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PubMed1999

Simplified reference region model for the kinetic analysis of [99mTc]TRODAT-1 binding to dopamine transporters in nonhuman primates using single-photon emission tomography.

Accurate quantification of neuroreceptors requires full kinetic modeling of the dynamic single-photon emission tomography (SPET) or positron emission tomography (PET) images, with highly invasive arterial blood sampling. This study investigated the application of a reference region kinetic model to the dynamics of [99mTc]TRODAT-1 in nonhuman primates, obviating the need for blood sampling. A series of dynamic SPET scans were performed on two baboons following the injection of approximately 700 MBq of [99mTc]TRODAT-1. Rapid arterial blood samples were taken automatically during scanning. Reconstructed SPET images were coregistered with magnetic resonance imaging (MRI) scans of the baboons, and regions of interest (ROIs) placed on the striatum, cerebellum and cerebral hemispheres. The ROI data were combined with metabolite-corrected blood data, and fitted to a three-compartment kinetic model using nonlinear least squares techniques. The same data were also used in a simplified reference region model, in which the input function was derived from the nondisplaceable tissue compartment. In addition, semiquantitative blinded analysis was performed by three raters to determine the point of transient equilibrium in the specific binding curves. All methods generated values for the ratio of the kinetic rate constants k3/k4, which gives an estimate of the binding potential, BP. These were compared with the full kinetic model. The mean values of k3/k4 for the three different analysis techniques for each baboon were: 1.17 +/- 0.21 and 1.12 +/- 0.13 (full kinetic model), 0.93 +/- 0.13 and 0.90 +/- 0.07 (reference region model), and 0.97 +/- 0.18 and 0.92 +/- 0.08 (equilibrium method). The reference region method gave significantly lower results than the full kinetic model (P = 0.01), but it also produced a much smaller spread and better quality fits to the kinetic data. The reference region model results for k3/k4 correlated very strongly with the full kinetic analysis (r2 = 0.992, P < 0.001), and with the equilibrium model (r2 = 0.88, P = 0.002). The subjectivity inherent in the equilibrium method produces inferior results compared with both kinetic analyses. It is suggested that the self-consistency of the reference region model, which requires no arterial blood sampling, provides a more precise and reliable estimate of the binding of [99mTc]TRODAT-1 to dopamine transporters than full kinetic modeling. The reference region method is also better suited to a routine clinical environment, and would be able to distinguish smaller differences in dopaminergic function between patient groups.

Animals↗

PubMed2006

JUICE: a data management system that facilitates the analysis of large volumes of information in an EST project workflow.

BACKGROUND: Expressed sequence tag (EST) analyses provide a rapid and economical means to identify candidate genes that may be involved in a particular biological process. These ESTs are useful in many Functional Genomics studies. However, the large quantity and complexity of the data generated during an EST sequencing project can make the analysis of this information a daunting task. RESULTS: In an attempt to make this task friendlier, we have developed JUICE, an open source data management system (Apache + PHP + MySQL on Linux), which enables the user to easily upload, organize, visualize and search the different types of data generated in an EST project pipeline. In contrast to other systems, the JUICE data management system allows a branched pipeline to be established, modified and expanded, during the course of an EST project. The web interfaces and tools in JUICE enable the users to visualize the information in a graphical, user-friendly manner. The user may browse or search for sequences and/or sequence information within all the branches of the pipeline. The user can search using terms associated with the sequence name, annotation or other characteristics stored in JUICE and associated with sequences or sequence groups. Groups of sequences can be created by the user, stored in a clipboard and/or downloaded for further analyses. Different user profiles restrict the access of each user depending upon their role in the project. The user may have access exclusively to visualize sequence information, access to annotate sequences and sequence information, or administrative access. CONCLUSION: JUICE is an open source data management system that has been developed to aid users in organizing and analyzing the large amount of data generated in an EST Project workflow. JUICE has been used in one of the first functional genomics projects in Chile, entitled "Functional Genomics in nectarines: Platform to potentiate the competitiveness of Chile in fruit exportation". However, due to its ability to organize and visualize data from external pipelines, JUICE is a flexible data management system that should be useful for other EST/Genome projects. The JUICE data management system is released under the Open Source GNU Lesser General Public License (LGPL). JUICE may be downloaded from http://genoma.unab.cl/juice_system/ or http://www.genomavegetal.cl/juice_system/.

