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PubMed1997

Cloning, purification, crystallization, and preliminary X-ray diffraction analysis of cystathionine gamma-synthase from E. coli.

The Escherichia coli metB gene has been PCR-extracted from genomic DNA and placed under the control of a tac and a T7 promoter in plasmids pCYB1 and pET22b(+), respectively, to produce overexpressing bacterial strains for the gene product, cystathionine gamma-synthase. Efficient purification procedures have been developed for a C-terminally intein-tagged version and the wild-type target protein, yielding the product in a quantity and homogeneity amenable to high-resolution single-crystal X-ray analysis. Crystals have been obtained in space group P1 with unit cell constants a=82.2 A, b=84.2 A, c=116.2 A, alpha=107.0 degrees, beta=96.3 degrees, gamma=108.0 degrees, suggesting eight monomers per asymmetric unit (V[M]=2.23 A3/Da). Crystals diffract to beyond 2.6 A resolution and a data set complete to 2.8 A resolution has been collected using a rotating anode X-ray source. A cryogenic buffer system has been developed to allow synchrotron data collection. Patterson self rotation searches reveal the presence of two independent tetramers with local 222 symmetry in an asymmetric unit. The crystallographic results corroborate and extend previous solution studies regarding the quaternary organization of the enzyme.

Carbon-Oxygen Lyases↗
PubMed1980

Structure of crystalline actin sheets.

Although actin is one of the most abundant proteins found in nature, little detailed information about its molecular structure is available beyond the amino acid sequence. Electron microscopy of negatively stained filaments combined with three-dimensional image reconstruction techniques have revealed the overall size and shape of the actin monomer at 25 A resolution. Higher resolution structural data can be expected from electron microscopy of two-dimensional crystalline arrays and X-ray diffraction analysis of three-dimensional crystals, but only very preliminary results have been reported so far. The original finding by Dos Remedios and Dickens was that skeletal muscle actin forms microcrystals and tubes in the presence of the trivalent lanthanide gadolinium (Gd3+). We have modified and refined their conditions to obtain large crystalline sheets of Acanthamoeba actin and present here a model of the actin monomer in projection to 15 A resolution. We have found that, depending on the ionic strength used, these sheets occur in three different forms: 'cylinders', 'square type' sheets and 'rectangular type' sheets. These different polymorphic forms are built from the same fundamental two-dimensional crystalline actin lattice, which we call the 'basic sheet'. The present concerns the structural analysis of these basic sheets; the crystal polymorphism will be discussed in detail elsewhere (U.A. et al., in preparation). Furthermore, in addition to demonstrating that actin is an elongated globular molecule with a pronounced asymmetric shape in and perpendicular to the plane of the sheet, our results indicate that these crystalline actin sheets might be suitable for three-dimensional structure determination by low-dose electron microscopy of unstained specimens to at least 10 A resolution.

Actins↗
PubMed2000

Satellites, space, time and the African trypanosomiases.

The human and animal trypanosomiases of Africa provide unique challenges to epidemiologists because of the spatial and temporal scales over which variation in transmission takes place. This chapter describes how our descriptions of the different components of transmission, from the parasites to the affected hosts, eventually developed to include geographical dimensions. It then briefly mentions two key analytical techniques used in the application of multi-temporal remotely sensed imagery to the interpretation of field data; temporal Fourier analysis for data reduction, and a variety of discriminant analytical techniques to describe the distribution and abundance of vectors and diseases. Satellite data may be used both for biological, process-based models and for statistical descriptions of vector populations and disease transmission. Examples are given of models for the tsetse Glossina morsitans in the Yankari Game Reserve, Nigeria, and in The Gambia. In both sites the satellite derived index of Land Surface Temperature (LST) is the best correlate of monthly mortality rates and is used to drive tsetse population models. The Gambia model is then supplemented with a disease transmission component; the mean infection rates of the vectors and of local cattle are satisfactorily described by the model, as are the seasonal variations of infection in the cattle. High and low spatial resolution satellite data have been used in a number of statistical studies of land cover types and tsetse habitats. In addition multi-temporal data may be related to both the incidence and prevalence of trypanosomiasis. Analysis of past and recent animal and human trypanosomiasis data from south-east Uganda supports the suggestion of the importance of cattle as a reservoir of the human disease in this area; mean infection prevalences in both human and animal hosts rise and fall in a similar fashion over the same range of increasing vegetation index values. Monthly sleeping sickness case data from the districts and counties of south-east Uganda are analysed and often show significant correlations with local LST. Case numbers increase with LST in areas that are relatively cooler than average for this part of Uganda, but decrease with LST in areas that are on average warmer. This indicates different seasonal cycles of risk across the region, and may be related to the differing vectorial roles of the two local tsetse, G. fuscipes and G. pallidipes. Finally, the increasing pace of change, and the likelihood of new or reemerging vector-borne diseases, highlight the need for accurate and timely information on habitat changes and the impacts these will have on disease transmission. The next generation of satellites will have significantly more spectral and spatial resolution than the current satellites, and will enable us to refine both statistical and biological predictions of trypanosomiasis and other vector-borne diseases within disease early warning systems.

