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PubMed2001

Towards defining the urinary proteome using liquid chromatography-tandem mass spectrometry. II. Limitations of complex mixture analyses.

With an emphasis on obtaining a multitude of high quality tandem mass spectrometry spectra for protein identification, instrumental parameters are described for the liquid chromatography-tandem mass spectrometry analysis of trypsin digested unfractionated urine using a hybrid quadrupole-time-of-flight (Q-TOF) mass spectrometer. Precursor acquisition rates of up to 20 distinct precursors/minute in a single analysis were obtained through the use of parallel precursor selection (four precursors/survey period) and variable collision induced dissociation integration time (1 to 6 periods summed). Maximal exploitation of the gas phase fractionated ions was obtained through the use of narrow survey scans and iterative data-dependent analyses incorporating dynamic exclusion. The impact on data fidelity as a product of data-dependent selection of precursor ions from a dynamically excluded field is discussed with regards to sample complexity, precursor selection rates, survey scan range and facile chemical modifications. Operational and post-analysis strategies are presented to restore data confidence and reconcile the greatest number of matched spectra.

Amino Acid Sequence↗

PubMed2002

Comparative bioinformatic analysis of complete proteomes and protein parameters for cross-species identification in proteomics.

Peptide mass fingerprinting (PMF) remains the most amenable technique for protein identification in proteomics, using mass spectrometry as the primary analytical technique coupled with bioinformatics. This relies on the presence of the amino acid sequence of the protein in the current databanks. Despite this, it is desirable to be able to use the technique for organisms whose genomes are not yet fully sequenced and apply cross-species protein identification. In this study, we have re-examined the feasibility of such approaches by considering the extent of protein similarity between genome sequences using a data set of 29 complete bacterial and two eukaryotic genomes. A range of protein and peptide features are considered, including protein isoelectric focussing point, protein mass, and amino acid conservation. The effectiveness of PMF approaches has then been tested with a series of computer simulations with varying peptide number and mass accuracy for several cross-species tests. The results show that PMF alone is unsuitable in general for divergent species jumps, or when protein similarity is less than 70% identity. Despite this, there exists a considerable enrichment above random of tryptic peptide conservation and PMF promises to remain useful when combined with other data than just peptide masses for cross-species protein identification.

Algorithms↗

PubMed1999

Redox regulation of TNF signaling.

TNF is produced during inflammation and induces, among other activities, cell death in sensitive tumour cells. We previously reported an increased generation of ROS in TNF-treated L929 fibrosarcoma cells prior to cell death. These ROS are of mitochondrial origin and participate in the cell death process. Presently, we focus on the identification of parameters that control ROS production and subsequent cytotoxicity. From the cytotoxic properties and susceptibility to scavenging of TNF-induced ROS as compared to pro-oxidant-induced ROS we conclude that TNF-mediated ROS generation and their lethal action are confined to the inner mitochondrial membrane. Oxidative substrates, electron-transport inhibitors, glutathione and thiol-reactive agents but also caspase inhibitors modulate TNF-induced ROS production and imply the existence of a negative regulator of ROS production. Inactivation of this regulator by a TNF-induced reduction of NAD(P)H levels and/or formation of intraprotein disulfides would be responsible for ROS generation.

Animals↗

PubMed2000

Prediction of liver allograft fibrosis after transplantation for hepatitis C virus: persistent elevation of serum transaminase levels versus necroinflammatory activity.

Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) remains a significant source of morbidity and mortality. Factors that reliably predict allograft injury from HCV have not been identified. Demographics, clinical data, and histopathological characteristics of recipients with and without persistently elevated serum transaminase levels (PEST) were compared. Twenty-four patients with HCV-induced end-stage liver disease who underwent OLT between October 1995 and December 1998 were entered into a longitudinal, prospective evaluation for identification of parameters associated with graft injury. Liver biopsies were performed preoperatively and between posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every 6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion and scored for rejection, necroinflammatory activity, extent of fibrosis, and infiltrating cell type, location, and magnitude. Transplant recipients with PEST (alanine transaminase level >1.5 times normal for 3 consecutive months) and cholestatic hepatitis showed an increased viral load compared with their own preoperative values (16-fold and 256-fold, respectively). Compared with control transplant recipients, PEST was associated with macrovesicular steatosis within 28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003) despite similar degrees of rejection and necroinflammatory activity. There was no difference in demographics or immunosuppression. Macrovesicular steatosis may be the earliest predictor of graft fibrosis. Despite similar degrees of necroinflammatory activity, transplant recipients with PEST had an increased rate of fibrosis that could be predicted on average within 6 months posttransplantation.

Alanine Transaminase↗

PubMed1989

Surgery for cancer of the buccal mucosa.

Buccal Mucosa cancer is common in India, T4 tumours being the most common (66%). T1 tumours are rarely seen (4%). Disease-free survival (DFS) at 18 mo with surgery alone for T2, T3, and T4 tumours is 57%, 43%, and 21%, respectively. Addition of postoperative radiation therapy (RT) for T3 and T4 lesions increases DFS to 60% and 35%, respectively. Marginal mandibulectomy is advocated for lesions close to the lower gingiva when the bone is clinically and radiologically uninvolved. The local control rate with marginal mandibulectomy is 79%. In T3/T4 tumours, results with supraomohyoid dissection are comparable to radical neck dissection when the upper jugular nodes are histologically negative. In T4 tumours, histological grading forms an important parameter for identification of a favourable subset. In well-differentiated tumours DFS was 48% with surgery and 72% with surgery and postoperative RT; in moderately differentiated tumours it was 12% and 21%, respectively; and in the poorly differentiated group there were no survivors.

Cheek↗

PubMed2000

Quantitative analysis and model simplification of an epidemic model with primary and secondary infection.

Models of particular epidemiological systems can rapidly become complicated by biological detail which can obscure their essential features and behaviour. In general, we wish to retain only those components and processes that contribute to the dynamics of the system. In this paper, we apply asymptotic techniques to an SEI-type model with primary and secondary infection in order to reduce it to a much simpler form. This allows the identification of parameter groupings discriminating between regions of contrasting dynamics and leads to simple approximations for the model's transient behaviour. These can be used to follow the evolution of the developing infection process. The techniques examined in this paper will be applicable to a large number of similar models.

Chenopodiaceae↗

PubMed1993

An artificial intelligence system to predict progression of immune dysfunction in healthy older patients.

In 1983, forty nine participants returning for their annual HEALTH WATCH evaluation were assessed for immune function status and served as healthy controls in an early study of "normal" reference values for T4 and T8 lymphocyte counts and T4/T8 lymphocyte ratios, B lymphocyte counts, and other laboratory tests for immune function then available. Balascopy, a computer-assisted pattern recognition system for detection, quantification and cognition of multiple imbalances among clinical laboratory and health behavioral parameters, facilitates identification of otherwise healthy individuals with evidence of early immune dysfunction. When the T4 and T8 immunology tests were combined with 7 health index behavioral subscores, and 24 routine clinical laboratory tests, we are able to obtain a bodyprint unique for each patient, providing a comprehensive health status profile specific for that individual. These bodyprints serve as tools for the evaluation of otherwise undetectable metabolic, immunological and behavioral imbalances in a given patient in an unprecedented individualized manner. We show here a longitudinal look at a balascopic evaluation of one patient who has evidence of progressive immune dysfunction with development of only mild clinical symptoms.

Aged↗

PubMed1994

[Trend analysis in Hodgkin disease mortality in the German Federal Republic 1955-1989: a comparison of log-linear models with descriptive standard methods].