Chromatography↗

PubMed1986

An evaluation of population pharmacokinetics in therapeutic trials. Part I. Comparison of methodologies.

NONMEM, a computer program that uses the method of extended least-squares analysis, has been advocated as a means of obtaining estimates of population pharmacokinetic parameters when only fragmentary information can be obtained from subjects. To assess the performance of this program, we compared NONMEM with traditional methods for the estimation of population pharmacokinetic parameters with data collected during a phase III clinical trial of alprazolam. NONMEM estimates of the population mean clearance and its coefficient of variation were identical to the estimates obtained with traditional pharmacokinetic techniques. Moreover, NONMEM estimates of these parameters remained stable even when a few as three data points were available per subject. NONMEM estimates of the mean volume of distribution and its coefficient of variation appear to be overestimated, apparently because of the sampling scheme used to generate data for the NONMEM analysis. Suggestions for the effective use of NONMEM in clinical trials, to maximize the benefits of this approach, are provided. Our results lend further support for the use of NONMEM to estimate population pharmacokinetic parameters of a drug from data generated during phase III clinical trials.

Administration, Oral↗

PubMed1998

Predictive model for the diagnosis of intraabdominal abscess.

RATIONALE AND OBJECTIVES: The authors investigated the use of an artificial neural network (ANN) to aid in the diagnosis of intraabdominal abscess. MATERIALS AND METHODS: An ANN was constructed based on data from 140 patients who underwent abdominal and pelvic computed tomography (CT) between January and December 1995. Input nodes included data from clinical history, physical examination, laboratory investigation, and radiographic study. The ANN was trained and tested on data from all 140 cases by using a round-robin method and was compared with linear discriminate analysis. A receiver operating characteristic curve was generated to evaluate both predictive models. RESULTS: CT examinations in 50 cases were positive for abscess. This finding was confirmed by means of laboratory culture of aspirations from CT-guided percutaneous drainage in 38 patients, ultrasound-guided percutaneous drainage in five patients, surgery in five patients, and characteristic appearance on CT scans without aspiration in two patients. CT scans in 90 cases were negative for abscess. The sensitivity and specificity of the ANN in predicting the presence of intraabdominal abscess were 90% and 51%, respectively. Receiver operating characteristic analysis showed no statistically significant difference in performance between the two predictive models. CONCLUSION: The ANN is a useful tool for determining whether an intraabdominal abscess is present. It can be used to set priorities for CT examinations in order to expedite treatment in patients believed to be more likely to have an abscess.

Abdominal Abscess↗

PubMed2003

Nonparametric comparison of two survival-time distributions in the presence of dependent censoring.

When testing the null hypothesis that treatment arm-specific survival-time distributions are equal, the log-rank test is asymptotically valid when the distribution of time to censoring is conditionally independent of randomized treatment group given survival time. We introduce a test of the null hypothesis for use when the distribution of time to censoring depends on treatment group and survival time. This test does not make any assumptions regarding independence of censoring time and survival time. Asymptotic validity of this test only requires a consistent estimate of the conditional probability that the survival event is observed given both treatment group and that the survival event occurred before the time of analysis. However, by not making unverifiable assumptions about the data-generating mechanism, there exists a set of possible values of corresponding sample-mean estimates of these probabilities that are consistent with the observed data. Over this subset of the unit square, the proposed test can be calculated and a rejection region identified. A decision on the null that considers uncertainty because of censoring that may depend on treatment group and survival time can then be directly made. We also present a generalized log-rank test that enables us to provide conditions under which the ordinary log-rank test is asymptotically valid. This generalized test can also be used for testing the null hypothesis when the distribution of censoring depends on treatment group and survival time. However, use of this test requires semiparametric modeling assumptions. A simulation study and an example using a recent AIDS clinical trial are provided.

Acquired Immunodeficiency Syndrome↗

PubMed1977

Genetic analysis of a strain of mice plateaued for litter size.

