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PubMed2004

An IMRT dose distribution study using commercial verification software.

The introduction of IMRT requires users to confirm that the isodose distributions and relative doses calculated by their planning system match the doses delivered by their linear accelerators. To this end the commercially available software, VeriSoft (PTW-Freiburg, Germany) was trialled to determine if the tools and functions it offered would be of benefit to this process. The CMS XiO (Computerized Medical System, St. Louis, MO) treatment planning system was used to generate IMRT plans that were delivered with an upgraded Elekta SL15 linac. Kodak EDR2 film sandwiched in RW3 solid water (PTW-Freiburg, Germany) was used to measure the IMRT fields delivered with 6 MV photons. The isodose and profiles measured with the film generally agreed to within +/- 3% or +/- 3 mm with the planned doses, in some regions (outside the field) the match fell to within +/- 5%. The isodose distributions of the planning system and the film could be compared on screen, allowing for electronic records of the comparison to be kept if desired. The features of this software would be of benefit to an IMRT QA program.

Benchmarking↗
PubMedDate not supplied

Preparing for change: concepts and education in medical informatics.

Medical informatics as a medical discipline has developed over the last decades in parallel with an even more amazing proliferative development in medicine. The question is raised whether this new science, based on formalized and methodological approaches, may contribute to the development of a general theory in medicine as a consequence of the recognition of the influence of control mechanisms and structured information in molecular biology. It is suggested that medical informatics dedicates research to problems 'inside medicine' and that curricula are developed which bring a basic understanding for medical informatics to the medical student. The following teaching is suggested: basic mandatory courses, electives and inclusions of aspect of medical informatics in the various parts of clinical teaching. The possibility is discussed that the resulting teaching approaches may also be used to convey knowledge in medicine: teaching concepts versus teaching details. Finally, a description of the functional topology of expert systems as they develop is attempted and brought into relation to the architecture of hospital information systems. The increasing importance of expert systems also raises the question of 'decisional trials' as verification procedures when these new tools enter medical practice.

Artificial Intelligence↗
PubMed2004

Dosimetric effects within target and organs at risk of interfractional patient mispositioning in left breast cancer radiotherapy.

PURPOSE: To investigate the effects of interfraction setup uncertainties on the dose distribution within the clinical target volume (CTV) and the organs at risk (OAR) of left-sided breast cancer patients undergoing external radiotherapy. METHODS AND MATERIALS: Interfractional setup errors were assessed by measuring surface control points displacements during 89 irradiation sessions in 4 patients, by means of opto-electronic localization. The measured position deviations were fed back to the treatment planning system for the evaluation of the corresponding dosimetric effects within CTV and OARs (lung, heart). RESULTS: Results revealed errors above 5 mm on some of the control points, but corresponding volumetric variations were on average below 2% for both the CTV within the 95-105% dose range and the OARs receiving more than 50% and 90% of the prescribed dose. A specific sensitivity to the setup errors was found as a function of the treatment plan design, leading to isolated cases exhibiting volumetric variations of CTV and OARs exceeding 2%. CONCLUSIONS: This study confirms the potential increase of treatment quality provided by the systematic patient position verification and highlights the role of opto-electronic position detection systems for the real-time check of patient setup errors and the evaluation of the corresponding dosimetric consequences, as a way to achieve consistent dose delivery.

Analysis of Variance↗
PubMed2000

Nondynamic kinetic resolution of configurationally stable biaryl lactones by reduction with oxazaborolidine-activated borane: AM1 studies and experimental verification

