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Biomedical subjects

D Geiger

Publications and source records attributed to D Geiger.

At least 19 recordsLinked to original sources
PubMed2006

Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers.

Computation of LOD scores is a valuable tool for mapping disease-susceptibility genes in the study of Mendelian and complex diseases. However, computation of exact multipoint likelihoods of large inbred pedigrees with extensive missing data is often beyond the capabilities of a single computer. We present a distributed system called "SUPERLINK-ONLINE," for the computation of multipoint LOD scores of large inbred pedigrees. It achieves high performance via the efficient parallelization of the algorithms in SUPERLINK, a state-of-the-art serial program for these tasks, and through the use of the idle cycles of thousands of personal computers. The main algorithmic challenge has been to efficiently split a large task for distributed execution in a highly dynamic, nondedicated running environment. Notably, the system is available online, which allows computationally intensive analyses to be performed with no need for either the installation of software or the maintenance of a complicated distributed environment. As the system was being developed, it was extensively tested by collaborating medical centers worldwide on a variety of real data sets, some of which are presented in this article.

Algorithms↗
PubMed2005

Modeling haplotype block variation using Markov chains.

Models of background variation in genomic regions form the basis of linkage disequilibrium mapping methods. In this work we analyze a background model that groups SNPs into haplotype blocks and represents the dependencies between blocks by a Markov chain. We develop an error measure to compare the performance of this model against the common model that assumes that blocks are independent. By examining data from the International Haplotype Mapping project, we show how the Markov model over haplotype blocks is most accurate when representing blocks in strong linkage disequilibrium. This contrasts with the independent model, which is rendered less accurate by linkage disequilibrium. We provide a theoretical explanation for this surprising property of the Markov model and relate its behavior to allele diversity.

Chromosome Mapping↗
PubMed2005

[Non-small-cell lung cancer third-line therapy with gefitinib].

The EGFR-inhibition via tyrosine-kinase-inhibitor gefitinib (Iressa) constitutes a new way to treat non-small-cell lung cancer. Recent research results enable us to better understand the basics of molecular targeted therapy (MTT). These results are helpful to re-interpret the clinical results obtained so far for gefitinib and to consider for the first time in a predictive manner factors for the selection of patients suitable for therapy. Three case reports are presented in this paper which illustrate that -- with view to the results from translational research -- the use of gefitinib offers an efficient new therapeutic modality for the treatment of chemotherapy-resistant non-small-cell lung cancer.

Aged↗
PubMed2004

AtTPK4, an Arabidopsis tandem-pore K+ channel, poised to control the pollen membrane voltage in a pH- and Ca2+-dependent manner.

The Arabidopsis tandem-pore K(+) (TPK) channels displaying four transmembrane domains and two pore regions share structural homologies with their animal counterparts of the KCNK family. In contrast to the Shaker-like Arabidopsis channels (six transmembrane domains/one pore region), the functional properties and the biological role of plant TPK channels have not been elucidated yet. Here, we show that AtTPK4 (KCO4) localizes to the plasma membrane and is predominantly expressed in pollen. AtTPK4 (KCO4) resembles the electrical properties of a voltage-independent K(+) channel after expression in Xenopus oocytes and yeast. Hyperpolarizing as well as depolarizing membrane voltages elicited instantaneous K(+) currents, which were blocked by extracellular calcium and cytoplasmic protons. Functional complementation assays using a K(+) transport-deficient yeast confirmed the biophysical and pharmacological properties of the AtTPK4 channel. The features of AtTPK4 point toward a role in potassium homeostasis and membrane voltage control of the growing pollen tube. Thus, AtTPK4 represents a member of plant tandem-pore-K(+) channels, resembling the characteristics of its animal counterparts as well as plant-specific features with respect to modulation of channel activity by acidosis and calcium.

Animals↗
PubMed2004

High density linkage disequilibrium mapping using models of haplotype block variation.