A strain of mice (S1) was successfully selected for large litter size for 31 generations, increasing the mean by 4.2 young per litter. After generation 31, there was no further progress and it was concluded that a selection plateau had been reached. Realized heritability decreased during the course of the experiment from 0.16+/-0.06 for the first 15 generations to 0.00+/-0.03 for generations 30 through 45.--In order to explore the nature of the selection plateau, the following groups were derived from line S1 at generation 34 or 35: Upward selection with inbreeding (SF), random (relaxed) selection (SO), and downward selection (SR). Selections were carried out for 10 to 11 generations. The means of SO and SF were similar to those of S1, ruling out any major effect of natural selection or overdominance. SR decreased, the mean averaging 2.3 young per litter below that of S1 during the last three generations. The fact that SR responded to selection indicates that genetic variance was still present in the plateaued population. The SF sublines were crossed when the inbreeding was 95% and a new line, SX, was formed. SX was maintained for three generations and the difference of +0.7 young per litter above the contemporary generations of S1 was significant. The results from this experiment suggest that the selection plateau in line S1 was caused by reduction of additive genetic variance to a very low level. Some nonadditive genetic variance remained, however, and was attributed to recessive alleles at low frequency. In agreement with results reported by Falconer (1971), inbreeding with selection followed by crossing of the inbred sublines proved to be effective in overcoming a selection plateau in litter size.

Animals↗

PubMed1997

A genome-based resource for molecular cardiovascular medicine: toward a compendium of cardiovascular genes.

BACKGROUND: Large-scale partial sequencing of cDNA libraries to generate expressed sequence tags (ESTs) is an effective means of discovering novel genes and characterizing transcription patterns in different tissues. To catalogue the identities and expression levels of genes in the cardiovascular system, we initiated large-scale sequencing and analysis of human cardiac cDNA libraries. METHODS AND RESULTS: Using automated DNA sequencing, we generated 43,285 ESTs from human heart cDNA libraries. An additional 41,619 ESTs were retrieved from public databases, for a total of 84,904 ESTs representing more than 26 million nucleotides of raw cDNA sequence data from 13 independent cardiovascular system-based cDNA libraries. Of these, 55% matched to known genes in the Genbank/EMBL/DDBJ databases, 33% matched only to other ESTs, and 12% did not match to any known sequences (designated cardiovascular system-based ESTs, or CVbESTs). ESTs that matched to known genes were classified according to function, allowing for detection of differences in general transcription patterns between various tissues and developmental stages of the cardiovascular system. In silico Northern analysis of known gene matches identified widely expressed cardiovascular genes as well as genes putatively exhibiting greater tissue specificity or developmental stage specificity. More detailed analysis identified 48 genes potentially overexpressed in cardiac hypertrophy, at least 10 of which were previously documented as differentially expressed. Computer-based chromosomal localizations of 1048 cardiac ESTs were performed to further assist in the search for disease-related genes. CONCLUSIONS: These data represent the most extensive compilation of cardiovascular gene expression information to date. They further demonstrate the untapped potential of genome research for investigating questions related to cardiovascular biology and represent a first-generation genome-based resource for molecular cardiovascular medicine.

Blotting, Northern↗

PubMed2001

Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression.

The use of transgenic animals in biomedical research is increasing rapidly and may be the best means of determining gene function. Generating transgenic animals typically requires time-consuming screening processes, and gene function is assessed by an array of difficult phenotypic and biochemical assays performed ex vivo. To address the unmet need in transgenic research for functional assays performed with ease in living animals, we demonstrate here that in vivo detection of luciferase enzyme as a transcriptional reporter facilitates rapid screening for both the presence and function of transgenes in intact living mice. Using this approach we identified three bioluminescent transgenic founders where the transgene consisted of the heme oxygenase promoter fused to the modified coding sequence of the luciferase gene. These founders were identified from 183 pups and confirmed by PCR analysis. Identification of HO-1-luc homozygotes from back- crossed F2 littermates was then accelerated by in vivo imaging. In another transgenic mouse line, where the transgene was comprised of the bone morphogenic-4 (BMP4) promoter fused to the modified luciferase gene, we were able to identify transgenic animals and in each line we were able to visualize patterns of expression in living animals over time. The light production from these transgenic mice indicated that the desired DNA fragment was functional and different expression profiles apparent at different ages and after gene induction.

Animals↗

PubMed1998

Hsp27 phosphorylation is induced in alveolar macrophages exposed to CdO-coated silica particles.