Africa↗
PubMed2005

Bishistidyl heme hexacoordination, a key structural property in Drosophila melanogaster hemoglobin.

Hemoglobins at high concentration have been isolated long ago from some insect larvae living in hypoxic environments. Conversely, a monomeric hemoglobin has been discovered recently in the fruit fly Drosophila melanogaster as intracellular protein expressed both in larvae and in the adult fly. Such a finding indicates that the oxygen supply in insects may be more complex than previously thought, relying not only on O2 diffusion through the tubular tracheal system, but also on carrier-mediated transport and storage. We present here the crystal structure of recombinant D. melanogaster hemoglobin at 1.20 A resolution. Spectroscopic data show that the protein displays a hexacoordinated heme, whose axial ligands are the proximal and distal His residues. Such bis-His ligation of the heme has sizable effects on the protein local structure. Three protein matrix cavities, comparable in size but not in topological locations with those of sperm whale myoglobin, are spread through the protein matrix; one of these can host a xenon atom. Additionally, D. melanogaster hemoglobin binds one molecule of 3-(cyclohexylamino)propanesulfonic acid (CAPS) buffer at a surface pocket, next to the EF hinge. Despite the high resolution achieved, no sequence/structure features specifically supporting the heme hexa- to pentacoordination transition required for diatomic ligand binding could be recognized.

Alkanesulfonic Acids↗
PubMed2001

Web-based tissue microarray image data analysis: initial validation testing through prostate cancer Gleason grading.

Tissue microarray technology promises to enhance tissue-based molecular research by allowing improved conservation of tissue resources and experimental reagents, improved internal experimental control, and increased sample numbers per experiment. Organized, well-validated collection and analysis of the voluminous image data produced by tissue microarray technology is critical to maximize its value. Web-based technology for visual analysis and searchable storage of microarray image data could provide optimal flexibility for research groups in meeting this goal, but this approach has not been examined scientifically. Toward this goal, a prostate tissue microarray block containing 432 tissue cores (0.6 mm diameter) was constructed. Moderately compressed (200 kb).jpg images of each tissue spot were acquired and were saved using a naming convention developed by the SPORE Prostate Tissue Microarray Collaborative Group. Four hundred three tissue array spot images were uploaded into a database developed for this study and were converted to.fpx format to decrease Internet transmission times for high-resolution image data. In phase I of the image analysis portion of the study, testing and preliminary analysis of the Web technology was performed by 2 pathologists (M.A.R. and G.S.B.). In phase II, 2 pathologists (J.I.E. and T.M.W.) with no previous exposure to this technology and no knowledge of the structure of the study were presented a set of 130 sequential tissue spot images via the Web on their office computers. In phase III, the same pathologists were presented a set of 193 images, including all 130 from phase II and 63 others, with image presentation order randomized. With each zoomable tissue spot image, each pathologist was presented with a nested set of questions regarding overall interpretability of the image, presence or absence of cancer, and predominant and second most frequent Gleason grade. In phases II and III of the study, 319 of 323 (99%) image presentations using this Web technology were rated interpretable. Comparing the 2 pathologists' readings in phases II and III, Gleason grade determinations by each pathologist were identical in 179 of 221 (81%) determinations and were within 1 point of each other in 221 of 221 (100%) determinations, a performance rate similar to if not better than that previously reported for direct microscopic Gleason grading. Interobserver comparison of Gleason score determinations and intraobserver comparisons for Gleason grade and score also showed a pattern of uniformity similar to those reported in direct microscope-based Gleason grading studies. Interobserver (7.5%) and intraobserver (5% and 3%) variability in determining whether diagnosable cancer was present point out the existence of a "threshold effect" that has rarely been studied but may provide a basis for identification of features that are most amenable to improved diagnostic standardization. In summary, storage and analysis of tissue microarray spot images using Web-based technology is feasible and practical, and the quality of images obtained using the techniques described here appears adequate for most tissue-based pathology research applications. HUM PATHOL 32:417-427.