Age-Period-Cohort (APC) models have become a widely accepted method to analyse incidence and mortality rates of cancer or other diseases. In this paper we compare simple descriptive methods such as plotting age-specific rates and standardized rates with regression models in order to investigate mortality rates of Morbus Hodgkin's disease in Germany (West-Germany) between 1955 and 1989. With any of the approaches it can be seen that the mortality of Morbus Hodgkin's disease has been decreasing around 1970. Although APC-models allow some detailed investigation of the separate influence of the age, period and cohort effect, the results are difficult to interpret as there is no unique solution for the parameter estimates (identification problem of APC-models). For the mortality of Morbus Hodgkin's, the result of the APC-modelling shows that the decrease of mortality is overestimated if the cohort effect is not taken into consideration. We therefore conclude that the interpretation of the APC-model should be done in connection with other methods to avoid misinterpretation. The combination of both approaches will lead to a better understanding of the incidence or mortality patterns of cancer.

Adult↗

PubMed2000

[Functional magnetic resonance tomography in the diagnosis and therapy monitoring in multiple myeloma].

AIM OF THE STUDY: Investigation of the quantitative microcirculation parameters amplitude A and exchange rate constant k21 determined by contrast-enhanced dynamic magnetic resonance imaging (d-MRI) in multiple myeloma (MM). METHODS: d-MRT of lumbar spine and right spina iliaca superior posterior of 16 controls (ctr) and 35 patients with active MM. Generation of colour-coded images of microcirculation parameters superimposed onto static MRI images. RESULTS: Amplitude A and k21 parameters were significantly increased in patients with MM and down modulated by therapy in 7 of 8 MM cases in a follow-up investigation [p < 0.01; median Actr = 0.2 (0.09-0.4); median AMM = 0.93 (0.2-1.52); median k21ctr = 0.09 min-1 (0.03-0.9); median k21MM = 4.57 min-1 (0.21-23.8)]. Thirteen patients revealed a "diffuse" and 22 a "focal" pattern of distribution of microcirculation parameters. Bone marrow biopsies in 8 cases revealed an correlation between bone marrow plasma cell infiltration and increased microcirculation parameters. CONCLUSION: Identification of microcirculation changes by d-MRI is a novel imaging technique for the detection and monitoring of MM bone lesions.

Antineoplastic Agents, Alkylating↗

PubMed1983

Clofibrate and tiadenol treatment in hyperlipoproteinemias. A comparative trial of drugs affecting lipoprotein catabolism and biosynthesis.

Changes in plasma lipoprotein levels and platelet reactivity were evaluated during sequential treatments with clofibrate and tiadenol, two hypolipidemic agents with apparently different mechanisms, in 27 hyperlipoproteinemic patients. The objective of the study was to determine the pattern of plasma lipoprotein variations, induced by a drug mainly affecting lipoprotein catabolism (clofibrate) and by a drug affecting biosynthesis (tiadenol), and to single out-patients specifically responding to either treatment. Both drugs proved significantly active in type IIA and IV hyperlipoproteinemias, not in type IIB. Clofibrate significantly lowered very low density lipoprotein (VLDL) associated cholesterol in all three hyperlipoproteinemia phenotypes, and it also lowered VLDL triglycerides in type IV, while increasing high density lipoprotein (HDL) cholesterol in type IIA patients. Low density lipoprotein (LDL) cholesterol levels were minimally reduced by clofibrate in type IIA (-4%), and increased in types IIB (+ 14.2%) and IV (+ 6.1%) patients. Conversely, tiadenol lowered VLDL cholesterol and triglycerides to a lesser extent, but it did significantly reduce LDL cholesterolemia in type IIA (-17.6%), while increasing HDL cholesterol in type IIB. Statistical evaluation of the results did not permit identification of parameters associated with the response to either drug, although individuals specifically responding to one or the other agent, or to both, were detected in all three phenotypes. The sensitivity to the major platelet aggregating factors, ADP, adrenaline and collagen, was not significantly altered after drug treatments. Evaluation of the hypolipidemic response to agents with different mechanisms may be of help in selecting the best treatment for individual patients.