Protein phosphorylation in bovine alveolar macrophages (BAM) activated by quartz dusts and metal oxide-coated silica particles was investigated by means of two-dimensional electrophoresis (2D-PAGE) and densitometric 32[P]-phosphate image analysis. BAM activity was monitored by determining generated superoxide anions and hydrogen peroxide. In vitro stimulation of BAM with cadmium oxide-coated silica particles (LiC-CdO) resulted in characteristic time-dependent changes in 2D-PAGE spot patterns, that were similar to the effects induced by 4ss-phorbol-12-myristate-13-acetate (PMA). Phosphorylation of two proteins with apparent molecular masses of 29 and 42 kDa appeared as main signals in both LiC-CdO and in PMA treated BAM but with different kinetics. Phosphoprotein spot pp29 was identified as an isoelectric form of Hsp27 by microsequence and Western blot analysis. In contrast to PMA stimulation, LiC-CdO-induced Hsp27 and p42 phosphorylation did not correlate with the amount of generated reactive oxygen intermediates. Other potent BAM activators like quartz dust SIKRON F600 or VO-coated silica particles did not show Hsp27 and p42 phosphorylation. LiC-CdO-mediated Hsp27 phosphorylation was inhibited by SB 203580 indicating that p38 MAP kinase is the upstream mediator of the activated signaling pathway(s), while MEK inhibitor PD 98059 had no effect.

Animals↗

PubMed1997

Lexipafant inhibits platelet activating factor enhanced neutrophil functions.

Platelet activating factor (PAF) enhances polymorphonuclear leukocyte (PMN) superoxide (.O2-) production, CD11b expression, and elastase release, all essential components in the pathophysiology of multiple-organ failure. This study was designed to determine the effects of Lexipafant, a PAF receptor antagonist, on PAF-mediated PMN functions. PMNs from 10 healthy volunteers were isolated and pretreated with various concentrations of Lexipafant (0-100 microM). PMNs were then incubated for 5 min with 200 nM PAF for .O2- detection or 2000 nM PAF for elastase measurement and activated with 1 microM N-formylmethionylleucylphenylalanine. The mean rate of .O2- production was determined by a cytochrome c reduction assay (nmole .O2-/min/1.33 x 10(5) PMN +/- SEM). Elastase release was measured by the cleavage of the synthetic elastase substrate Meo-Suc-Ala-Ala-Pro-Val-pNA (mean elastolytic activity +/- SEM). In parallel experiments, PMNs were incubated with 200 nM PAF for 30 min following pre-treatment with Lexipafant and CD11b expression was determined by flow cytometry (mean fluorescence intensity +/- SEM). Statistical analysis was performed using repeated-measures ANOVA (P < 0.05). Lexipafant inhibited PAF-enhanced PMN .O2- generation, CD11b expression and elastase release in a dose dependent fashion. The IC50 of Lexipafant for .O2- production, CD11b expression, and elastase release was 0.046, 0.285, and 0.05 microM, respectively. Lexipafant attenuated the PAF-mediated upregulation of PMN .O2- production, CD11b expression, and elastase release in a dose dependent fashion. These data support the hypothesis that Lexipafant may reduce the severity of the inflammatory response to injury produced by PAF-enhanced activation of PMNs.

Dose-Response Relationship, Drug↗

PubMed2000

Insertion of in-frame sequence tags into proteins using transposons.

Several methods based on the use of transposons allow the efficient generation of relatively short (e.g., <35 residues) in-frame insertions in proteins. The analysis of such insertions has provided a simple means to identify sites that tolerate dramatic sequence changes without loss of function ("permissive" sites) and to dissect protein structure-function relationships. In addition, epitope and protease cleavage site "tags" introduced in such insertions have made it possible to analyze the oligomerization state and transmembrane topologies of several proteins. Finally, the DNA inserted by these methods generally carries restriction sites which may facilitate the construction of in-frame deletions and gene fusions encoding a variety of chimeric proteins.

Amino Acid Sequence↗

PubMed1987

Membrane IgD-positive B cells of "low-IgD serum phenotype" individuals fail to secrete IgD and fail to shift to preferential lambda light-chain expression in vitro.

