Biomedical subjects

I Koch

Publications and source records attributed to I Koch.

At least 19 recordsLinked to original sources

PubMed2006

Impact of FDG-PET/MRI image fusion on the detection of pancreatic cancer.

BACKGROUND: This study assessed the value of image fusion with (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) in patients suspected of having pancreatic cancer. METHODS: 32 patients (12 women, 20 men; age 24-79 years; mean 56.6 years) were included. All patients underwent whole-body FDG-PET examinations and contrast-enhanced MRI. Image fusion used a semiautomatic voxel-based algorithm. Separate reading, side-by-side analysis and evaluation of fused PET/MRI images were performed. Results were correlated to histopathology (n = 30), or clinical follow-up (n = 2). RESULTS: 15/32 patients had pancreas cancer and 17/32 patients benign disease. The sensitivity and specificity for cancer detection by FDG-PET were 93 and 41% for visual and 86 and 58% for semiquantitative analysis whereas MRI achieved 100 and 76% respectively. Topographical assignment of PET foci by image fusion was superior to side-by-side analysis in 11/39 (28%) foci (in 8/32 patients). However, a true impact on therapeutic strategy was observed only in 1/8 patients as the presence of multiple metastases, irresectable primaries or medical reasons for inoperability prevented a curative setting. CONCLUSION: Compared to side-by-side analysis, PET/MRI image fusion improves the anatomical assignment and interpretation of FDG foci. The therapeutic benefit for the patient however is limited in patients with multiple lesions or incurable primaries.

Adenocarcinoma↗

PubMed2005

Experiences of a poison center network with renal insufficiency in acetaminophen overdose: an analysis of 17 cases.

OBJECTIVE: Renal insufficiency is less common than liver failure in acetaminophen overdose but renal tubular damage occurs even in the absence of hepatotoxicity. Data published on this topic are rare consisting mostly of case reports or reports in a small number of patients. Presently, a larger number of patients with renal insufficiency associated with acetaminophen overdose should be analyzed using a multicenter approach. STUDY DESIGN: Retrospective analysis of patients with acetaminophen-related nephrotoxicity reported to a poison center network from 1995 to 2003. Renal insufficiency was defined as elevated serum creatinine of more than double of the normal range (>2.4 mg/dL [212 micromol/L]). Patients were classified into 4 groups (A: creatinine 2.4-5.0 mg/dL, B: creatinine>5.0 mg/dL requiring no dialysis, C: creatinine>5.0 mg/dL requiring dialysis, D: creatinine>5.0 mg/dL with fatal outcome). RESULTS: Seventeen patients were included (8 female, 9 male, average age 31.7 +/- 21.1 yrs) with 6 patients in group A (B: 7, C: 2, D: 2). In 5 patients renal insufficiency occurred without elevation of liver enzymes. Regarding possible risk factors 5 patients concomitantly ingested nephrotoxic substances, 4 presented with dehydration due to vomiting, 4 with chronic excessive dosing (overdose) of acetaminophen, 3 showed pre-existing renal insufficiency, 2 pre-existing liver disease and 2 died with multiple organ failure. CONCLUSIONS: Renal insufficiency in acetaminophen overdose mostly resolved without dialysis and occurred isolated without hepatotoxicity in less than one-third of the investigated patients. Conditions which might play a role as influencing factors for renal complications included concomitant ingestion of nephrotoxic drugs, dehydration, chronic excessive dosing (overdose) of acetaminophen, pre-existing renal or liver disease and multiple organ failure. Renal function should be monitored in acetaminophen overdose particularly in patients showing the latter comorbidity.

Acetaminophen↗

PubMed2004

Linear interpolation error in measured surfaces in a dental erosion study.

An extensive palatal erosion study, which is currently being undertaken at the University of Dundee, aims to detect erosion through the precise mapping of replicas of children's incisors. All perceived sources of error are being scrutinised closely. The error due to the interpolation of surface positions from discrete point measurements has been investigated so that its contribution to the erosion estimates can be gauged. The calculation of the error statistics made use of covariance functions to express the undulation of the tooth surfaces. It has been found that, for the measurement point spacing of 150 microm being used in the current project, the interpolation error for an incisor is typically about 25 microm, to be compared with the root-mean-square error due to tooth impression and replication procedures, assessed as being in the order of +/- 3 microm, and replica measurement, assessed as being in the order of +/- 5 microm. The interpolation error constitutes a surprisingly large proportion of the overall system error. The same error estimation technique can be applied usefully and without difficulty to other research studies concerning erosion or wear in natural or restorative dental surfaces.