The complete mechanistic course of the atroposelective ring opening of a lactone-bridged biaryl, dinaphth[2,1-c:1',2'-e]oxepin-3-(5H)-one (3), with a chiral oxazaborolidine-BH3 complex was calculated using the semiempirical AM1 method. The first hydride transfer to the activated carbonyl function of the adduct complexes was elaborated to be the selectivity-determining step in the postulated five-step mechanism. The calculated enantioselectivity is in good accordance with the experimental results, so that related calculations were performed on the atroposelective ring opening of a sterically strongly hindered and therefore also configurationally stable six-membered biaryl lactone, 1,3-di-tert-butyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one (6f). These calculations predicted a highly (M)-selective reduction of 6f (kM/kP = 358 at -78 degrees C), which, after the smooth preparation of 6f by intramolecular biaryl coupling in high yields, was fully confirmed experimentally (kM/kP > 200 at -78 degrees C). Isolation of the intermediate hydroxy aldehyde (M)-14 at the beginning of the reaction with the same enantiomeric excess as found for the corresponding alcohol (M)-7f conclusively showed the first hydride transfer step to determine the selectivity of this process. The good agreement of computationally predicted and experimentally confirmed values proves the suitability of the AM1 method for mechanistic studies on even such complex reactions and opens a most efficient overall synthesis of sterically highly hindered biaryls, in excellent chemical (for the ring closure) and optical (for the ring cleavage) yields and for any desired axial configuration.

Journal Article↗
PubMed2006

Potential of a 16S rRNA-based taxonomic microarray for analyzing the rhizosphere effects of maize on Agrobacterium spp. and bacterial communities.

Bacterial diversity is central to ecosystem sustainability and soil biological function, for which the role of roots is important. The high-throughput analysis potential of taxonomic microarray should match the breadth of bacterial diversity. Here, the power of this technology was evidenced through methodological verifications and analysis of maize rhizosphere effect based on a 16S rRNA-based microarray developed from the prototype of H. Sanguin et al. (Environ. Microbiol. 8:289-307, 2006). The current probe set was composed of 170 probes (41 new probes in this work) that targeted essentially the Proteobacteria. Cloning and sequencing of 16S rRNA amplicons were carried out on maize rhizosphere and bulk soil DNA. All tested clones that had a perfect match with corresponding probes were positive in the hybridization experiment. The hierarchically nested probes were reliable, but the level of taxonomic identification was variable, depending on the probe set specificity. The comparison of experimental and theoretical hybridizations revealed 0.91% false positives and 0.81% false negatives. The microarray detection threshold was estimated at 0.03% of a given DNA type based on DNA spiking experiments. A comparison of the maize rhizosphere and bulk soil hybridization results showed a significant rhizosphere effect, with a higher predominance of Agrobacterium spp. in the rhizosphere, as well as a lower prevalence of Acidobacteria, Bacteroidetes, Verrucomicrobia, and Planctomycetes, a new taxon of interest in soil. In addition, well-known taxonomic groups such as Sphingomonas spp., Rhizobiaceae, and Actinobacteria were identified in both microbial habitats with strong hybridization signals. The taxonomic microarray developed in the present study was able to discriminate and characterize bacterial community composition in related biological samples, offering extensive possibilities for systematic exploration of bacterial diversity in ecosystems.

Cloning, Molecular↗
PubMed2003

Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array.

Despite the growing interest in selenium intervention of prostate cancer in humans, scanty information is currently available on the molecular mechanism of selenium action. Our past research indicated that methylseleninic acid (MSA) is an excellent reagent for investigating the anticancer effect of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in PC-3 human prostate cancer cells. After exposure to physiological concentrations of MSA, these cells exhibited a dose- and time-dependent inhibition of growth. MSA retarded cell cycle progression at multiple transition points without changing the proportion of cells in different phases of the cell cycle. Flow cytometric analysis of annexin V- and propidium iodide-labeled cells showed a marked induction of apoptosis by MSA. Array analysis with the Affymetrix human genome U95A chip was then applied to profile the gene expression changes that might mediate the effects of selenium. Gene profiling was done in a time course experiment (at 12, 24, 36, and 48 h) using synchronized cells. A large number of potential selenium-responsive genes with diverse biological functions were identified. These genes fell into 12 clusters of distinct kinetics pattern of modulation by MSA. The expression changes of 10 genes known to be critically involved in cell cycle regulation were selected for verification by Western analysis to determine the reliability of the array data. An agreement rate of 70% was obtained based on these confirmation experiments. The array data enabled us to focus on the role of potential key genes (e.g., GADD153, CHK2, p21(WAF1), cyclin A, CDK1, and DHFR) that might be targets of MSA in impeding cell cycle progression. The data also provide valuable insights into novel biological effects of selenium, such as inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling. The present study demonstrates the utility of a genome-wide analysis to elucidate the mechanism of selenium chemoprevention.

