hair follicle spacing, using a combined experimental and computational modeling approach. Transgenic DKK overexpression reduces overall appendage density. Moderate suppression of endogenous WNT signaling forces follicles to form clusters during an otherwise normal morphogenetic program. These results confirm predictions of a WNT/DKK-specific mathematical model and provide in vivo corroboration of the reaction-diffusion mechanism for epidermal appendage formation.

Animals↗
PubMed2006

Capillary physiology of human medulloblastoma: impact on chemotherapy.

BACKGROUND: Advances in the treatment of medulloblastoma have largely been attributed to the introduction of chemotherapy, although Phase III trials have shown advantages for chemotherapy only in subgroups. Because the efficacy of chemotherapy depends on tumor vascularization, the vascular physiology of human medulloblastomas was evaluated. METHODS: Seven patients with histologically proven medulloblastomas underwent measurements of capillary permeability and vascular plasma volume using contrast-enhanced dynamic computer tomography. Regional blood flow was measured in 5 patients using xenon computed tomography (CT). RESULTS: The capillary permeability-surface product for water-soluble compounds ranged from 1.7 +/- 5.5 to 17.6 +/- 12.3 muL/g/min with a mean of 10.5 +/- 6.3 microL/g/min. The vascular plasma volume ranged from 0.02 +/- 0.021 to 0.045 +/- 0.049 mL/g with a mean of 0.03 +/- 0.01 mL/g. The efflux rate ranged from 0.012 +/- 0.007 to 0.065 +/- 0.064 1/min with a mean of 0.039 +/- 0.020 1/min. Regional tumoral blood flow showed a mean of 19.86 +/- 6.8 mL/100g/min as compared with normal cerebellum with 45.4 +/- 12.03 mL/100g/min (P < .005). CONCLUSIONS: The current study demonstrated a low capillary permeability and blood flow in medulloblastomas that could explain the limited response rates of partially resected tumors even after aggressive high-dose chemotherapy, as recently reported.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays.

Recurrent genomic aberrations are important prognostic parameters in chronic lymphocytic leukemia (CLL). High-resolution 10k and 50k Affymetrix SNP arrays were evaluated as a diagnostic tool for CLL and revealed chromosomal imbalances in 65.6% and 81.5% of 70 consecutive cases, respectively. Among the prognostically important aberrations, the del13q14 was present in 36 (51.4%), trisomy 12 in 9 (12.8%), del11q22 in 9 (12.8%), and del17p13 in 4 cases (5.7%). A prominent clustering of breakpoints on both sides of the MIRN15A/MIRN16-1 genes indicated the presence of recombination hot spots in the 13q14 region. Patients with a monoallelic del13q14 had slower lymphocyte growth kinetics (P=.002) than patients with biallelic deletions. In 4 CLL cases with unmutated VH genes, a common minimal 3.5-Mb gain of 2p16 spanning the REL and BCL11A oncogenes was identified, implicating these genes in the pathogenesis of CLL. Twenty-four large (>10 Mb) copy-neutral regions with loss of heterozygosity were identified in 14 cases. These regions with loss of heterozygosity are not detectable by alternative methods and may harbor novel imprinted genes or loss-of-function alleles that may be important for the pathogenesis of CLL. Genomic profiling with SNP arrays is a convenient and efficient screening method for simultaneous genome-wide detection of chromosomal aberrations.

Adult↗
PubMed2006

Oscillatory cerebral hemodynamics--the macro- vs. microvascular level.