Child↗

PubMed2002

Exploring the pathway structure of metabolism: decomposition into subnetworks and application to Mycoplasma pneumoniae.

MOTIVATION: Reconstructing and analyzing the metabolic map of microorganisms is an important challenge in bioinformatics. Pathway analysis of large metabolic networks meets with the problem of combinatorial explosion of pathways. Therefore, appropriate algorithms for an automated decomposition of these networks into smaller subsystems are needed. RESULTS: A decomposition algorithm for metabolic networks based on the local connectivity of metabolites is presented. Interrelations of this algorithm with alternative methods proposed in the literature and the theory of small world networks are discussed. The applicability of our method is illustrated by an analysis of the metabolism of Mycoplasma pneumoniae, which is an organism of considerable medical interest. The decomposition gives rise to 19 subnetworks. Three of these are here discussed in biochemical terms: arginine degradation, the tetrahydrofolate system, and nucleotide metabolism. The interrelations of pathway analysis of biochemical networks with Petri net theory are outlined.

Algorithms↗

PubMed2001

Prediction of deleterious human alleles.

Single nucleotide polymorphisms (SNPs) constitute the bulk of human genetic variation, occurring with an average density of approximately 1/1000 nucleotides of a genotype. SNPs are either neutral allelic variants or are under selection of various strengths, and the impact of SNPs on fitness remains unknown. Identification of SNPs affecting human phenotype, especially leading to risks of complex disorders, is one of the key problems of medical genetics. SNPs in protein-coding regions that cause amino acid variants (non-synonymous cSNPs) are most likely to affect phenotypes. We have developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein. We estimate that approximately 20% of common human non-synonymous SNPs damage the protein. The average minor allele frequency of such SNPs in our data set was two times lower than that of benign non-synonymous SNPs. The average human genotype carries approximately 10(3) damaging non-synonymous SNPs that together cause a substantial reduction in fitness.

Alleles↗

PubMed2001

Automatic and intentional activation of task sets.

Four experiments examined automatic and intentional activation of task sets in a switching paradigm. Experiment 1 demonstrated incidental task sequence learning that was not accompanied by verbalizable task sequence knowledge. This learning did not affect task shift cost and may be attributed to automatic task-set activation. In Experiment 2, both shift cost and learning effect increased when the response-cue interval was short, indicating the influence of residual, persisting activation of the preceding task set. In Experiment 3, learning disappeared with a long cue-stimulus interval (CSI), which resulted in a strong preparation effect. This preparation, however, reduced reaction time level but was not specific to task shifts. Finally, Experiment 4 showed that a within-subject C

Adult↗

PubMed2001

Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene.

Proteins encoded by the human CYP3A genes metabolize every second drug currently in use. The activity of CYP3A gene products in the general population is highly variable and may affect the efficacy and safety of drugs metabolized by these enzymes. The mechanisms underlying this variability are poorly understood, but they include gene induction, protein inhibition and unknown genetic polymorphisms. To better understand the regulation of CYP3A expression and to provide a basis for a screen of genetic polymorphisms, we determined and analysed the sequence of the human CYP3A locus. The 231 kb locus sequence contains the three CYP3A genes described previously (CYP3A4, CYP3A5 and CYP3A7), three pseudogenes as well as a novel CYP3A gene termed CYP3A43. The gene encodes a putative protein with between 71.5% and 75.8% identity to the other CYP3A proteins. The highest expression level of CYP3A43 mRNA is observed in the prostate, an organ with extensive steroid metabolism. CYP3A43 is also expressed in several other tissues including liver, where it can be induced by rifampicin. CYP3A43 transcripts undergo extensive splicing. The identification of a new member of the CYP3A family and the characterization of the full CYP3A locus will aid efforts to identify the genetic variants underlying its variable expression. This, in turn, will lead to a better optimization of therapies involving the numerous substrates of CYP3A proteins.

Amino Acid Sequence↗

PubMed2001

The genetic determinants of the CYP3A5 polymorphism.