IgD production by short-term human peripheral blood mononuclear cell (PBM) cultures was studied to establish the in vitro correlates of low serum IgD expression. Cells of persons with less than 3 micrograms/ml IgD in the serum, referred to as the low-serum IgD phenotype (LISP), were analyzed. Advantage was taken of recently developed data on spontaneous IgD biosynthesis by human B cells and the observation that lambda light chains are preferentially expressed by IgD-secreting cells in vitro. Initial analysis of an IgD serum distribution showed that all LISP sera contained low but detectable amounts of IgD, with a mean value of 0.85 microgram/ml; this figure was 30- to 35-fold lower than the mean of the majority of the population. LISP PBM contained normal numbers of IgD-positive B cells which displayed a normal intensity of IgD per cell using comparative analysis of mean channel fluorescence by cell flow cytometry. Several lines of evidence suggested that IgD-secreting cells could not be generated from LISP lymphocytes in vitro. Namely, it was found that no IgD immunoglobulin-containing cells were found among PBM of LISP persons; cell lysates enriched for the intracellular fraction by Triton X-114 phase separation showed low IgD in LISP cells despite "normal" amounts of IgD in membrane-enriched fraction preparations; there was no spontaneous IgD secretion by any LISP PBM cultures; and neither LISP sera nor cellular IgD preparations showed IgD lambda/kappa ratios greater than 1.0, indicative of the absence of the preferential lambda light-chain expression associated with secretion of IgD.(ABSTRACT TRUNCATED AT 250 WORDS)

B-Lymphocytes↗

PubMed2003

PCR-based identification of microcystin-producing genotypes of different cyanobacterial genera.

Microcystins are harmful hepatotoxins produced by many, but not all strains of the cyanobacterial genera Anabaena, Microcystis, Anabaena, Planktothrix, and Nostoc. Waterbodies have to be monitored for the mass development of toxic cyanobacteria; however, because of the close genetic relationship of microcystin-producing and non-producing strains within a genus, identification of microcystin-producers by morphological criteria is not possible. The genomes of microcystin-producing cells contain mcy genes coding for the microcystin synthetase complex. Based on the sequence information of mcy genes from Microcystis and Planktothrix, a primer pair for PCR amplification of a mcyA gene fragment was designed. PCR with this primer pair is a powerful means to identify microcystin-producing strains of the genera Anabaena, Microcystis, and Planktothrix. Moreover, subsequent RFLP analysis of the PCR products generated genus-specific fragments and allowed the genus of the toxin producer to be identified. The assay can be used with DNA from field samples.

Anabaena↗

PubMed1991

Autoradiographic characterization and localization of vasoactive intestinal peptide binding sites in albino rat and rabbit eyes.

Localization and pharmacological properties of vasoactive intestinal peptide (VIP) binding sites were investigated in eyes from albino rabbits and rats using an in vitro autoradiographic method. [125I]VIP was used as ligand, and various unlabelled peptides were studied to test the specificity of binding. Autoradiograms were generated by apposing 20-microns-thick cryostat eye sections to [3H]Hyperfilm or autoradiographic emulsion and quantified by means of image analysis procedures. Specific binding represented about 85% of total binding. Kinetic studies showed that equilibrium was reached after a 120-min incubation at room temperature. Biochemical investigations demonstrated that [125I-]VIP bound to a population of sites with high affinity (Kd = 2.27 +/- 0.25 nM). Inhibition of [125I]VIP binding with VIP and related peptides indicated the following rank order of potency: VIP greater than Peptide histidine isoleucine greater than secretin greater than human growth hormone-releasing factor, glucagon, VIP1-14, VIP14-28. In both species, specific binding was found in conjunctiva, iris, ciliary processes, choroid and retina. Moderate grain densities of VIP binding sites were also present in the rat cornea. Quantitative analysis of the autoradiograms revealed that the highest densities of [125I]VIP binding sites were located in the iris and ciliary epithelia in rabbits and in the inner retina in rats. Our findings suggest that VIP may play an important role in several ocular functions, especially in aqueous humor dynamics and retinal neuromodulation.

Animals↗

PubMed1996

The discharge behaviour of single sympathetic neurones supplying human sweat glands.