The phase shift between oscillations of blood pressure (BP) and Doppler middle cerebral artery flow velocity (MCAFV) reflects continuous cerebral autoregulatory action. It is not known whether a similar phase shift exists for cortical hemodynamics ('microvascular level') assessed by near infrared spectroscopy (NIRS) and what the effects are of pathological conditions. This study investigates the phase relations between oscillations of BP, MCAFV and NIRS parameters in 38 healthy older adults and 28 patients with unilateral severe obstructive carotid disease. BP was recorded noninvasively by finger plethysmography. Stable 0.1 Hz oscillations of all hemodynamic parameters were induced by regular breathing at a rate of 6/min. Basic results were that: (1) BP-induced cortical microvascular oscillations (NIRS) follow those of macrovascular oscillations (MCAFV) with a phase of 80-90 degrees (corresponding to 2-2.5 s at 0.1 Hz), most likely reflecting a transit time phenomenon; (2) oxy- and deoxyhemoglobin thereby oscillate in counterphase; (3) hemodynamic compromise in carotid obstruction leads to (a) delayed NIRS oscillations in comparison to BP which are highly correlated to a shorter phase lead of MCAFV against BP and (b) a decoupling of the oxy-/deoxyhemoglobin counterphase to 240 degrees . Cortical hemodynamic responses to BP oscillations follow specific phase relationships due to cerebral autoregulatory action and circulatory transit times. With hemodynamic impairment, as in unilateral carotid obstruction, these phases are significantly changed reflecting disturbed autoregulation.

Aged↗
PubMed2006

Spatio-temporal patient-individual assessment of synchronization changes for epileptic seizure prediction.

OBJECTIVE: Abnormal synchronization of neurons plays a central role for the generation of epileptic seizures. Therefore, multivariate time series analysis techniques investigating relationships between the dynamics of different neural populations may offer advantages in predicting epileptic seizures. METHODS: We applied a phase and a lag synchronization measure to a selected subset of multicontact intracranial EEG recordings and assessed changes in synchronization with respect to seizure prediction. RESULTS: Patient individual results, group results, spatial aspects using focal and extra-focal electrode contacts as well as two evaluation schemes analyzing decreases and increases in synchronization were examined. Averaged sensitivity values of 60% are observed for a false prediction rate of 0.15 false predictions per hour, a seizure occurrence period of half an hour, and a prediction horizon of 10 min. For approximately half of all 21 patients, a statistically significant prediction performance is observed for at least one synchronization measure and evaluation scheme. CONCLUSIONS: The results indicate that synchronization changes in the EEG dynamics preceding seizures can be used for seizure prediction. Nevertheless, the underlying pathogenic mechanisms differ and both decreases and increases in synchronization may precede epileptic seizures depending on the structures investigated. SIGNIFICANCE: The prediction method, optimized values of intervention times, as well as preferred brain structures for the EEG recordings have to be determined for each patient individually offering the chance of a better patient-individual prediction performance.

Adolescent↗
PubMed2006

Partial phase synchronization for multivariate synchronizing systems.

Graphical models applying partial coherence to multivariate time series are a powerful tool to distinguish direct and indirect interdependencies in multivariate linear systems. We carry over the concept of graphical models and partialization analysis to phase signals of nonlinear synchronizing systems. This procedure leads to the partial phase synchronization index which generalizes a bivariate phase synchronization index to the multivariate case and reveals the coupling structure in multivariate synchronizing systems by differentiating direct and indirect interactions. This ensures that no false positive conclusions are drawn concerning the interaction structure in multivariate synchronizing systems. By application to the paradigmatic model of a coupled chaotic Roessler system, the power of the partial phase synchronization index is demonstrated.

Journal Article↗
PubMed2006

Gene profiling of polycystic kidneys.