Databases, Factual↗
PubMed2006

Effect of spatial smoothing on physiological noise in high-resolution fMRI.

Physiological noise dominates the SNR of the fMRI time-course at commonly used spatial resolutions at field strengths of 3 T and above. Operating in this physiological noise dominated regime limits some benefits of high field acquisition since increases in image SNR produce only modest increases in time-course SNR. Although previous studies have shown that the physiological noise dominance can be mitigated by using higher spatial resolutions, not all functional studies require voxel sizes smaller than the thickness of the human cortex. In this study, we examine the effect of acquiring high spatial resolution, thermal noise dominated time-courses and spatially smoothing the images to lower resolutions, which would otherwise be physiological noise dominated. At high field strengths, where physiological noise is most problematic, this strategy lowered the overall time-course variance compared to direct acquisition at commonly used spatial resolution. At 7 T for example, 5 x 5 x 3 mm3 resolution images derived from smoothing 1.5 x 1.5 x 3 mm3 data improved time-course SNR by a factor of 1.89 compared to a time-series acquired at 5 x 5 x 3 mm3. Presumably, this effect was derived from the reduced physiological-to-thermal noise ratio in the high spatial resolution data followed by a smoothing operation that improves SNR without adding physiological noise. Our findings demonstrate that in contrast to conventional SNR penalties associated with spatially smoothing Fourier data, the time-course SNR of smoothed high-resolution data can be improved compared to direct acquisition at the desired resolution.

Artifacts↗
PubMed1996

A system for the analysis of foot and ankle kinematics during gait.

A five-camera Vicon (Oxford Metrics, Oxford, England) motion analysis system was used to acquire foot and ankle motion data. Static resolution and accuracy were computed as 0.86 +/- 0.13 mm and 98.9%, while dynamic resolution and accuracy were 0.1 +/- 0.89 and 99.4% (sagittal plane). Spectral analysis revealed high frequency noise and the need for a filter (6 Hz Butterworth low-pass) as used in similar clinical situations. A four-segment rigid body model of the foot and ankle was developed. The four rigid body foot model segments were 1) tibia and fibula, 2) calcaneus, talus, and navicular, 3) cuneiforms, cuboid, and metatarsals, and 4) hallux. The Euler method for describing relative foot and ankle segment orientation was utilized in order to maintain accuracy and ease of clinical application. Kinematic data from a single test subject are presented.

Ankle Joint↗
PubMed1985

Hydrogen MR imaging of the head at 0.35 T and 0.7 T: effects of magnetic field strength.

To determine whether hydrogen magnetic resonance imaging at 0.7 T provides added clinical value over imaging at 0.35 T, images of the heads of patients with various intracranial disorders were obtained at these field strengths. Measurements of tissue contrast (C), signal-to-noise (S/N) ratio, and T1 and T2 relaxation times were determined. For a given spin-echo sequence with equal imaging time, resolution, and data sampling window, the product C X S/N was somewhat lower for the lower field strength. Under conditions of imaging with equal chemical shift artifact, C X S/N at 0.35 T was equal to or greater than that measured at 0.7 T. With an increase in field strength, T1 of pathologic areas and surrounding normal tissues increased, resulting in a corresponding loss of absolute signal level and decrease in contrast. Lesions were equally well seen at both 0.35 T and 0.7 T. The increased T1 and decreased C X S/N for higher magnetic fields--when measured with a fixed imaging time, resolution, chemical shift, and sequence--suggest that such field strengths may not improve tissue contrast, diagnostic ability, or clinical throughput when compared with lower field strength systems.

