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PubMed2001

Identification and classification of key variables and their role in environmental impact assessment: methodology and software package INTRA.

There is, as yet, no proven methodology to enable, objectively, the identification of key parameters out of a large number one normally encounters during any EIA. As EIA is a costly and time-consuming exercise, it is necessary to separate the man from the boys--so to speak--in order to optimize costs and efforts. In this paper a methodology for distinguishing the more important parameters from the less important ones, developed by us, is described. The methodology aims at identifying and shortlisting the key parameters which ought to be studied in a given EIA situation, thereby helping in reducing time, effort, and cost of EIA. With this methodology a system structure is developed which gives hierarchical pattern of inter-parameter interaction, and reveals several distinguishing features of each parameter. A software package INTRA (INTer-parameter Relationship Analysis) based on this methodology, has been developed. The paper also describes a case study in which INTRA has been used to study the environmental impacts of urbanization of a typical third world town (Roorkee).

Developing Countries↗

PubMed1993

The use of causal indicators in covariance structure models: some practical issues.

In conventional representations of covariance structure models, indicators are defined as linear functions of latent variables, plus error. In an alternative representation, constructs can be defined as linear functions of their indicators, called causal indicators, plus an error term. Such constructs are not latent variables but composite variables, and they have no indicators in the conventional sense. The presence of composite variables in a model can, in some situations, result in problems with identification of model parameters. Also, the use of causal indicators can produce models that imply zero correlation among many measured variables, a problem resolved only by the inclusion of a potentially large number of additional parameters. These phenomena are demonstrated with an example, and general principles underlying them are discussed. Remedies are described so as to allow for the evaluation of models that contain causal indicators.

Analysis of Variance↗

PubMed1988

Low retinal noise in animals with low body temperature allows high visual sensitivity.

The weakest pulse of light a human can detect sends about 100 photons through the pupil and produces 10-20 rhodopsin isomerizations in a small retinal area. It has been postulated that we cannot see single photons because of a retinal noise arising from randomly occurring thermal isomerizations. Direct recordings have since demonstrated the existence of electrical 'dark' rod events indistinguishable from photoisomerization signals. Their mean rate of occurrence is roughly consistent with the 'dark light' in psychophysical threshold experiments, and their thermal parameters justify an identification with thermal isomerizations. In the retina of amphibians, a small proportion of sensitive ganglion cells have a performance-limiting noise that is low enough to be well accounted for by these events. Here we study the performance of dark-adapted toads and frogs and show that the performance limit of visually guided behaviour is also set by thermal isomerizations. As visual sensitivity limited by thermal events should rise when the temperature falls, poikilothermous vertebrates living at low temperatures should then reach light sensitivities unattainable by mammals and birds with optical factors equal. Comparison of different species at different temperatures shows a correlation between absolute threshold intensities and estimated thermal isomerization rates in the retina.

Animals↗

PubMed2000

Kinetics of early therapeutic response as measured by quantitative PCR predicts survival in a murine xenograft model of human T cell acute lymphoblastic leukemia.

The identification of prognostic parameters and surrogate markers for defining patient risk has been beneficial in effectively guiding therapy and increasing the survival of leukemia patients. It has been hypothesized that the therapeutic response, as measured by a change in tumor burden during therapy, might serve as a new surrogate marker of survival. Here we describe the development of a murine SCID xenograft model of human T cell acute lymphoblastic leukemia (T-ALL), and the use of a sensitive, quantitative PCR assay for the measurement of tumor levels to investigate the relationships between tumor burden quantification, therapeutic response and survival. Animals engrafted with the CCRF-CEM (CEM) human T-ALL cell line develop leukemia that closely resembles the human disease. Quantitative PCR detects the expanding tumor mass in the peripheral blood of the animals several weeks before death. In response to induction therapy with chemotherapeutic agents, both the level of minimal residual disease (MRD) in peripheral blood at the end of therapy and the rate of tumor reduction in peripheral blood during therapy strongly correlated with animal survival. Thus, these surrogate markers, which can be measured during the early stages of therapy, may help improve patient survival through dynamic risk stratification.

Animals↗

PubMed2001

Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis.

Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X(L) only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Molecular taxonomy of Trichophyton mentagrophytes and T. tonsurans.