CYP3A proteins comprise a significant portion of the hepatic cytochrome P450 (CYP) protein and they metabolize around 50% of drugs currently in use. The dissection of the individual contributions of the four CYP3A genes identified in humans to overall hepatic CYP3A activity has been hampered by sequence and functional similarities. We have investigated the expression of CYP3A5 and its genetic determinants in a panel of 183 Caucasian liver samples. CYP3A5 expression is increased in 10% of livers in this ethnic group. Using a high density map of CYP3A5 variants, we searched for genetic markers of the increased CYP3A5 expression. In agreement with an independent, recent study, we report that a SNP within intron 3 (g.6986G>A) is the primary cause of the CYP3A5 protein polymorphism. The frequencies of the g.6986A variant which allow for normal splicing of CYP3A5 transcripts are 5% in Caucasians, 29% in Japanese, 27% in Chinese, 30% in Koreans and 73% in African-Americans. In the last ethnic group, the expression of CYP3A5 in some individuals who carry the g.6986A variant is affected adversely by a frame shift mutation (CYP3A5*7, D348., q = 0.10). In summary, these results should add to efforts to identify clinically relevant, CYP3A5-specific reactions and to further elucidate traits responsible for variable expression of the entire CYP3A family.

Alternative Splicing↗

PubMed2000

Patterns, chunks, and hierarchies in serial reaction-time tasks.

The impact of relational structures (i.e., the systematicity of relations between successive items) on incidental sequence learning was investigated in a serial reaction-time (SRT) task while keeping constant the statistical structure. In order to assess the influence of relational structures in stimulus and response sequences separately, the strength of relational patterns in sequences of digits as stimuli and of keystrokes as responses was orthogonally varied. In Exps. 1 and 2, the variation of relational patterns was mainly effective in the keystroke sequence. In Exp. 2, in addition to the variation of relational patterns, the presentation of stimuli was delayed at serial positions that were incongruent with the relational structure. The results show that these incongruent pauses reduced the learning of strongly structured sequences of keystrokes but improved the learning of weakly structured sequences. Experiment 3 suggests that even higher-order relations between elementary patterns are utilized to accelerate responses. The data are interpreted as evidence for the impact of relational patterns, in addition to statistical redundancies, on the formation of chunks. Reasons are discussed for the finding that relational chunking was more pronounced in the keystroke than in the digit sequences.

Adolescent↗

PubMed2000

The role of stimulus-based and response-based spatial information in sequence learning.

In 4 experiments, relational structures were independently varied in stimulus and response sequences in a serial reaction time task. Moreover, the use of spatial and symbolic stimuli and responses was varied between experiments. In Experiment 1, spatial stimuli (asterisk locations) triggered spatial responses (keystrokes); in Experiment 2, spatial stimuli triggered symbolic responses (verbal digit naming); in Experiment 3, symbolic stimuli (digits) triggered keystrokes; and in Experiment 4, digits triggered verbal responses. The results showed that there is a remarkably stronger effect of relational structures in spatial sequences than in symbolic sequences, irrespective of whether stimulus or response sequences are concerned. This suggests that learning is particularly effective for sequences of spatial locations. It is argued that spatial learning is a critical determinant for the debate on perceptual and motor learning.

Adult↗

PubMed1999

Arsenic in the Meager Creek hot springs environment, British Columbia, Canada.

Levels of arsenic in water from Meager Creek hot springs, British Columbia, Canada, were found to be naturally elevated. Biota including microbial mats, green algae, sedge, cedar, fleabane, monkey flower, moss, mushrooms and lichens, that were expected to be impacted by the water, were analyzed for total levels of arsenic and for arsenic species. The major arsenic species extracted from all samples were arsenate and arsenite, which are toxic forms of arsenic. Additionally, small amounts of arsenosugars X and XI were detected in microbial mats and green algae, implying that cyanobacteria/bacteria, and possibly green algae are capable of synthesizing arsenosugars from arsenate. Low to trace amounts of arsenosugars X and XI were detected in lichens and the fungus Tarzetta cupularis. A large fraction (on average, greater than 50%) of arsenic was not extracted by using methanol/water (1:1) and the chemical and toxicological significance of this arsenic remains unknown.

Arsenic↗

PubMed1997

RNA-RNA interaction is required for the formation of specific bicoid mRNA 3' UTR-STAUFEN ribonucleoprotein particles.