Brain↗
PubMed2006

Brain magnetic resonance imaging at 3 Tesla using BLADE compared with standard rectilinear data sampling.

OBJECTIVES: We sought to evaluate Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction (PROPELLER; BLADE) data acquisition in comparison with standard k-space sampling techniques for axial and sagittal brain imaging at 3 T regarding imaging artifacts. MATERIAL AND METHODS: Forty patients who gave consent were included in a prospective comparison of standard and PROPELLER (BLADE) k-space sampling techniques. All examinations were performed at 3 T with comparison of standard T2-weighted fluid-attenuated inversion recovery (FLAIR) to PROPELLER T2-weighted FLAIR in the axial image orientation and standard T1-weighted gradient echo to PROPELLER T1-weighted FLAIR in the sagittal image orientation. Imaging protocols were matched for spatial resolution, with data evaluation performed by 2 experienced neuroradiologists. Image data were compared regarding various image artifacts and overall image quality. Reader agreement was assessed by Cohen's kappa statistics. RESULTS: PROPELLER T2-weighted axial data acquisition showed significantly less pulsation and Gibb's artifacts than the standard T2-weighted scan. Even without motion correction, the frequency of ghosting (motion) artifacts was substantially lower in the PROPELLER T2-weighted data and readers concordantly (kappa = 1) rated PROPELLER as better than or equal to the standard T2-weighted scan in the majority of cases (95%; P < 0.0001). In the comparison of sagittal T1-weighted data sets, readers showed only fair agreement (kappa = 0.24) and noted consistent wrap artifacts in PROPELLER T1-weighted FLAIR. CONCLUSION: PROPELLER (BLADE) brain magnetic resonance imaging is also applicable at 3 T. In addition to minimizing motion artifacts, the PROPELLER acquisition scheme reduces other magnetic resonance artifacts that would otherwise degrade scan quality.

Adult↗
PubMed2006

Carotid stenosis index revisited with direct CT angiography measurement of carotid arteries to quantify carotid stenosis.

BACKGROUND AND PURPOSE: All carotid stenosis ratio methods are based on the inability of digital subtraction angiography to measure in millimeters. Each method has potential flaws. The Carotid Stenosis Index (CSI) was designed to reduce ambiguities of NASCET and ECST ratios. We test this method's ability to correctly estimate carotid stenosis using direct computed tomography angiography millimeter measures of the carotid arteries. METHODS: Two neuroradiologists reviewed computed tomography angiographies of 268 carotids with atherosclerotic disease. Millimeter measurements were obtained at the narrowest diameter of the residual stenotic lumen, actual carotid bulb diameter (at level of greatest stenosis), and common carotid artery. Pearson correlation compared the CSI estimate of the carotid bulb to the actual carotid bulb measurement. Ratio calculations of the stenosis were performed using (1) CSI carotid bulb estimate and (2) actual carotid bulb measurement as denominator data. A paired-sample Wilcoxon signed rank test compared the results of these 2 ratio measurements per carotid. RESULTS: Interobserver variability was good to excellent (0.64 to 0.87). The CSI estimate of the carotid bulb size overestimated the measured carotid bulb by an average of 1.5 mm in a random distribution (correlation=0.39, N=151). Paired-sample Wilcoxon signed rank test demonstrated a significant difference between the 2 sets of ratios (z-value of -9.87, P<0.001). CONCLUSIONS: Direct measurement of carotid stenosis, vessel wall soft tissues, and computed tomography plaque imaging is now possible with the high-resolution anatomic data present in high-speed computed tomography angiography, alleviating the need for ratios and inaccurate mathematic estimations of carotid anatomy for carotid stenosis quantification.