Most members of the anamorph genus Trichophyton are anthropophilic and have evolved with the human host. Classical parameters for the identification of dermatophytes include clinical features, cultural characteristics, conidial morphology and physiological test results. Phenotypic variability and pleomorphism due to culturing on artificial media is common among this group of organisms and has led to the description of numerous species. The validity of taxa around T. mentagrophytes and T. tonsurans was verified. Morphological and physiological features were compared to results of three different molecular techniques (sequencing of the internal transcribed spacer (ITS) region of the ribosomal operon, PCR fingerprinting and amplified fragment length polymorphism (AFLP) analysis). Twenty-four species or varieties investigated could be reduced to five taxa and were reclassified or synonymized as Trichophyton tonsurans, T. interdigitale, T. mentagrophytes, T. simii and T. erinacei.

Animals↗

PubMed2002

Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features.

BACKGROUND: The clinical relevance of distinguishing two types of glomerulonephritis (GN) with non-amyloid organized immunoglobulin (Ig) deposits-fibrillary GN (FGN) and immunotactoid (microtubular) GN (IT/MTGN)-on the basis of ultrastructural organization, is debated. METHODS: Twenty-three patients with organized glomerular Ig deposits were classified into two groups based on the fibrillar or microtubular ultrastructural appearance of the deposits. Kidney biopsy samples were studied by immunofluorescence microscopy, using anti-light chain conjugates (all cases) and anti-IgG subclass conjugates (13 patients). In each group, we studied clinicopathological features, associated monoclonal gammapathy (detected by immunoelectrophoresis and/or immunoblot) or B-cell lymphoproliferative disease, effects of chemotherapy and long-term renal outcome. RESULTS: In 14 IT/MTGN and 9 FGN patients, clinical symptoms [hypertension, nephrotic syndrome (NS) and hematuria] and the mean diameters of the substructures were similar. In 13 IT/MTGN patients, glomerular (IgG1, 2 or 3) deposits were monotypic (kappa, 7 cases; lambda, 6 cases). Glomerular deposits were associated with a monoclonal Ig of the same isotype in eight patients, detected in the serum (5 cases), and/or in the cytoplasm of lymphocytes (4 cases), and with lymphoproliferative disease in seven patients. The ultrastructural features of monoclonal Ig inclusions in lymphocytes were similar to those of glomerular microtubular deposits. In contrast, none of the FGN patients presented lymphoplasmocytic proliferation or paraproteinemia. Glomerular Ig deposits were polyclonal in eight cases and contained IgG4 in all three cases studied. Although patient and renal survival did not differ significantly between the two groups, chemotherapy led to remission of NS in ten IT/MTGN patients, with parallel improvement in hematological parameters. CONCLUSIONS: The identification of ultrastructural patterns in these nephropathies is important. GN with organized microtubular monoclonal deposits (GOMMID) probably accounts for a large proportion of immunotactoid (microtubular) GN cases.

Adrenal Cortex Hormones↗

PubMed2006

[Genetic factors and colorectal cancers development: therapeutic impact].

Colorectal tumorigenesis is associated with the progressive increase of epithelium dysplasia and wall invasion. These criteria are evaluated through histological staging, that enables a reliable estimation of patient prognosis, and is the best tool for therapeutic decision. Adjuvant chemotherapy is systematically proposed in case of lymph nodes and/or distant metastases (stages III and IV respectively). Its benefit in stage II tumors however remains unclear. Independently of the nature of the treatment, one third of all stage II-III tumors will metastasize. One important element to improve our tools for therapeutic decision is the identification of prognostic parameters, independent of the histological and morphological classifications. In a preliminary study, we allelotyped a series of 401 colon tumors and have shown that 5q and 8p allelic status were significantly predictive of the patients evolution. As a first approach, analysis of 47 tumors using microarray expression measures has allowed to validate the strong correlation between RNA levels and genomic status (i.e. mutation and allelic status) of known genes (APC, SMAD4, TP53, MLH1). We are now planning to characterize a series of 185 stage II-III colon tumors at both genomic and transcriptomic levels, in combination with the clinicopathological findings. Disease-free patients were followed at least 3 years after surgical resection. A tight collaboration of 5 departments of digestive oncology allowed to collect all clinical and biological resources for this project. Depending on our findings, correlations will be made between gene expression levels and somatic mutations of the coreesponding genes. Real time RT-PCR and immunohistochemical analyses will be performed on selected genes. Finally, biological mechanisms will be investigated to look for new therapeutic targets.