BACKGROUND: While the genetic basis of autosomal dominant polycystic kidney disease (ADPKD) has been clearly established, the pathogenesis of renal failure in ADPKD remains elusive. Cyst formation originates from proliferating renal tubular epithelial cells that de-differentiate. Fluid secretion with cyst expansion and reactive changes in the extracellular matrix composition combined with increased apoptosis and proliferation rates have been implicated in cystogenesis. METHODS: To identify genes that characterize pathogenical changes in ADPKD, we compared the expression profiles of 12 ADPKD kidneys, 13 kidneys with chronic transplant nephropathy and 16 normal kidneys using a 7 k cDNA microarray. RT-PCR and immunohistochemical techniques were used to confirm the microarray data. RESULTS: Hierarchical clustering revealed that the gene expression profiles of normal, ADPKD and rejected kidneys were clearly distinct. A total of 87 genes were specifically regulated in ADPKD; 26 of these 87 genes were typical for smooth muscle, suggesting epithelial-to-myofibroblast transition (EMT) as a pathogenetic factor in ADPKD. Immunohistology revealed that smooth muscle actin, a typical marker for myofibroblast transition, and caldesmon were mainly expressed in the interstitium of ADPKD kidneys. In contrast, up-regulated keratin 19 and fibulin-1 were confined to cystic epithelia. CONCLUSION: Our results show that the end stage of ADPKD is associated with increased markers of EMT, suggesting that EMT contributes to the progressive loss of renal function in ADPKD.

Cluster Analysis↗
PubMed2006

Modeling of single noninactivating Na+ channels: evidence for two open and several fast inactivated states.

Voltage-gated Na(+) channels play a fundamental role in the excitability of nerve and muscle cells. Defects in fast Na(+) channel inactivation can cause hereditary muscle diseases with hyper- or hypoexcitability of the sarcolemma. To explore the kinetics and gating mechanisms of noninactivating muscle Na(+) channels on a molecular level, we analyzed single channel currents from wild-type and five mutant Na(+) channels. The mutations were localized in different protein regions which have been previously shown to be important for fast inactivation (D3-D4-linker, D3/S4-S5, D4/S4-S5, D4/S6) and exhibited distinct grades of defective fast inactivation with varying levels of persistent Na(+) currents caused by late channel reopenings. Different gating schemes were fitted to the data using hidden Markov models with a correction for time interval omission and compared statistically. For all investigated channels including the wild-type, two open states were necessary to describe our data. Whereas one inactivated state was sufficient to fit the single channel behavior of wild-type channels, modeling the mutants with impaired fast inactivation revealed evidence for several inactivated states. We propose a single gating scheme with two open and three inactivated states to describe the behavior of all five examined mutants. This scheme provides a biological interpretation of the collected data, based on previous investigations in voltage-gated Na(+) and K(+) channels.

Cell Line↗
PubMed2006

Analysis of single ion channel data incorporating time-interval omission and sampling.

Hidden Markov models are widely used to describe single channel currents from patch-clamp experiments. The inevitable anti-aliasing filter limits the time resolution of the measurements and therefore the standard hidden Markov model is not adequate anymore. The notion of time-interval omission has been introduced where brief events are not detected. The developed, exact solutions to this problem do not take into account that the measured intervals are limited by the sampling time. In this case the dead-time that specifies the minimal detectable interval length is not defined unambiguously. We show that a wrong choice of the dead-time leads to considerably biased estimates and present the appropriate equations to describe sampled data.

Algorithms↗
PubMed2006

Host cell responses induced by hepatitis C virus binding.

Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.

Antigens, Viral↗
PubMed2006

Testing statistical significance of multivariate time series analysis techniques for epileptic seizure prediction.

Nonlinear time series analysis techniques have been proposed to detect changes in the electroencephalography dynamics prior to epileptic seizures. Their applicability in practice to predict seizure onsets is hampered by the present lack of generally accepted standards to assess their performance. We propose an analytic approach to judge the prediction performance of multivariate seizure prediction methods. Statistical tests are introduced to assess patient individual results, taking into account that prediction methods are applied to multiple time series and several seizures. Their performance is illustrated utilizing a bivariate seizure prediction method based on synchronization theory.

Algorithms↗
PubMed2006

Do false predictions of seizures depend on the state of vigilance? A report from two seizure-prediction methods and proposed remedies.

