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Validation of a new non-invasive portable tonometer for determining arterial pressure wave and pulse wave velocity: the PulsePen device.

OBJECTIVE: To validate a new, small portable tonometer (PulsePen) that is able to assess carotid artery pressure and to measure pulse wave velocity (PWV) non-invasively. Its software provides absolute arterial pressure values, an assessment of arterial pulse wave contours, an estimation of reflection waves and measurements of PWV. DESIGN AND METHODS: Two validation studies were carried out. The aim of the first study was to compare arterial pressure values and pulse wave contours recorded in the carotid artery using the PulsePen versus intra-arterial simultaneous measurements in 10 patients undergoing cardiac catheterization. The pulse wave contour was assessed using Fourier analysis. The comparison between the two methods showed no difference in arterial pressure wave spectral moduli from harmonics 1 to 6. The second study compared PWV measurements taken with the PulsePen (one tonometer) and measurements performed with two Millar tonometers in 68 subjects (32 men, 36 women). PulsePen measurements were realized as two consecutive measurements in the carotid and femoral arteries, both synchronized by electrocardiogram. The pulse wave transit time was calculated as the difference between the time delay of the femoral pulse wave and the carotid pulse wave in relation to the R wave of the electrocardiogram. These measurements were compared with PWV obtained by simultaneous carotid and femoral measurements with the two Millar tonometers. No difference between the two methods was found, with a variation coefficient of 7.7%. The variation coefficients of the inter-observer and intra-observer reproducibility for the PulsePen were 7.9 and 7.2%, respectively. CONCLUSIONS: These results show that the PulsePen enables an easy and reliable evaluation of central arterial pressure and stiffness in clinical ambulatory practice, especially in high-risk patients in whom arterial stiffness has been shown to be a significant indicator of morbidity and mortality.

Adult↗

In vivo basal ganglia volumetry through application of NURBS models to MR images.

Volumetry of basal ganglia (BG) based on magnetic resonance imaging (MRI) provides a sensitive marker in differential diagnosis of BG disorders. The non-uniform rational B-spline (NURBS) surfaces are mathematical representations of three-dimensional structures which have recently been applied in volumetric studies. In this study, a volumetric evaluation of BG based on NURBS was performed in 35 right-handed volunteers. We aimed to compare and validate this technique with respect to manual MRI volumetry and evaluate possible side differences between these structures. Intra- and interobserver biases less than 1.5% demonstrated the method's stability. The mean percentage differences between NURBS and manual methods were less than 1% for all the structures considered; however, the internal segments of the globus pallidus showed a mean percentage difference of about 1.7%. Rightward asymmetry was found for the caudate nucleus (mean+/-SD 3.20+/-0.20 cm(3) vs. 3.10+/-0.19 cm(3), P<0.001) for both its head (1.44+/-0.10 cm(3) vs. 1.41+/-0.09 cm(3), P<0.01) and its body/tail (1.73+/-0.11 cm(3) and 1.68+/-0.12 cm(3), P<0.01), and for the globus pallidus (1.23+/-0.08 cm(3) and 1.18+/-0.09 cm(3), P<0.001) for both the internal (0.33+/-0.05 cm(3) vs. 0.31+/-0.05 cm(3), P<0.01) and external (0.90+/-0.05 cm(3) vs. 0.86+/-0.05 cm(3), P<0.001) segments. No volumetric side differences were found for the putamen (3.43+/-0.14 cm(3) vs. 3.39+/-0.17 cm(3), P>0.05). The rightward asymmetry of the BG may be ascribed to the predominant use of the right hand. In conclusion, NURBS is an accurate and reliable method for quantitative volumetry of nervous structures. It offers the advantage of giving a three-dimensional representation of the structures examined.

Adult↗

Relationship between molecular connectivity and carcinogenic activity: a confirmation with a new software program based on graph theory.

For a database of 826 chemicals tested for carcinogenicity, we fragmented the structural formula of the chemicals into all possible contiguous-atom fragments with size between two and eight (nonhydrogen) atoms. The fragmentation was obtained using a new software program based on graph theory. We used 80% of the chemicals as a training set and 20% as a test set. The two sets were obtained by random sorting. From the training sets, an average (8 computer runs with independently sorted chemicals) of 315 different fragments were significantly (p < 0.125) associated with carcinogenicity or lack thereof. Even using this relatively low level of statistical significance, 23% of the molecules of the test sets lacked significant fragments. For 77% of the molecules of the test sets, we used the presence of significant fragments to predict carcinogenicity. The average level of accuracy of the predictions in the test sets was 67.5%. Chemicals containing only positive fragments were predicted with an accuracy of 78.7%. The level of accuracy was around 60% for chemicals characterized by contradictory fragments or only negative fragments. In a parallel manner, we performed eight paired runs in which carcinogenicity was attributed randomly to the molecules of the training sets. The fragments generated by these pseudo-training sets were devoid of any predictivity in the corresponding test sets. Using an independent software program, we confirmed (for the complex biological endpoint of carcinogenicity) the validity of a structure-activity relationship approach of the type proposed by Klopman and Rosenkranz with their CASE program.