Adult↗

PubMed2006

Type or extension of intestinal metaplasia and immature/atypical "indefinite-for-dysplasia" lesions as predictors of gastric neoplasia.

At present, no information exists on the neoplastic potential of the immature hyperproliferative and atypical lesions of the gastric mucosa, which have been recently labeled "indefinite for dysplasia." In addition, uncertainties still exist concerning the risk contribution of intestinal metaplasia (IM) type and extension, as well as Helicobacter pylori infection. In this study, 471 dyspeptic patients showing IM 10% or higher (median, 40; 25th-75th percentile, 20-60) in antral, angulus, or corpus endoscopic biopsies were submitted to repeated examinations (median, 3; 2-5) over 52 (26-85) months of follow-up, during which 44 neoplastic cases were recorded. IM extension, incomplete, sulfomucin-positive, or CAR5 antigen-positive IM; H pylori infection; and indefinite-for-dysplasia lesions (IDLs), as found at first examination, all showed significant neoplastic potential. However, only IDL, ongoing H pylori infection, and patient's age retained independent predictive power in a multivariate model. On the other hand, IM extension 20% or higher proved to be more sensitive as first screening parameter for identification of subjects with increased neoplastic risk. We suggest that patients with IM, when infected, should undergo H pylori eradication to reduce their cancer risk; only those bearing IDL or very extensive IM (which strongly correlates with IDL) should be followed up with endoscopies and biopsies.

Adult↗

PubMed2000

Multidisciplinary approach to esophageal and gastric cancer.

Despite marked advances in surgical therapy for patients with esophageal, esophagogastric, and gastric cancers, the overall prognosis of these patients has not markedly improved during the past decades. Multidisciplinary approaches using adjuvant postoperative and neoadjuvant preoperative therapeutic principles have received increasing attention with regard to the management of these patients. A series of randomized, prospective trials has demonstrated that adjuvant postoperative radiation or chemotherapy does not result in a convincing survival advantage after complete tumor resection in esophageal, esophagogastric junction, or gastric cancer. The available data on the role of neoadjuvant preoperative therapy are not yet conclusive. Although neoadjuvant therapy may reduce the tumor mass in many patients, several randomized, controlled trials have shown that, compared with primary resection, a multimodal approach does not result in a survival benefit in patients with locoregional, that is, potentially resectable, tumors. In contrast, in patients with locally advanced tumors, that is, patients in whom complete tumor removal with primary surgery seems unlikely, neoadjuvant therapy increases the likelihood of complete tumor resection on subsequent surgery, but only patients with objective histopathologic response to preoperative therapy seem to benefit from this approach. Consequently, in the future, improvements in the overall survival of patients with esophageal, esophagogastric junction, or gastric cancer most likely will be achieved only by tailored therapeutic strategies that are based on the individual tumor location, tumor stage, and consideration of established prognostic factors. A clear classification of the underlying tumor entity, a profound knowledge of the prognostic factors applicable, a thorough preoperative staging, and identification of parameters that allow for the prediction of response to preoperative therapy will become essential for the selection of the optimal therapeutic modality for individual patients.

Adenocarcinoma↗

PubMed2003

Intelligent optimal control with dynamic neural networks.

The application of neural networks technology to dynamic system control has been constrained by the non-dynamic nature of popular network architectures. Many of difficulties are-large network sizes (i.e. curse of dimensionality), long training times, etc. These problems can be overcome with dynamic neural networks (DNN). In this study, intelligent optimal control problem is considered as a nonlinear optimization with dynamic equality constraints, and DNN as a control trajectory priming system. The resulting algorithm operates as an auto-trainer for DNN (a self-learning structure) and generates optimal feed-forward control trajectories in a significantly smaller number of iterations. In this way, optimal control trajectories are encapsulated and generalized by DNN. The time varying optimal feedback gains are also generated along the trajectory as byproducts. Speeding up trajectory calculations opens up avenues for real-time intelligent optimal control with virtual global feedback. We used direct-descent-curvature algorithm with some modifications (we called modified-descend-controller-MDC algorithm) for the optimal control computations. The algorithm has generated numerically very robust solutions with respect to conjugate points. The adjoint theory has been used in the training of DNN which is considered as a quasi-linear dynamic system. The updating of weights (identification of parameters) are based on Broyden-Fletcher-Goldfarb-Shanno BFGS method. Simulation results are given for an intelligent optimal control system controlling a difficult nonlinear second-order system using fully connected three-neuron DNN.