Colorectal Neoplasms↗

PubMed2006

Modeling global vector fields of chaotic systems from noisy time series with the aid of structure-selection techniques.

We address the problem of reconstructing a set of nonlinear differential equations from chaotic time series. A method that combines the implicit Adams integration and the structure-selection technique of an error reduction ratio is proposed for system identification and corresponding parameter estimation of the model. The structure-selection technique identifies the significant terms from a pool of candidates of functional basis and determines the optimal model through orthogonal characteristics on data. The technique with the Adams integration algorithm makes the reconstruction available to data sampled with large time intervals. Numerical experiment on Lorenz and Rossler systems shows that the proposed strategy is effective in global vector field reconstruction from noisy time series.

Algorithms↗

PubMed1989

Parasite survey of eight wild animals in the Ruma National Park.

Eight game animals representing seven species in the Ruma National Park in South Nyanza, Kenya, were examined for the presence of blood protozoa, ectoparasites, and helminthic and coccidian endoparasites using standard parasite-identification methods. Haematological parameters were also determined. The oribi was positive for Trypanosoma brucei ssp. and the reedbuck for T. congolense. No other blood protozoans were found. Strongyle eggs were found in the faeces of all species except the water buck. Five of eight animals harboured liver flukes and five were parasitized by ticks of the genus Amblyomma. One roan antelope was anaemic, but the other animals had haemoglobin levels within the normal range and appeared to be in a good state of health.

Animals↗

PubMed2004

Flow cytometry for diagnosis and assessment of prognosis in patients with myelodysplastic syndromes.

The Myelodysplastic Syndrome (MDS) comprises a spectrum of hematopoietic stem cell disorders. Identification of additional parameters that might distinguish different risk groups or entities would be useful. Flow cytometric studies have begun to characterize individual or composite immunophenotypic abnormalities as well as light scatter properties that may be helpful for diagnosis and of prognostic value for the natural course of the disease and for outcome after therapy. Here we review the current state of the art of the use of flow cytometry in patients with MDS.

Flow Cytometry↗

PubMed2005

Charge state estimation for tandem mass spectrometry proteomics.

High-throughput protein analysis by tandem mass spectrometry produces anywhere from thousands to millions of spectra that are being used for peptide and protein identifications. Though each spectrum corresponds only to one charged peptide (ion) state, repetitive database searches of multiple charge states are typically conducted since the resolution of many common mass spectrometers is not sufficient to determine the charge state. The resulting database searches are both error-prone and time-consuming. We describe a straightforward, accurate approach on charge state estimation (CHASTE). CHASTE relies on fragment ion peak distributions, and by using reliable logistic regression models, combines different measurements to improve its accuracy. CHASTE's performance has been validated on data sets, comprised of known peptide dissociation spectra, obtained by replicate analyses of our earlier developed protein standard mixture using ion trap mass spectrometers at different laboratories. CHASTE was able to reduce number of needed database searches by at least 60% and the number of redundant searches by at least 90% virtually without any informational loss. This greatly alleviates one of the major bottlenecks in high throughput peptide and protein identifications. Thresholds and parameter estimates can be tailored to specific analysis situations, pipelines, and instrumentations. CHASTE was implemented in Java GUI-based and command-line-based interfaces.

Computer Graphics↗

PubMed2006

Left intraventricular myocardial deformation dyssynchrony identifies responders to cardiac resynchronization therapy in patients with heart failure.

AIMS: We tested the hypothesis that dyssynchrony of left ventricular (LV) myocardial deformation evaluated by ultrasound can predict success of cardiac resynchronization therapy (CRT) in patients with heart failure (HF). METHODS AND RESULTS: Thirty-seven patients with dilated cardiomyopathy, New York Heart Association class III-IV, LV ejection fraction (EF) < or =35%, QRS > 120 ms were studied before, at pre-discharge, and after 3 and 6 months of CRT. The M-mode peak septal-to-posterior wall motion and thickening delay (SPWMD and SPWTD, ms) and the standard deviation of the averaged time-to-peak strain (TPS-SD, ms) of 12 middle and basal LV segments obtained from the three standard apical views were calculated. Responders were defined at month 6 by > or =20% EF increase and/or > or =15% end-systolic volume (ESV) decrease with respect to baseline. Baseline SPWTD (not SPWMD) and TPS-SD differentiated responders from non-responders with good accuracy and reproducibility. A value > or =194 ms for SPWTD and > or =60 ms for TPS-SD was significantly associated with responder identification. Baseline dyssynchrony parameters correlated significantly with EF (r = 0.53 for SPWTD and r = 0.86 for TPS-SD) and ESV variations (r = -0.42 for SPWTD and r = -0.73 for TPS-SD). CONCLUSION: Patients with chronic HF should undergo ultrasound evaluation to quantify dyssynchrony of LV myocardial deformation, which would help identifying CRT responders.