MOTIVATION: The presence of millions of single nucleotide polymorphisms (SNPs) in the human genome has spurred interest in genetic mapping methods based on linkage disequilibrium. The recently discovered haplotype block structure of human variation promises to improve the effectiveness of these methods. A key difficulty for mapping techniques is the cost involved in separately identifying the haplotypes on each of an individual's chromosomes. RESULTS: We present a new approach for performing linkage disequilibrium mapping using high density haplotype or genotype data. Our method is based on a statistical model of haplotype block variation, which takes account of recombination hotspots, bottlenecks, genetic drift and mutation. We test our technique on two empirically determined high density datasets, attempting to recover the location of an SNP which was hidden and converted into phenotype information. We compare the results against a mapping method based on individual SNPs as well as a competing haplotype-based approach. We show that our strategy significantly outperforms these other approaches when used as a guide for resequencing and that it can also deal with both unphased genotype data and low penetrance diseases. AVAILABILITY: HaploBlock executables for Linux, Mac OS X and Sun OS, as well as user documentation, are available online at http://bioinfo.cs.technion.ac.il/haploblock/

Artificial Intelligence↗
PubMed2004

Model-based inference of recombination hotspots in a highly variable oncogene [corrected].

An emergent problem in the study of pathogen evolution is our ability to determine the extent to which their rapidly evolving genomes recombine. Such information is necessary and essential for locating pathogenicity loci using association studies, and it also directs future screening, therapeutic and vaccination strategies. Recombination also complicates the use of phylogenetic approaches to infer evolutionary parameters including selection pressures. Reliable methods that identify the presence of regions of recombination are therefore vital. We illustrate the use of an integrated model-based approach to inferring recombination structure using all available sequences of the highly variable, transforming Kaposi's sarcoma-associated herpesviral gene, ORF-K1. This technique learns the parameters of a statistical model that takes recombination hotspots, population genetic effects, and variable rates of mutation into account. As there are no known mechanisms to explain the high mutation rate in this DNA viral gene, recombination may account for some of the variability observed. We infer recombination hotspots in conserved sites such as the tyrosine kinase signaling motif, referred to here as recombination drift, as well as in nonconserved sites, a process described as recombination shift.

Bayes Theorem↗
PubMed2004

Influence of individual competition level on back kinematics of horses jumping a vertical fence.

REASONS FOR PERFORMING STUDY: The costs and investments required for the purchase and training of showjumpers justify the need to find selection means for jumping horses. Use of objective kinematic criteria correlated to jumping ability could be helpful for this assessment. OBJECTIVES: To compare back kinematics between 2 groups of horses of different competition levels (Group 1, competing at high level; Group 2 competing at low level) while free jumping over a 1 m vertical fence. METHODS: Three-dimensional recordings were performed using 2 panning cameras. Kinematic parameters of the withers and tuber sacrale (vertical displacement, vertical and horizontal velocities), backline inclination and flexion-extension motion of the 3 main dorsal segments (thoracic, thoracolumbar and lumbosacral) were analysed. RESULTS: Group 2 horses had a lower displacement of their withers and tuber sacrale from the end of the last approach stride until the first departure stride (P<0.05). As a result, they increased the flexion of their thoracolumbar and lumbosacral junctions during the hindlimb swing phase before take-off (P<0.05). However, withers and tuber sacrale velocities were slightly modified. Group 1 horses pitched their backline less forward during the forelimb stance phase before take-off and straightened it more after landing (P<0.05), probably indicating a more efficient strutting action of their forelimbs. CONCLUSIONS AND POTENTIAL RELEVANCE: Because significant differences in back motion were found between good and poor jumpers when jumping a 1 m high fence, criteria based on certain back kinematics can be developed that may help in the selection of talented showjumpers.

Animals↗
PubMed2003

[Pulmonary infiltrates with blood eosinophilia in a 62-year-old patient].

A 62-year-old woman was admitted because of chronic cough and bilateral infiltrates on chest roentgenogram. Additional history revealed that the patient had been taken diclofenac emulgel during the previous 10 years for arthrosis. Diagnostic bronchoscopy showed eosinophilic alveolitis. After ruling out infectious, parasitic or systemic diseases drug-induced eosinophilic pneumonia was diagnosed due to topical diclofenac therapy and subsequent percutaneous drug absorption. No previous case of eosinophilic pneumonia to topical diclofenac was discovered in our review of the literature. The diclofenac therapy was discontinued. Oral corticosteroid therapy cleared bilateral infiltrates on CT scan within seven days. Drug reactions are the most common cause of pulmonary infiltrates with blood eosinophilia and/or eosinophilic alveolitis and should be considered as a differential diagnosis.