Artificial Intelligence↗

PubMed1999

Epithelial cell plasticity in development and tumor progression.

Various mechanisms of epithelial cell plasticity in morphogenesis have been studied at the genetic and molecular levels. Several control genes have been identified including genes encoding transcription factors and growth factor receptors. These mechanisms may be reactivated during the progression of carcinomas. One of the mechanisms underlying epithelial plasticity is the epithelial-mesenchymal transition. This process has been extensively studied using the NBT-II bladder carcinoma cell line. Cells of this line undergo a reversible transition following exposure to several growth factors including FGF-1, EGF, TGFalpha and SF/HGF, which activate tyrosine kinase surface receptors. Two separate transduction pathways have been identified. The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes. These two pathways cooperate to induce the morphological transition, scattering and locomotion of fibroblast-like cells. Growth/scatter factor-producing NBT-II cells are more invasive than cells that do not contain this factor, in orthotopic confrontation assay. In vivo, these cells are very tumorigenic and may confer a more malignant phenotype on parental cells via a community effect. The role of several growth factors and their receptors has been investigated in human bladder carcinomas. A subset of these tumors with poor outcomes produce low levels of FGFR2-IIIb. The synthesis of this receptor de novo in bladder cell lines reduces proliferation in vitro and tumor growth in nude mice. FGFR2-IIIb functions as a tumor suppressor, consistent with the differentiation-inducing capacities of FGF receptors in the suprabasal cells of the skin. FGFR2-IIIb signaling may be involved in the maintenance of E-cadherin, the prototype epithelial adhesion molecule, which is only downregulated in a fraction of tumors with low FGFR2-IIIb synthesis. Human bladder tumors may also activate autocrine loops such as that for EGFR and their ligands, as already demonstrated for murine bladder tumors. Therefore, our results suggest that multifunctional growth factors and their receptors are involved in cell proliferation and epithelial cell plasticity, acting either as positive or negative regulators of tumor progression. The effect on the morphological transition is also clearly relevant to the mechanism governing dissemination and the formation of micrometastatic tumor cells. The extrapolation of these discoveries to human carcinomas should provide markers facilitating the more accurate prediction of the biological behavior of a given tumor and identify clinically and pathologically significant parameters. The identification of critical changes in the growth factor pathways involved in tumor progression will not only provide insight into the genetic and molecular basis of this process, but should also identify targets for new therapies.

Animals↗

PubMed2002

5.1 The demography of oral diseases, future challenges and the implications for dental education.

This Section considered the immense challenges presented by the changing demography of populations (in particular, cross-boundary flow), changing oral and dental disease trends. It also considered the difficulties of gathering data on such information. It then considered how these challenges may affect the education of the dental team in the future. The Section considered the concept of the 'global village' as a representation of the changing world demography. We were at pains to recognize that our role was in considering both emerging and established market economies. In fact, a major part of the Section's activities concentrated on the development of the professional ethic of social responsibility - represented at the local, regional, national and international levels. We considered a finite group of oral and dental diseases, namely dental caries, periodontal diseases, oral cancer and cranio-facial disorders. In addition, we chose to comment on systemic diseases influenced by oral diseases, oral diseases influenced by systemic diseases and iatrogenic diseases (including prion disorders and cross-infection control issues). The Section recognized the profound difference between needs and demands in the provision of oral and dental health care. We considered the concept of best practices within our working remit and named these as: * the gathering of valid data on health trends; * uniformity in the measurement of disease and diagnostic parameters; * the identification of a core curriculum which best addresses an increased awareness of changing demography; and * a multidisciplinary approach to education and research in the context of global collaboration. The Section recognized the enormous potential for global networking with the explosion of information and communication technology. We investigated the requirements in converging towards higher global standards, while accepting and appreciating important regional and continental differences. To this end, the Section has put forward a number of important recommendations and realistic goals.