Apoptosis↗
PubMed1998

Immunocytochemical localization of IdiA, a protein expressed under iron or manganese limitation in the mesophilic cyanobacterium Synechococcus PCC 6301 and the thermophilic cyanobacterium Synechococcus elongatus.

Iron-deficiency-induced protein A (IdiA) with a calculated molecular mass of 35 kDa has previously been shown to be essential under manganese- and iron-limiting conditions in the cyanobacteria Synechococcus PCC 6301 and PCC 7942. Studies of mutants indicated that in the absence of IdiA mainly photosystem II becomes damaged, suggesting that the major function of IdiA is in Mn and not Fe metabolism (Michel et al. 1996, Microbiology 142: 2635-2645). To further elucidate the function of IdiA, the immunocytochemical localization of IdiA in the cell was examined. These investigations provided evidence that under mild Fe deficiency IdiA is intracellularly localized and is mainly associated with the thylakoid membrane in Synechococcus PCC 6301. The protein became distributed throughout the cell under severe Fe limitation when substantial morphological changes had already occurred. For additional verification of a preferential thylakoid membrane association of IdiA, these investigations were extended to the thermophilic Synechococcus elongatus. In this cyanobacterium Mn deficiency could be obtained more rapidly than in the mesophilic Synechococcus PCC 6301 and PCC 7942, and the thylakoid membrane structure proved to be more stable under limiting growth conditions. The immunocytochemical investigations with this cyanobacterium clearly supported a thylakoid membrane association of IdiA. In addition, evidence was obtained for a localization of IdiA on the cytoplasmic side of the thylakoid membrane. All available data support a function of IdiA as an Mn-binding protein that facilitates transport of Mn via the thylakoid membrane into the lumen to provide photosystem II with Mn. A possible explanation for the observation that IdiA was not only expressed under Mn deficiency but also under Fe deficiency is given in the discussion.

Bacterial Proteins↗
PubMed2006

Comparison of dose distributions in IMRT planning using the gamma function.

Intensity-modulated radiotherapy (IMRT) (1) is an advanced form of 3-D conformal radiotherapy. It uses non uniform spatial modifications in the intensity of the beams across the irradiated field. Consequently, it is necessary to develop sophisticated tools to compare measured and calculated dose distributions in order to verify the accuracy of the results of the planned dose distribution. Different methods have been developed to evaluate the accordance between measured and calculated doses, such as the point-to-point dose difference or the evaluation of the distance between two closed points having the same dose value (2-4). The verification method proposed by Low (5-7) seems to be more complete since it takes into account both the dose difference (DD) and the distance to agreement (DTA), allowing to define a "score", the gamma value, at each point of interest. A software tool (DDE: Dose Distribution Evaluator), based on Low's method, to evaluate the agreement between dose distribution matrices has been implemented. In particular, the proposed gamma curve, as a function of the isodose levels, gives real-time information useful for decision making about the treatment plan. The paper describes the software, and reports the obtained results in a simple geometry and in several clinical cases (head-neck and prostate). Comparison between measured data (film and MapCheck) and calculated data (CadPlan) using DDE has shown very good agreements. Thanks to its higher resolution, film dosimetry showed better accuracy than the MapCheck technique. Similar results can be obtained also with the MapCheck technique when proper measurement methods are used.

Dose-Response Relationship, Radiation↗
PubMed1994

Computer program for connection and data management of an automated coagulation system: the KC 10.