Firing properties of single sudomotor axons were studied via tungsten microelectrodes inserted percutaneously into cutaneous fascicles of the peroneal nerve in awake subjects. Sweating was induced by radiant heat and measured by changes in skin electrical resistance within the innervation territory on the dorsum of the foot. Eight units were classified as sudomotor neurones because spike-triggered averaging revealed a time-locked relationship between the unitary discharge and the subsequent decrease in skin resistance (1.12 +/- 0.05 s), but no relationship to skin blood flow (measured by a laser-doppler probe). Sudomotor units usually fired only one (maximum six) spike(s) in a sympathetic burst. The mean firing rate was 0.62 Hz, but instantaneous frequencies above 50 Hz could be generated. R-wave triggered histograms and coherence analysis revealed significant coupling between the firing of three sudomotor neurones and the ECG. Moreover, the firing of four sudomotor neurones showed a weak but significant correlation with the spontaneous fluctuations in cardiac interval, diastolic pressure, or the rate of fall in arterial pressure. We conclude that the discharge of human sudomotor neurones is modulated by baroreceptor input.

Adult↗

PubMed1998

Utilization of thermoluminescent dosimetry in total skin electron beam radiotherapy of mycosis fungoides.

PURPOSE: The purpose of this report is to discuss the utilization of thermoluminescent dosimetry (TLD) in total skin electron beam (TSEB) radiotherapy to: (a) compare patient dose distributions for similar techniques on different machines, (b) confirm beam calibration and monitor unit calculations, (c) provide data for making clinical decisions, and (d) study reasons for variations in individual dose readings. METHODS AND MATERIALS: We report dosimetric results for 72 cases of mycosis fungoides, using similar irradiation techniques on two different linear accelerators. All patients were treated using a modified Stanford 6-field technique. In vivo TLD was done on all patients, and the data for all patients treated on both machines was collected into a database for analysis. Means and standard deviations (SDs) were computed for all locations. Scatter plots of doses vs. height, weight, and obesity index were generated, and correlation coefficients with these variables were computed. RESULTS: The TLD results show that our current TSEB implementation is dosimetrically equivalent to the previous implementation, and that our beam calibration technique and monitor unit calculation is accurate. Correlations with obesity index were significant at several sites. Individual TLD results allow us to customize the boost treatment for each patient, in addition to revealing patient positioning problems and/or systematic variations in dose caused by patient variability. The data agree well with previously published TLD results for similar TSEB techniques. CONCLUSION: TLD is an important part of the treatment planning and quality assurance programs for TSEB, and routine use of TLD measurements for TSEB is recommended.

Electrons↗

PubMed2003

Inducible expression system and marker-linked mutagenesis approach for functional genomics of Haemophilus influenzae.

Complete bacterial genomic DNA sequences have allowed application of genome-scale strategies to identify essential genes. Efficient generation of conditional loss of function mutations provides a means of characterization of this class of genes. Promoter systems conferring tight regulation are particularly applicable to generating such mutations and we sought to apply this approach for the analysis of an essential gene of Haemophilus influenzae. Therefore, we developed the use of a D-xylose-inducible promoter for verification of an essential role in growth for yraM, which encodes a putative periplasmic lipoprotein, in both H. influenzae Rd and virulent type b strains. This promoter was sufficiently tightly regulated to generate conditionally viable strains by inducible expression of YraM. A second approach was used to further characterize YraM. Natural transformation and an ordered mutant collection spanning the H. influenzae genome provide the means to target any gene of interest for mutagenesis and temperature-sensitive (TS) mutant isolation. This strategy was applied to generate a conditionally lethal allele of yraM. The resulting TS mutation was directly mapped to a single amino acid substitution within a motif conserved in all putative YraM orthologs and this mutation was shown to be sufficient to confer the TS phenotype.

Bacterial Proteins↗

PubMed1996

Why sequence the genome of Mycobacterium tuberculosis?

Radical measures are required to prevent the grim predictions of the World Health Organisation for the deterioration of the global tuberculosis epidemic in the next century from becoming reality. Study of the nerve centre of the tubercle bacillus, its genome, by means of systematic deoxyribonucleic acid sequence analysis will provide a wealth of information about Mycobacterium tuberculosis that will undoubtedly fuel the next generation of research. In the coming year, this highly cost-effective approach will deliver an unprecedented amount of knowledge to catalyse the development of new, more efficient diagnostic tools and therapeutic interventions to detect, control and, ultimately, eliminate tuberculosis.

Animals↗