Carotid Arteries↗
PubMed2003

More taxa, more characters: the hoatzin problem is still unresolved.

The apparently rapid and ancient diversification of many avian orders complicates the resolution of their relationships using molecular data. Recent studies based on complete mitochondrial DNA (mtDNA) sequences or shorter lengths of nuclear sequence have helped corroborate the basic structure of the avian tree (e.g., a basal split between Paleognathae and Neognathae) but have made relatively little progress in resolving relationships among the many orders within Neoaves. We explored the potential of a moderately sized mtDNA data set ( approximately 5000 bp for each of 41 taxa), supplemented with data from a nuclear intron ( approximately 700 bp per taxon), to resolve relationships among avian orders. Our sampling of taxa addresses two issues: (1). the sister relationship and monophyly, respectively, of Anseriformes and Galliformes and (2). relationships of the enigmatic hoatzin Opisthocomus hoazin. Our analyses support a basal split between Galloanserae and Neoaves within Neognathae and monophyly of both Galliformes and Anseriformes. Within Galliformes, megapodes and then cracids branch basally. Within Anseriformes, mitochondrial data support a screamer (Anhimidae) plus magpie goose (Anseranatidae) clade. This result, however, may be an artifact of divergent base composition in one of the two anatids we sampled. With deletion of the latter taxon, Anseranas is sister to anatids as in traditional arrangements and recent morphological studies. Although our data provide limited resolution of relationships within Neoaves, we find no support for a sister relationship between either cuckoos (Cuculiformes) or turacos (Musophagiformes) and hoatzin. Both mitochondrial and nuclear data are consistent with a relationship between hoatzin and doves (Columbiformes), although this result is weakly supported. We also show that mtDNA sequences reported in another recent study included pervasive errors that biased the analysis towards finding a sister relationship between hoatzin and turacos.

Animals↗
PubMed2000

Crystallization and preliminary X-ray diffraction analysis of Thermus thermophilus prolyl-tRNA synthetase.

Prolyl-tRNA synthetase from Thermus thermophilus (ProRSTT) was purified to homogeneity using a five-step purification procedure and was crystallized using ethylene glycol as a precipitant. Crystals of ProRSTT belong to the space group P2(1)2(1)2, with unit-cell parameters a = 132, b = 191, c = 125 A, have two homodimers per asymmetric unit and diffract to 2.4 A resolution. A complete native data set to 2.43 A resolution has been collected and a data set from ProRSTT in complex with proline has been collected to 2.9 A resolution.

Amino Acyl-tRNA Synthetases↗
PubMed2026

Beyond data and technology: the need for new thinking to enable the era of precision prevention.

BACKGROUND: Global flagship initiatives increasingly advocate for proactive health maintenance to alleviate the growing burden on reactive, disease-focused healthcare systems. Precision prevention is conceived as the targeted modulation of causal pathways across the disease continuum, from latent risk and pre-disease states to clinical manifestation, surpassing conventional public health prevention strategies that prioritise managing population-level risk factors. Traditional discovery and implementation models, however, remain poorly aligned with the pace and breadth of scientific and technological advances. This review outlines key barriers to scaling precision prevention and argues for the integration of conceptual, methodological, and policy perspectives into a single implementation&#x2011;oriented framework. MAIN: Individualised risk stratification lies at the core of precision prevention. Genomics serves as a stable substrate for lifetime susceptibility assessment, while meaningful prediction in multifactorial chronic disease requires additional risk monitoring using dynamic intermediate molecular markers and high-resolution exposomic data. Machine learning and other artificial intelligence (AI) methods are increasingly helpful tools for integrating large, heterogeneous and temporally structured real-world data to generate personalised predictions of health trajectories. Trustworthy AI-enabled risk prediction or decision-support systems are expected to provide transparency about model logic, assumptions and performance. In discovery, existing diagnostic classifications and conventional case-control designs can obscure mechanistic heterogeneity. Shifting toward precision phenotyping and biologically grounded disease redefinition could reveal a new layer of molecular understanding. Evidence generation strategies that reflect the temporal change of disease, including high&#x2011;risk enrichment, surrogate endpoints, and adaptive, trajectory-based monitoring, are particularly important for common conditions with prolonged latency periods (e.g., cancer, cardiovascular disease). Features often dismissed as "noise", such as stochastic molecular variation and minimal exposures, may in fact encode meaningful individual-level signals and thus merit investigation. CONCLUSION: To shift healthcare from reactive treatment toward proactive health maintenance requires coordinated action from stakeholders to reshape the pillars of discovery, reform outcome assessments and modernise implementation strategies.