The formation of the anterior pattern of the Drosophila embryo is dependent on the localization of the mRNA of the morphogen Bicoid (bcd) to the anterior pole of the egg cell. Staufen protein (STAU) is required in a late step of the localization to anchor the bcd mRNA in the anterior cytoplasm. We have shown previously that endogenous STAU associates specifically with injected bcd mRNA 3'-untranslated region (UTR), resulting in the formation of characteristic RNA-protein particles that are transported along microtubules of the mitotic spindles in a directed manner. The regions recognized by STAU in this in vivo assay are predicted to form three stem-loop structures involving large double-stranded stretches. Here, we show that the STAU interaction requires a double-stranded conformation of the stems within the RNA localization signal. In addition, base pairing between two single-stranded loops plays a major role in particle formation. This loop-loop interaction is intermolecular, not intramolecular; thus dimers or multimers of the RNA localization signal must be associated with STAU in these particles. The bcd mRNA 3' UTR can also dimerize in vitro in the absence of STAU. Thus, in addition to RNA-protein interactions, RNA-RNA interaction might be involved in the formation of ribonucleoprotein particles for transport and localization.

Animals↗

PubMed1997

Detection of distant structural similarities in a set of proteins using a fast graph-based method.

We introduce a method for finding weak structural similarities in a set of protein structures. Proteins are considered at their secondary structure level. The method uses a rigorous graph-theoretical algorithm which finds all structural similarities. Protein structures are modelled as undirected labelled graphs, the so-called protein graphs. We suggest that for detecting the similarities between two protein structures it is sufficient to find similarities in the protein core which consists of tightly packed secondary structure elements. Therefore, we can restrict ourselves to solving the maximal common connected subgraph problem instead of the maximal common subgraph problem. We have modified the algorithm by Bron and Kerbosch for solving that problem. The speed of the algorithm increases drastically. After calculating all maximal common connected substructures for all pairwise comparisons in a set of protein graphs the common substructure in all proteins can be calculated by intersecting them. In this paper we characterize the method briefly and explain the modelling of the protein structure in detail. For the pairwise alignment the similarity of porin (1OMF) with bacteriochlorophyll a (3BCL) and BirA protein (1BIB) with DNA polymerase III (2POL) will be discussed. In the case of the multiple structure alignment the similarity in variants of four phosphatases and in subtilisin Carlsberg, carboxypeptidase, elongation factor Tu, and flavodoxin will be represented. Our first experiments show that the method works correctly and fast. The method can be used for arbitrary graphs. Thus, different graph-theoretical models of protein structures can be examined.

Algorithms↗

PubMed1996

An algorithm for finding maximal common subtopologies in a set of protein structures.

For the comparison and analysis of protein structures, it is of interest to find maximal common substructures in a given set of proteins. This question is also relevant for motif definition and structure classification. In this paper we describe first a new suitable representation of the secondary structure topology of a protein by an undirected labeled graph. Based on this representation we developed a new fast algorithm that finds all common subtopologies in a set of protein structures. Our method is based on the algorithm by Bron and Kerbosch (1973), which enumerates all maximal cliques in a graph. The main improvement of our algorithm is to restrict the search process to cliques that represent connected substructures. This restriction reduces the number of cliques to be considered during the search process and the size of the search tree drastically. Thus we are able to handle large proteins. Experiments show the efficiency and superiority of our algorithm in comparison with other existing algorithms basing on graph-theoretical methods.

Algorithms↗

PubMed1995

Interleukin 1 modulates growth of human renal carcinoma cells in vitro.

We have investigated the influence of interleukin 1 (IL-1) on growth of human renal carcinoma cells in vitro. Using a capillary soft-agar cloning system, 18% of freshly explanted renal carcinomas were stimulated to grow by IL-1 and 4% were inhibited. Subsequent experiments with established renal cancer cell lines demonstrated that two out of four cell lines (Caki-2, A-498) were sensitive to IL-1. [3H]Thymidine incorporation as well as monolayer growth was enhanced in Caki-2 cells in the presence of high (10%) and low (1%) serum concentrations. Although clonogenic growth of A-498 cells was stimulated by IL-1, overall [3H]thymidine incorporation and monolayer proliferation were decreased. Using radioligand experiments, 250 cell-surface receptors of high affinity (KD 4.5 x 10(-11) M) and 2500 receptors of low affinity (KD 1.3 x 10(-9) M) were detected on A-498 cells. IL-1 binding was reduced under the influence of IL-1. Competition experiments with inhibiting antibodies against IL-1 receptor type I and type II revealed that signal transduction was performed via type I receptors. After cross-linking to IL-1, receptor type I was immunoprecipitated using anti-IL-1 antibodies. We hypothesise that, since IL-1 modulates in vitro growth of a subgroup of human renal cancer cells, interference with its mechanism of action may be of potential value in order to modulate tumour proliferation.