Administration, Topical↗
PubMed2002

Remodeled-matrix contraction by fibroblasts: numerical investigations.

It is well known that the fibroblast-collagen-matrix contraction model is a unique way to study mechanical interactions that regulate wound contraction of connective tissue cells. This contraction, due to cell traction, plays important roles in wound healing and pathological contractures. A continuum model initially used for the study of mesenchymal morphogenesis is revisited and numerically investigated by assuming that the extracellular matrix has adaptive-elastic properties. The set of non-linear partial differential equations is solved numerically by a finite difference method and the obtained results are discussed.

Animals↗
PubMed2002

Exact genetic linkage computations for general pedigrees.

MOTIVATION: Genetic linkage analysis is a useful statistical tool for mapping disease genes and for associating functionality of genes with their location on the chromosome. There is a need for a program that computes multipoint likelihood on general pedigrees with many markers that also deals with two-locus disease models. RESULTS: In this paper we present algorithms for performing exact multipoint likelihood calculations on general pedigrees with a large number of highly polymorphic markers, taking into account a variety of disease models. We have implemented these algorithms in a new computer program called SUPERLINK which outperforms leading linkage software with regards to functionality, speed, memory requirements and extensibility.

Algorithms↗
PubMed2001

[Conceptual and practical aspects of creating an internet presentation of a surgical department].

Until recently an internet presentation of a surgical department could rarely be found on the World Wide Web (WWW). Today an increasing number of departments provide a Web site, but often contents and graphics can still be improved. For more than 4 years the Department of Surgery at the University Hospital of Würzburg has maintained an internet presentation (www.chirurgie.uni-wuerzburg.de). Contents and technical features have been continuously updated. In order to provide a powerful Web site, contents were structured for the 3 target groups: visitors, that are patients including their relatives (consultation hours, directions, maps of campus and wards), physicians (main points in diagnostics and therapy, research, publications, further education, job offers) and medical students (teaching schedules, courses, learning materials). Concerning the technical aspects of the Web site, emphasis was put on a distinct layout and clear design. Therefore, text was arranged in tables or lists and a limited number of standard fonts was used. Graphics were compressed to a minimum file size. To allow effortless navigation for the visitor two roll-over menu banners, a sitemap, a search tool and easy-to-follow symbols were implemented. The internet is an important source of information, and used correctly, the WWW is very useful for the presentation and communication of a surgical department.

Family↗
PubMed2001

The pore of plant K(+) channels is involved in voltage and pH sensing: domain-swapping between different K(+) channel alpha-subunits.

Plant K(+) uptake channel types differ with respect to their voltage, Ca(2)+, and pH dependence. Here, we constructed recombinant chimeric channels between KST1, a member of the inward-rectifying, acid-activated KAT1 family, and AKT3, a member of the weakly voltage-dependent, proton-blocked AKT2/3 family. The homologous pore regions of AKT3 (amino acids 216 to 287) and KST1 (amino acids 217 to 289) have been exchanged to generate the two chimeric channels AKT3/(p)KST1 and KST1/(p)AKT3. In contrast to AKT3 wild-type channels, AKT3/(p)KST1 revealed a strong inward rectification reminiscent of that of KST1. Correspondingly, the substitution of the KST1 by the AKT3 pore led to less pronounced rectification properties of KST1/(p)AKT3 compared with wild-type KST1. Besides the voltage dependence, the interaction between the chimera and extracellular H(+) and Ca(2)+ resembled the properties of the inserted rather than the respective wild-type pore. Whereas AKT3/(p)KST1 was acid activated and Ca(2)+ insensitive, extracellular protons and Ca(2)+ inhibited KST1/(p)AKT3. The regulation of the chimeric channels by cytoplasmic protons followed the respective wild-type backbone of the chimeric channels, indicating that the intracellular pH sensor is located outside the P domain. We thus conclude that essential elements for external pH and Ca(2)+ regulation and for the rectification of voltage-dependent K(+) uptake channels are located within the channel pore.