In Europe, the KC 10, manufactured by Amelung Germany, is one of the instruments most commonly found in coagulation laboratories. For facilitating the work of technical validation, we wrote a software adapted to any IBM or compatible PC running under MS-DOS, to manage the analyser performance. Data are automatically collected via the BCD interface from the analyser or keyed in for the other techniques. The software deals with 64 different analyses entirely 'user defined'. An 'electronic worksheet' presents the results, by page of ten patients. This enables the laboratory technician to assess the coherence of the various data and to perform verifications or complementary tests if necessary. As an option, a blinking asterisk can signal all results outside predetermined range. By moving the cursor through the table, a test result can be deleted, modified or added. A function displays the patient's previous files in a window because the data are recorded in long-term archives at the end of the day. This long-term recording allows a search of previous files to decide additional tests if the patient is unknown. A daily archive function classifies and prints the whole day's work in alphabetical order. A protocol of communication allows connection to a mainframe Bayer-Technicon computer. This program and the user's manual are free, available on request from address above.

Blood Coagulation Tests↗
PubMed2006

Combination of a modified scoring function with two-dimensional descriptors for calculation of binding affinities of bulky, flexible ligands to proteins.

Bulky, flexible molecules such as peptides and peptidomimetics are often used as lead compounds during the drug discovery process. Pathophysiological events, e.g., the formation of amyloid fibrils in Alzheimer's disease, the conformational changes of prion proteins, or beta-secretase activity, may be successfully hindered by the use of rationally designed peptide sequences. A key step in the molecular engineering of such potent lead compounds is the prediction of the energetics of their binding to the macromolecular targets. Although sophisticated experimental and in silico methods are available to help this issue, the structure-based calculation of the binding free energies of large, flexible ligands to proteins is problematic. In this study, a fast and accurate calculation strategy is presented, following modification of the scoring function of the popular docking program package AutoDock and the involvement of ligand-based two-dimensional descriptors. Quantitative structure-activity relationships with good predictive power were developed. Thorough cross-validation tests and verifications were performed on the basis of experimental binding data of biologically important systems. The capabilities and limitations of the ligand-based descriptors were analyzed. Application of these results in the early phase of lead design will contribute to precise predictions, correct selections, and consequently a higher success rate of rational drug discovery.

Amyloid Precursor Protein Secretases↗
PubMedDate not supplied

Fibroblast senescence in pressure ulcers.

Pressure ulcers appear as localized chronic wounds in the middle of normal functioning skin. This study focuses on pressure ulcer fibroblasts cultured from the ulcer bed, ulcer margin, and normal, nonulcerated skin adjacent to the wound. From these areas we show that pressure ulcer fibroblasts become prematurely senescent. Verification of senescence was based on failure of cell populations to undergo a 0.5 population doubling after 1 week in culture, light microscopic appearance of late-passage senescent cells in culture, light microscopic verification of senescence in vivo and in vitro by anti-terminin staining, and ultrastructural identification of senescent fibroblasts by anti-terminin colloidal gold labeling. Although not all ulcer fibroblasts are senescent, there is a range of proliferative ability. The senescent phenotype of ulcer fibroblasts remains intact in vitro as these cells remain viable but are unable to complete DNA synthesis. Fibroblast senescence is not uniform in chronic wounds but varies within areas of the ulcer bed and from patient to patient. Although ulcer fibroblasts exhibit limited proliferative ability, fibroblasts from the ulcer margin and adjacent normal skin show a continued ability to divide. However, in all areas of the wound, the mean generation time of the fibroblast population is longer than commonly observed for cultured human diploid fibroblasts. At first passage, the mean generation time for fibroblasts from all patients is significantly different (p = .001, analysis of variance) among fibroblasts from the ulcer bed (4.2 2.2 days), ulcer margin (2.9 +/- 1.3 days), and adjacent normal skin (1.9 +/- 0.6 days). Analysis of the three cell groups by the post hoc Tukey test, using corrected p values shows that the difference between mean generation times among fibroblast populations from adjacent normal skin and ulcer bed are significantly different (p < 0.05), whereas the difference between fibroblasts from adjacent normal skin and ulcer margin and ulcer margin and ulcer bed are not significantly different (p > 0.05). These data may help to explain the poor response of certain pressure sores to aggressive medical treatment.