Adult↗

PubMed2000

Gene expression profiling of primary breast carcinomas using arrays of candidate genes.

Breast cancer is characterized by an important histoclinical heterogeneity that currently hampers the selection of the most appropriate treatment for each case. This problem could be solved by the identification of new parameters that better predict the natural history of the disease and its sensitivity to treatment. A large-scale molecular characterization of breast cancer could help in this context. Using cDNA arrays, we studied the quantitative mRNA expression levels of 176 candidate genes in 34 primary breast carcinomas along three directions: comparison of tumor samples, correlations of molecular data with conventional histoclinical prognostic features and gene correlations. The study evidenced extensive heterogeneity of breast tumors at the transcriptional level. A hierarchical clustering algorithm identified two molecularly distinct subgroups of tumors characterized by a different clinical outcome after chemotherapy. This outcome could not have been predicted by the commonly used histoclinical parameters. No correlation was found with the age of patients, tumor size, histological type and grade. However, expression of genes was differential in tumors with lymph node metastasis and according to the estrogen receptor status; ERBB2 expression was strongly correlated with the lymph node status (P < 0.0001) and that of GATA3 with the presence of estrogen receptors (P < 0.001). Thus, our results identified new ways to group tumors according to outcome and new potential targets of carcinogenesis. They show that the systematic use of cDNA array testing holds great promise to improve the classification of breast cancer in terms of prognosis and chemosensitivity and to provide new potential therapeutic targets.

Adult↗

PubMed1991

In vitro replication of heavy strand DNA in permeabilized human mitochondria.

We have characterized some of the experimental conditions that are essential for initiation of human mitochondrial DNA synthesis. Mitochondria were purified from HeLa cells and were permeabilized with Triton X-100. When supplied with rNTPs and dNTPs, the permeabilized mitochondria synthesized nucleic acids that ranged in size from about 600 to 2000 nucleotides. In vitro DNA synthesis occurred on endogenous DNA templates and required a continuous supply of ATP. Analyses of the synthetic products revealed that almost all of them were of heavy-strand sequence and included authentic 7S DNA. Most of the synthetic products had 5' ends that mapped to similar locations as those previously identified for nascent heavy-strand DNA. Identification of these parameters should facilitate our efforts to achieve in vitro replication of heavy-strand mitochondrial DNA.

Base Sequence↗

PubMed2000

Hepatocellular carcinoma: correlation between gadobenate dimeglumine-enhanced MRI and pathologic findings.