Amino Acid Sequence↗
PubMed2001

Three-dimensional kinematics of the proximal interphalangeal joint: effects of raising the heels or the toe.

The proximal interphalangeal joint (PIPJ) has always been considered as a low-motion joint with an almost constant angle during loading of the limb. Until very recently, its motion was not taken into account in kinematic studies in vivo. Recent in vivo studies yielded surprisingly high ranges of motion in this joint. The aim of this study was to measure, in terms of the 3 possible rotations (flexion/extension, collateromotion and axial rotation), the movements of the PIPJ in vitro during limb loading in a neutral position (500-6000 N) and after the addition of heel and toe wedges (6 degrees and 12 degrees). The joint coordinate system, as it was recently described for use in the horse, was used to compute the 3 components of rotation. With the hoof in neutral position, low-amplitude flexion movements (7.9 degrees) were observed. They were not associated with collateromotion or axial rotation. The flexion of the joint increased exponentially with load suggesting that, during the midstance phase, heavy loads are necessary to evoke substantial flexion. Raising the heels induced an early flexion of the joint with an increase of its total amplitude. Raising the toe produced an extension at 500 N, beyond which the amount of flexion was reduced. These results show that PIPJ flexion/extension during in vitro loading remains substantially smaller than suggested by in vivo studies based on skin markers. Raising the toe or heel directly affects the behaviour of this joint, but does not induce motion outside the sagittal plane. Hoof wedges are commonly used in clinical practice for purposes other than affecting PIPJ motion. In these cases, their biomechanical effects on this joint should be taken into account.

Animals↗
PubMed2001

Kinematic analysis of the symmetry of limb movements in lame trotting horses.

This study was undertaken to describe the symmetry of movements of fore- and hindlimbs in horses suffering from various spontaneous lamenesses. Two groups of horses were studied: 13 clinically sound horses and 24 lame horses. Using a 3-dimensional (3-D) kinematic analysis system, movements of both sides of each horse were recorded simultaneously while trotting on a track. The differences in motion between left and right homologous joints of each horse were quantified using symmetry indices based on an intercorrelation method. Symmetry indices obtained for each lame horse were then compared with those of sound horses. This comparison showed that the most sensitive lameness indicators were the symmetry indices of the vertical displacement of the proximal markers of the limbs. Symmetry indices of each lame horse were also compared with those of the other lame horses, using correlation coefficients to determine whether or not various lamenesses generate similar alterations of the locomotion symmetry. Values of these coefficients allowed 2 types of lameness to be distinguished. In 21 lame horses, the largest alterations in the symmetry of vertical movements were observed for the proximal markers of the limbs, which may reflect the supporting component of these lamenesses. In contrast, the asymmetries in vertical movements were more pronounced for the distal markers in 3 horses (one stringhalt and 2 carpal injuries), which may reflect the swinging component of these lamenesses. This cross-correlation method can be implemented easily in a computer programme and may represent a first step in the development of an expert system.

Animals↗
PubMed2001

[Growth factors for preventing amputation in delayed wound healing].

Growth factors are mediators with essential importance for undisturbed repair process after wounding. The coordinated concert of these substances is necessary for healing with complete restoration of function and morphology. These complex mechanisms are disturbed during secondary and delayed repair. Local and systemic application of these growth factors seems to add important instruments for therapeutic use in the treatment of chronic wounds. Knowledge from experimental research is encouraging, although the exact mechanisms of synergistic action are not completely understood. However, the results from clinical use in controlled studies do not meet these expectations by far. Leading results from experimental and clinical studies are summarized in detail. Further intensive research however is required for the rational use of growth factors in the clinical setting.

Amputation, Surgical↗
PubMed2000

A method to synchronise cameras using the direct linear transformation technique.

The aim of this paper is to present a method which enables the recordings of cameras that are not equipped with a synchronisation system to be synchronised a posteriori. Using the Direct Linear Transformation technique, this method estimates the phase difference between two cameras by minimising the reconstruction errors of a moving point. Once the phase difference value is known, one of the recordings is chosen as a reference and the second one is synchronised to the first by cubic spline interpolation.

Animals↗