Analysis of Variance↗
PubMed2002

Quantitative prediction of NF-kappa B DNA-protein interactions.

We describe a general method based on principal coordinates analysis to predict the effects of single-nucleotide polymorphisms within regulatory sequences on DNA-protein interactions. We use binding data for the transcription factor NF-kappaB as a test system. The method incorporates the effects of interactions between base pair positions in the binding site, and we demonstrate that such interactions are present for NF-kappaB. Prediction accuracy is higher than with profile models, confirmed by crossvalidation and by the experimental verification of our predictions for additional sequences. The binding affinities of all potential NF-kappaB sites on human chromosome 22, together with the effects of known single-nucleotide polymorphisms, are calculated to determine likely functional variants. We propose that this approach may be valuable, either on its own or in combination with other methods, when standard profile models are disadvantaged by complex internucleotide interactions.

Base Sequence↗
PubMed1998

Identification of urokinase as a hyperoxia-inducible gene.

Hyperoxia has deleterious effects on lung form and function; however, the molecular events initiated by oxygen exposure remain unclear. We hypothesized that macrophages function as important intermediaries in the protective response of lung tissues after exposure to hyperoxia. This hypothesis was tested by exposing cultured macrophages (RAW 264.7 cells) to hyperoxia for 24 h and then applying the conditioned medium from these cells to cultured pulmonary epithelial cells or to pulmonary microvascular endothelial cells. We observed that the expression of manganese superoxide dismutase mRNA increased in both target cell lines. Therefore, we next hypothesized that exposure of these macrophages to hyperoxia results in a change in gene expression which could be detected by differential display PCR (ddPCR). This hypothesis was tested by exposing RAW 264.7 cells to > or = 95% oxygen (or normoxia) for 24 h, harvesting RNA, and performing ddPCR. A cDNA fragment upregulated by hyperoxia was identified and reamplified. Verification of differential expression of mRNA was done by Northern analysis. A mRNA which was reproducibly upregulated by hyperoxia, as well as by lipopolysaccharide and interferon gamma, was identified. The differentially expressed PCR product was cloned and sequenced, revealing a product with 99% identity to mouse urokinase mRNA. We speculate that one function of pulmonary macrophages following a hyperoxic exposure is to secrete urokinase.

Animals↗
PubMed1996

A data management software for the Sysmex NE 8000 haematology analyser.

The Sysmex NE 8000 (TOA-Japan) is a haematology analyser that performs blood cells count and leukocyte differential count. For facilitating the work of technical validation, we developed a software adapted to any IBM or compatible PC running under MS-DOS, to manage the analyser. Data are automatically collected via the RS-232 interface from the analyser or keyed in for the other techniques. The software deals with 64 different analyses entirely "user defined". Six technical alarms of the analyser are taken in account for red or white cells and platelets. An "electronic worksheet" presents the results or alarms with 10 patients to a page. This enables the lab technician to assess the coherence of the various data and to perform verifications or complementary tests if necessary. As an option, a blinking asterisk can signal any results out of predetermined range. By moving the cursor through the table, a test result can be deleted, modified or added. A function displays the patient previous files in a window because the data are recorded in long term archives at the end of the day. This long term recording allows a search of previous files to decide additional tests if the patient is unknown. If the patient is known, with additional tests previously performed, this procedure is time saving. A daily archive function classifies and prints the whole day's work in alphabetical order. A protocol of communication allows a connection to a mainframe computer Bayer-Technicon. This program and the user's manual are free of charge, available on request from J. P. Cambus.

Blood Cell Count↗
PubMed2003

Analysis of site-directed mutagenesis constructs by capillary electrophoresis using linear polymer sieving matrices.