Carcinoma, Renal Cell↗

PubMed1994

Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP)-2 gene expression in spleens of juvenile rats.

Growth and development of the spleen involves the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To evaluate the molecular mechanism of these effects we studied the effect of hypophysectomy (Hx) and GH replacement therapy on the expression of IGF-I, the IGF-I receptor and IGF-binding protein-2 (IGFBP-2) in juvenile rats. Hx resulted in a 30% reduction in body weight. GH replacement therapy for seven days partially prevented these effects. IGF-I mRNA levels were reduced 30% by Hx, IGFBP-2 mRNA levels fell 50% whereas IGF-I receptor mRNA levels were unaffected. GH therapy prevented the reduction in IGF-I and IGFBP-2 mRNA levels. These results suggest that the GH effect on splenic growth and development is via local (paracrine) IGF-I expression, in addition to any effect by circulating (endocrine) IGF-I.

Animals↗

PubMed1993

Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats.

In the adult rat, expression of the liver GH receptor, insulin-like growth factor-I (IGF-I), and IGF-I-binding protein-3 (IGFBP-3) genes has been shown to be under GH control. Additionally, hypophysectomy and GH treatment have a differential effect on the relative abundance of liver IGF-I mRNA variants in adult rats. To further elucidate the time of appearance and the extent of GH control of liver GH receptor, IGF-I, and IGFBP-3 gene expression, we studied the effect of hypophysectomy and GH and IGF-I treatment in juvenile rats. Male Wistar rats were hypophysectomized (Hx) on postnatal day 26 and received twice daily sc injections of saline, recombinant human GH (2.5 U/kg.day), or recombinant human IGF-I (500 micrograms/kg.day) for 7 days. Sham-operated rats received the same treatment. Hx animals also received T4 (20 micrograms/kg.day). In Hx animals, there was a significant reduction in body weight (69.8 +/- 6.6 vs. 100.4 +/- 5.4 g; P < 0.001). GH, but not IGF-I, treatment increased body weight (79.6 +/- 9.6 g after GH vs. 69.8 +/- 6.6 g before GH; P < 0.05). GH treatment partially maintained liver, kidney, and lung weights in Hx animals and increased them in intact animals, whereas IGF-I treatment did so only in the lungs of intact and Hx animals. Serum GH and IGF-I levels were markedly reduced in Hx animals compared with those in intact controls, and GH treatment maintained, albeit partially, circulating IGF-I levels compared with those in saline-treated Hx animals. IGF-I mRNA levels were markedly reduced in Hx liver (25.0 +/- 5.4%; P < 0.001 compared with intact controls). GH treatment for 7 days increased IGF-I mRNA levels by 4.8-fold over the levels in 9-day Hx animals and increased IGF-I mRNA levels by 2.2-fold in control rats. Hypophysectomy decreased exon 2-containing transcripts by 7.0-fold and exon 1-containing transcripts by 4.1-fold. GH treatment, however, affected both exon 1- and exon 2-containing transcripts similarly. Hepatic IGFBP-3 mRNA levels were reduced in Hx (53.2 +/- 1.8%; P < 0.01 compared with intact controls) and IGF-treated Hx animals, but were not decreased in Hx GH-treated animals (100.6 +/- 9.5). No changes in GH receptor or GH-binding protein mRNA levels were caused by Hx, GH, or IGF-I treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Applying machine learning methods for finding significant amino acid properties in proteins.

There are several possibilities for definition and derivation of sequence patterns associated with structural motifs, in particular on the secondary structure level which may be used to predict these structure elements. Sequence patterns consist of a number of consecutive positions along the polypeptide chain from which a certain quantity is specified. One of the important factors in deriving sequence patterns in terms of amino acid properties is how to find the most characteristic properties to specify a certain position and thus to avoid redundant physical information. We have applied machine learning methods to select the most significant amino acid properties describing a structurally determined sequence position. Results are given for the beginning of alpha-helices. These methods may link the gap between amino acid patterns and property patterns and thus are valuable to improve protein structure prediction.

Amino Acids↗