PURPOSE: Available seizure-prediction algorithms are accompanied by high numbers of false predictions to achieve high sensitivity. Little is known about the extent to which changes in EEG dynamics contribute to false predictions. This study addresses potential causes and the circadian distribution of false predictions as well as their relation to the sleep-wake cycle. METHODS: In 21 patients, each with 24 h of interictal invasive EEG recordings, two methods, the dynamic similarity index and the mean phase coherence, were assessed with respect to time points of false predictions. Visual inspection of the invasive EEG data and additional scalp electroencephalogram data was performed at times of false predictions to identify possible correlates of changes in the EEG dynamics. RESULTS: A dependency of false predictions on the time of day is shown. Renormalized to the duration of the period patients are asleep and awake, 86% of all false predictions occurred during sleep for the dynamic similarity index and 68% for the mean phase coherence, respectively. Combining two reference intervals, one during sleep and one in an awake state, the dynamic similarity index increases its performance by reducing the number of false predictions by almost 50% without major changes in sensitivity. No obvious dependence of false predictions was noted on visible epileptic activity, such as spikes, sharp waves, or subclinical ictal patterns. CONCLUSIONS: Changes in the EEG dynamics related to the sleep-wake cycle contribute to limits of specificity of both seizure-prediction methods investigated. This may provide a clue for improving prediction methods in general. The combination of reference states yields promising results and may offer opportunities to increase further the performance of prediction methods.

Adolescent↗
PubMed2006

Detection of directed information flow in biosignals.

Several analysis techniques have been developed for time series to detect interactions in multidimensional dynamic systems. When analyzing biosignals generated by unknown dynamic systems, awareness of the different concepts upon which these analysis techniques are based, as well as the particular aspects the methods focus on, is a basic requirement for drawing reliable conclusions. For this purpose, we compare four different techniques for linear time series analysis. In general, these techniques detect the presence of interactions, as well as the directions of information flow, in a multidimensional system. We review the different conceptual properties of partial coherence, a Granger causality index, directed transfer function, and partial directed coherence. The performance of these tools is demonstrated by application to linear dynamic systems.

Algorithms↗
PubMed2005

Design principles of a bacterial signalling network.

Cellular biochemical networks have to function in a noisy environment using imperfect components. In particular, networks involved in gene regulation or signal transduction allow only for small output tolerances, and the underlying network structures can be expected to have undergone evolution for inherent robustness against perturbations. Here we combine theoretical and experimental analyses to investigate an optimal design for the signalling network of bacterial chemotaxis, one of the most thoroughly studied signalling networks in biology. We experimentally determine the extent of intercellular variations in the expression levels of chemotaxis proteins and use computer simulations to quantify the robustness of several hypothetical chemotaxis pathway topologies to such gene expression noise. We demonstrate that among these topologies the experimentally established chemotaxis network of Escherichia coli has the smallest sufficiently robust network structure, allowing accurate chemotactic response for almost all individuals within a population. Our results suggest that this pathway has evolved to show an optimal chemotactic performance while minimizing the cost of resources associated with high levels of protein expression. Moreover, the underlying topological design principles compensating for intercellular variations seem to be highly conserved among bacterial chemosensory systems.

Adaptation, Physiological↗
PubMed2005

Testing for directed influences among neural signals using partial directed coherence.

One major challenge in neuroscience is the identification of interrelations between signals reflecting neural activity. When applying multivariate time series analysis techniques to neural signals, detection of directed relationships, which can be described in terms of Granger-causality, is of particular interest. Partial directed coherence has been introduced for a frequency domain analysis of linear Granger-causality based on modeling the underlying dynamics by vector autoregressive processes. We discuss the statistical properties of estimates for partial directed coherence and propose a significance level for testing for nonzero partial directed coherence at a given frequency. The performance of this test is illustrated by means of linear and non-linear model systems and in an application to electroencephalography and electromyography data recorded from a patient suffering from essential tremor.

Algorithms↗
PubMed2005

Direct or indirect? Graphical models for neural oscillators.

Univariate and bivariate time series analysis techniques have enabled new insights into neural processes. However, these techniques are not feasible to distinguish direct and indirect interrelations in multivariate systems. To this aim multivariate times series techniques are presented and investigated by means of simulated as well as physiological time series. Pitfalls and limitations of these techniques are discussed.

Algorithms↗