Site-directed mutagenesis is a novel molecular biology tool, which introduces mutations into DNA fragments of interest in a well-defined manner. Sequences with designed mutations can be generated in this way to express altered protein sequences for structure-function relationship studies. However, prior to gene expression, it is important to analyze the DNA construct to see whether the introduction of the mutation was indeed successful. Currently DNA sequencing is the method of choice for this verification. This paper introduces the combination of primer extension and capillary electrophoresis using linear polymer sieving matrices as an efficient alternative for this type of mutation analysis. The site-directed mutagenesis construct served as template in the primer extension reaction that employed a fluorophore labeled primer in close proximity to the mutation. Appropriate ddNTP was used to block the extension when the mutation was present, while the other three dNTPs enabled elongation of the primer. Alternatively, non-labeled primers can be used with the proper fluorophore labeled ddNTPs to block the reaction. Rapid analysis of the labeled primer extension products (mutant or wild type) was obtained by capillary electrophoresis using denaturing sieving matrix and laser-induced fluorescence detection.

Base Sequence↗
PubMed1980

Tracing the time course of picture--word processing.

A number of independent lines of research have suggested that semantic and articulatory information become available differentially from pictures and words. The first of the experiments reported here sought to clarify the time course by which information about pictures and words becomes available by considering the pattern of interference generated when incongruent pictures and words are presented simultaneously in a Stroop-like situation. Previous investigators report that picture naming is easily disrupted by the presence of a distracting word but that word naming is relatively immune to interference from an incongruent picture. Under the assumption that information available from a completed process may disrupt an ongoing process, these results suggest that words access articulatory information more rapidly than do pictures. Experiment 1 extended this paradigm by requiring subjects to verify the category of the target stimulus. In accordance with the hypothesis that picture access the semantic code more rapidly than words, there was a reversal in the interference pattern: Word categorization suffered considerable disruption, whereas picture categorization was minimally affected by the presence of an incongruent word. Experiment 2 sought to further test the hypothesis that access to semantic and articulatory codes is different for pictures and words by examining memory for those items following naming or categorization. Categorized words were better recognized than named words, whereas the reverse was true for pictures, a result which suggests that picture naming involves more extensive processing than picture categorization. Experiment 3 replicated this result under conditions in which viewing time was held constant. The last experiment extended the investigation of memory differences to a situation in which subjects were required to generate the superordinate category name. Here, memory for categorized pictures was as good as memory for named pictures. Category generation also influenced memory for words, memory performance being superior to that following a yes--no verification of category membership. These experiments suggest a model of information access whereby pictures access semantic information were readily than name information, with the reverse being true for words. Memory for both pictures and words was a function of the amount of processing required to access a particular type of information as well as the extent of response differentiation necessitated by the task.

Form Perception↗
PubMed2001

Systolic and diastolic heart failure--diagnostic and therapeutic dilemmas.

Clinical suspicion of congestive heart failure (CHF) always requires a careful diagnostic workup. This comprises the verification of the presence of CHF (in contrast to other conditions that cause nonspecific phenomena such as shortness of breath and edema), evaluation of the underlying cause of heart failure, and assessment of left ventricular (LV) systolic function. In addition to clinical examination, echocardiography is warranted in most cases. On the basis of this information, patients can be selected for further studies, such as exercise testing, cardiac catheterization and coronary angiography. In view of the serious prognosis of heart failure, especially systolic CHF, the threshold for specialist consultation should be low. Although the classification of CHF into systolic and diastolic forms is complex, clinically meaningful data can be derived simply by determining whether LV systolic function is impaired (predominantly systolic CHF) or not (probable diastolic CHF). In the latter case, treatment is mainly symptomatic in addition to the management of the underlying condition (e.g. hypertension). In systolic CHF, considerable therapeutic advances have recently been made and it is important that patients receive appropriate care to improve their prognosis. These measures include angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone.

Diastole↗