Humans↗
PubMed2006

Development of a collimator blurring compensation method using fine angular sampling projection data in SPECT.

Due to the collimator aperture, spatial resolution of SPECT data varies with source-to-detector distance. Since the radius of detector rotation is bigger when scanning larger patients, spatial resolution is degraded in these cases. Emitted gamma rays travel not only along the central axis of the collimator hole but also off-axis due to the collimator aperture. However, an off-axis ray at one angle would be a central-axis ray at another angle; therefore, raw projection data at one angle can be thought of as an ensemble of central-axis rays collected from a small arc equal to the collimator aperture. Thus, fine angular sampling can compensate for collimator blurring. By using a sampling pitch of less than half the collimator aperture angle, compensation was performed by subtracting the weighted sum of the projection data from the raw projection data. Collimator geometry and detector rotation radius determined the weighting function. Cylindrical phantom with four different-sized rods and torso phantom for Tl-201 cardiac SPECT simulation were used for evaluation. Aperture angle of the collimator was 7 degrees. Projection sampling pitch was 2 degrees. In both phantom studies, the proposed method showed improvement in contrast and reduction of partial volume effect, thereby indicating that the proposed method can compensate adequately for image blurring caused by the collimator aperture.

Artifacts↗
PubMed1998

Effect of ring size on conformations of aromatic amine-DNA adducts: the aniline-C8 guanine adduct resides in the B-DNA major groove.

While the one-ring amine aniline (AN) has only slight genetic activity, the polycyclic aromatic amines 2-aminofluorene (AF) and 1-aminopyrene (AP) are significant mutagens and carcinogens. Moreover, the bulkier AP is more mutagenic per adduct than AF in the tetracycline-resistance gene of plasmid pBR322 [Melchior et al. (1994) Carcinogenesis 15, 889]. To elucidate possible conformational origins of the differing mutagenic effects of these three adducts, which may stem from their differing ring sizes, we have examined their conformations in two mutation-susceptible sequences from the above gene: TTGAG*GCCG (sequence I) and GAATG*GTGC (sequence II), where G* = C8-modified guanine. No experimental high-resolution NMR data are yet available for the aniline adduct in a DNA duplex. Minimized potential energy calculations were carried out, using the molecular mechanics program DUPLEX to explore the conformation space of these adducts. In the case of AN, a relatively unperturbed B-DNA helix with the amine in the major groove was strongly favored in both sequences. In the case of AF- and AP-modified DNA, however, several differing conformations were competitive in energy. They included major groove structures, as well as conformations with syn-modified guanine and the polycyclic amine in the minor groove, or the amine rings intercalated into the helix with displacement of the modified guanine, in overall harmony with high-resolution NMR solution structures. Thus, aniline distorts DNA structure to a lesser extent than larger aromatic amine ring systems, since a number of different conformations are energetically feasible and have been observed for the larger systems. This result may be relevant to their enhanced mutagenicity and their repair propensity, in contrast to aniline's low mutagenic effect.

Aniline Compounds↗
PubMed2006

Generation, characterization and crystallization of a highly active and stable cytochrome bc1 complex mutant from Rhodobacter sphaeroides.