RATIONALE AND OBJECTIVES: To correlate the appearance of hepatocellular carcinoma on delayed (60 minutes) postcontrast T1-weighted gradient echo images with the mode of action of gadobenate dimeglumine (Gd-BOPTA) and the anatomic and pathologic characteristics of the lesions. METHODS: A total of 34 patients with hepatocellular carcinoma and varying degrees of diffuse liver disease were studied. T2-weighted spin echo and T1-weighted spin echo and gradient echo images were acquired before and 60 minutes after the intravenous administration of 0.1 mmol/kg Gd-BOPTA. Qualitative and quantitative evaluations of the images were performed and correlated with histologic findings. The quantitative evaluation, performed on T1-weighted gradient echo images, looked at the percentage increase of liver enhancement after Gd-BOPTA administration, the lesion-to-liver contrast/noise (C/N) ratio before and after Gd-BOPTA administration, and the C/N variation after Gd-BOPTA administration. Qualitative assessment considered the morphologic features of the lesions as well as the visual variation of contrast before and after Gd-BOPTA administration. Finally, a histologic evaluation was made of the degree of differentiation of the lesions and of the presence of fatty metaplasia, necrosis, bile, or intratumoral peliosis. RESULTS: Among the parameters affecting lesion identification were the extent of liver function, degree of vascularization, residual functionality of the tumor cells, and characteristics of the neoplastic tissue. Positive correlations (Spearman coefficients = 0.359 and 0.393, respectively) were observed precontrast between the degree of liver failure and the amount of contrast noise, and postcontrast between the amount of intralesional fatty metaplasia and the extent to which lesion conspicuity worsened after Gd-BOPTA administration. An inverse correlation (Spearman coefficient = -0.330) was observed between the degree of lesion differentiation and the visible appearance after Gd-BOPTA administration, with well-differentiated lesions tending toward worsened conspicuity postcontrast. A statistically significant difference (P = 0.001) was observed in the mean precontrast C/N ratio for lesions later showing unchanged conspicuity and worse conspicuity on postcontrast images, respectively. Marked variation (P = 0.019) was also observed between Child A and B cirrhotic patients for the degree of hepatic enhancement on postcontrast images. CONCLUSIONS: The results suggest that liver parenchyma signal intensity is influenced by the extent to which liver function is compromised, that residual hepatocytic functionality permits Gd-BOPTA uptake by certain lesions and that this uptake might subsequently impair the observed C/N ratio on delayed images, and that the worsening of lesion conspicuity on postcontrast images is influenced also by high quantities of intralesional fatty metaplasia.

Carcinoma, Hepatocellular↗

PubMed1995

Serum manganese superoxide dismutase is a new tumour marker for malignant melanoma.

Malignant melanoma in its disseminated stage is incurable. The most widely accepted criteria for the prognostic evaluation of melanoma are histopathological and clinical parameters, and the identification of additional simple, serological tumour markers is thus of paramount importance. Manganese-containing superoxide dismutase (MnSOD) belongs to a family of metalloproteins that catalyse the metabolization of oxygen radicals in order to protect these cells from radical damage. In patients with epithelial ovarian carcinomas, serum MnSOD levels have been shown to be elevated in accordance with the progression of their clinical disease. Recently, an overexpression of MnSOD was shown to suppress the malignant phenotype of human malignant melanoma cells. Therefore, we determined serum MnSOD concentrations in 33 patients with malignant melanoma at different clinical stages. Whereas MnSOD serum levels in normal subjects (n = 11) and in dermatological patients with type I allergies (n = 10) or chronic non-allergic urticaria (n = 7) were below 200 ng/ml, the MnSOD serum concentrations in melanoma patients were statistically elevated in all clinical stages compared with normal (p < 0.005). These data suggest that elevated MnSOD serum concentrations correspond to tumour load and correlate with progression of malignant melanoma. Measurement of MnSOD serum levels might therefore provide a sensitive tool for monitoring the clinical course of melanoma.

Adult↗

PubMed2001

Systematic triage in the emergency department using the Australian National Triage Scale: a pilot project.

The objective of this study was to evaluate the validity in Belgium of the National Triage Scale for judgement of the urgency of a patient's condition and making a case-mix description of the patient profiles in the different urgency categories. The study is of a descriptive retrospective and descriptive correlational design and was carried out in the emergency department at the University Hospital Gasthuisberg in Leuven, Belgium. The urgency of patients arriving at the emergency department was evaluated during one randomly selected shift a day over 12 weeks in 1997 by one of the four triage-educated nurses, using an instrument based on the National Triage Scale. Patient identification and outcome parameters were retrieved from the existing computer system. The data were mainly analysed using the Ridit analysis. Overall 3650 patients were evaluated: Category 1, 4.19%; Category 2, 24.44%; Category 3, 39.32%; Category 4, 27.97%; Category 5, 4.08%. Any similarity between sentinel diagnoses as well as between the admission percentages in this pilot study and the reference from Australia (Z = 0.827; p > 0.05) was noted. Different aspects influenced the triage nurses while determining the degree of urgency. Urgency categories profiles revealed a significant effect of age (Kruskall-Wallis = 530.5; p = 0.000). Higher categories of urgency resulted in a higher degree of admission (t (df = 3640) = 643.45; p = 0.000). It is concluded that a resemblance between the pilot study and the reference confirms the predictive validity of the scale used. Patient profiles in the different urgency categories give a description of the emergency department population.

Adolescent↗