Computer Communication Networks↗

PubMed1990

Development and application of a quality assurance information system in cardiac surgery (QUADRA study).

Preventive measures for quality in cadiac surgery which are based on electronic data processing initially have to overcome a variety of obstacles. Some of the most serious encountered are the need for more extensive but more precise and correct documentation, the definition of quality and the identification of parameters to assess it, fears that means to check everything and everybody are being installed, and finding ways to found the measures. The measures have two aims at least: ensuring a broad general standard of treatment which every patient can expect, and supporting efforts at a continuous improvement of treatment methods and thus of the results. These aims dictate that any measures instituted have to be of a permanent nature: they cannot be reached in the long term by a simple supplementary activity such as a research project. On the contrary, a complete integration in the general hospital routine and in the standard documentation and information processes is necessary. As these today still are not usually based on clinical progress reports which are formally suitable for data processing, reorganisation to achieve this is a prerequisite for successful quality assurance. This means, however, that those responsible for quality must help in the reorganisation.

Cardiac Surgical Procedures↗

PubMedDate not supplied

Quantitative gated blood pool SPECT: analysis of 3-dimensional models for the assessment of regional myocardial wall motion.

BACKGROUND: Gated blood pool single photon emission computed tomography (SPECT) (GBPS) uses truly 3-dimensional (3D) data, requiring attention to appropriate reference systems and segmentation models for proper quantification. To date, optimal 3D reference models have not been evaluated. In this study several techniques for 3D GBPS were evaluated. METHODS AND RESULTS: Static and dynamic cardiac phantom evaluations were performed, and GBPS studies for 3 healthy subjects and 9 patients were processed by a variety of 3D analysis techniques to determine the optimum parameters for identification of abnormal segments when compared with coronary arteriography and left ventriculography. Left ventricular wall motion was quantified by calculation of regional ejection fraction (rEF) through use of count, volume, and cord length changes from end diastole to end systole. Three contractile models were evaluated: (1) fixed center of mass (COM), (2) floating COM, and (3) a modification of the method developed by Slager et al (J Am Coll Cardiol 1986;7:317-26), based on the motion of implanted endocardial markers. Eight, twelve, and eighteen 3D segments were analyzed by means of the 3 contractile models and correlated against coronary artery disease assessed by coronary arteriography. Single-head gamma-camera acquisition provided adequate counting statistics to reliably compute rEF for up to 18 left ventricular segments. Using count changes the overall results were able to identify myocardium supplied by diseased coronary arteries when compared with coronary arteriography. Cord length and, to a lesser degree, volume changes provided somewhat poorer sensitivities and specificities when compared with rEF computed from regional count changes, as compared with coronary arteriography. CONCLUSIONS: Three-dimensional quantitative GBPS appears to be a sensitive method for assessing wall motion defects due to coronary artery disease.

Adult↗

PubMed1998

Two-Dimensional Automatic Control Modeling of a Posture Control System.

A posture control model has been developed on the basis of the 2-dimensional feedback control theory. Human postural characteristics were investigated in 5 healthy participants. Tests were performed with eyes open and eyes closed. After 5 s of quiet standing, each participant was unexpectedly pulled forward by 30 mm at his pelvis height and then released. Postural sway was measured over 20 s at a rate of 100 per second. Transfer functions to represent the posture control characteristic were identified by the least squares' method. These showed good results of the model's fitness, predictability, and stability. The response of the eyes-closed condition to perturbation is more oscillatory than that of the eyes-open condition. It seems that the model identified could be applicable to ergonomics, sports, or clinical situations.

model fitness↗