The availability of the three dimensional structure of mitochondrial enzyme, obtained by X-ray crystallography, allowed a significant progress in the understanding of the structure-function relation of the cytochrome bc(1) complex. Most of the structural information obtained has been confirmed by molecular genetic studies of the bacterial complex. Despite its small size and simple subunit composition, high quality crystals of the bacterial complex have been difficult to obtain and so far, only low resolution structural data has been reported. The low quality crystal observed is likely associated in part with the low activity and stability of the purified complex. To mitigate this problem, we recently engineered a mutant [S287R(cytb)/V135S(ISP)] from Rhodobacter sphaeroides to produce a highly active and more stable cytochrome bc(1) complex. The purified mutant complex shows a 40% increase in electron transfer activity as compared to that of the wild type enzyme. Differential scanning calorimetric study shows that the mutant is more stable than the wild type complex as indicated by a 4.3 degrees C increase in the thermo-denaturation temperature. Crystals formed from this mutant complex, in the presence of stigmatellin, diffract X-rays up to 2.9 Angstroms resolution.

Calorimetry, Differential Scanning↗
PubMed1995

Pharmacokinetic analysis of the time course of effect of atracurium.

OBJECTIVE: To examine the ability to determine clinically important pharmacokinetic and pharmacodynamic parameters of atracurium by the analysis of the time course of effect without the use of plasma concentration data. DESIGN: Neuromuscular transmission was monitored with train-of-four stimulation and electromyographic quantitation of the first (T1) and fourth (T4) responses in eight anesthetized patients undergoing elective surgery. The time course of onset and recovery of neuromuscular blockade by three successive bolus doses of atracurium was recorded. Equations describing the theoretic time course of concentrations in the effect compartment and the dose-response relationship were fitted simultaneously to these data; the parameters of these equations derived from the fit of two doses were used to predict the response to a third dose. Fitting the equations to all three doses was also performed to assess the accuracy of predictions for atracurium. RESULTS: From the depression of the first twitch after three consecutive doses in eight patients, the half-lives of uptake into and elimination from the effect compartment were 2.1 +/- 0.2 minutes (mean +/- SEM) and 25.8 +/- 2.3 minutes (n = 8). The doses producing 50% and 95% depression of the first twitch (ED50 and ED95) were 168 +/- 15 and 280 +/- 25 micrograms/kg, respectively, with a Hill coefficient of 6.1 +/- 0.5. The half-life of elimination estimated from the fourth twitch was similar to that from the first twitch. CONCLUSIONS: The analysis of high-resolution effect data is capable of giving pharmacokinetic and pharmacodynamic parameters with clinically acceptable accuracy within a short sampling time, without resorting to laboratory analysis. This method is specific for active drug and would be of value for individualization of administration for short-term treatment.

Atracurium↗
PubMed1992

[Value of high resolution tomodensitometry in pulmonary histiocytosis X. Radiological, clinical and functional correlations].

Histiocytosis is a rare cause of diffuse interstitial pneumonia. Its aetiology is not known and the outcome is often unsatisfactory. In 10 subjects in whom the diagnosis of histiocytosis X was established at CHU in Grenoble, 7 could be followed up. We report the clinical, functional, radiological and high resolution tomographic data on these 7 subjects suffering from histiocytosis X and followed up for a period between 3 and 13 years (8 +/- 3 years). All the subjects were symptomatic at the time of diagnosis. The clinical outcome amongst the 10 subjects included 2 patients who died, 2 who stabilised, 1 worsened and there were 4 clinical cures, 1 patient was lost to follow up. The respiratory function tests of the 7 subjects who were followed up was characterised by the appearance of airflow obstruction and a significant fall in the DLCO/VA (KCO) of 68 +/- 17% of the predicted value to 43 +/- 13%. An analysis comparing the initial pulmonary radiography to the current films showed that the reticular nodular lesions tended to progress to a diminution in size, while there was an increase in the reticulation. The high resolution computed tomography was confirmed as better technique than pulmonary radiography in detailing the cystic and nodular lesions. This was the only examination which correlated with DLCO/VA (R: 0.8; p: 0.018). A progressive model for computed tomographic lesions is proposed. Computed tomography appears to be the key examination, orientating the diagnosis based on the association of the nodules and cysts and enabling a better appreciation of the severity of the pulmonary disease taking account of its excellent correlation with diffusion.

Adult↗