Carcinogens↗

Computerized measurement of retinal blood vessel calibre: description, validation and use to determine the influence of ageing and hypertension.

OBJECTIVE: To validate a computer-based method for measuring the calibre of retinal blood vessels, and use it to determine the effects of ageing and arterial hypertension on the calibres of these vessels and on their ratio. METHODS: Digital eye fundus images covering a 50 degrees field and centred on the optic disc were obtained using a 540 nm filter. The boundaries of blood vessels crossing a series of circles concentric with the optic disc were located by an image analysis program; the calibres of vessels crossing the circles perpendicularly were determined automatically, the average arteriole and average vein calibres were calculated, and the arteriovenous ratio (AVR) was calculated as the ratio of these averages. The within-operator, between-operator and within-eye reliability of this method was investigated using images of 30 or 40 eyes; the effects of ageing on average vessel calibres and AVR using both eyes of each of 120 normotensive volunteers aged 10-69 years (60 males, 60 females); and the effects of arterial hypertension using a group of 54 hypertensive patients aged 50.9 +/- 13.9 years. RESULTS: Within-operator, between-operator and within-eye correlation coefficients for AVR were all better than 0.95, and the corresponding coefficients of variation were all better than 3%. The results of Bland Altman approach show a very good agreement. There were no significant differences between right and left eyes or between the sexes in either the normotensive or the hypertensive group. In the normotensive group, vein calibre was almost constant (111 +/- 6 microm), but arteriole calibre and AVR fell significantly from 96 +/- 6 microm and 0.870 +/- 0.046, respectively, in the second decade of life to 85 +/- 4 microm and 0.761 +/- 0.044 in the seventh decade. Arterial hypertension was not associated with changes in vein calibre, but was associated with decreases in arteriole calibre (from 91 +/- 7 microm among normotensive individuals to 84 +/- 2 microm) and AVR (from 0.816 +/- 0.056 to 0.755 +/- 0.027). Age significantly modulated the AVR-reducing influence of hypertension (P = 0.003). CONCLUSION: The proposed method of measuring retinal blood vessel calibres is reliable and precise (especially for the AVR). In this study, its results confirmed that increasing age and arterial hypertension are both associated with reductions in retinal arteriole calibre and AVR.

Adolescent↗

In silico prediction of harmful effects triggered by drugs and chemicals.

While the computer-assisted discovery and optimization of drug candidates based on the known three-dimensional structure of the macromolecular target (structure-based design) or a binding-site surrogate (receptor modeling) is doubtless one of the more potent approaches in rational drug design, the simulation and quantification of side effects triggered by drugs and chemicals are still in their infancy. Major obstacles include the often not available 3D structure of the molecular target, the low specificity of the involved bioregulators and the identification of the controlling metabolic pathways. In the recent past, our laboratory has explored concepts allowing to simulate receptor-mediated toxic phenomena by developing algorithms, allowing to construct realistic 3D binding-site surrogates of receptors known or assumed triggering adverse effects and validating them against large batches of molecular data. The underlying technology (software Quasar and Raptor, respectively) specifically allows for induced fit, solvation phenomena and entropic effects. It has been applied to various systems both of pharmacological and toxicological interest including the neurokinin-1, chemokine-3, bradykinin B(2), steroid, 5 HT(2A), aryl hydrocarbon, estrogen and androgen receptor, respectively. In this account, we describe the design of a virtual laboratory allowing for a reliable estimation of harmful effects triggered by drugs, chemicals and their metabolites in silico. In the recent past, the Biographics Laboratory 3R has compiled a 3D database including the surrogates of three major receptor systems known to mediate adverse effects (the aryl hydrocarbon, the estrogen and the androgen receptor, respectively) and validated them against a total of 345 compounds (drugs, chemicals, toxins) using multidimensional QSAR technologies. Within this pilot project, we could demonstrate that our virtual laboratory is able to both recognize toxic compounds substantially different from those used in the training set as well as to classify harmless compounds as being nontoxic. This suggests that our approach may be used for the prediction of adverse effects of drug molecules and chemicals. It is the aim to provide cost-covering access to this technology--particularly to universities, hospitals and regulatory bodies--as it bears a significant potential to recognize hazardous compounds early in the development process and hence improve resource and waste management as well as reduce animal testing. The Biographics Laboratory 3R is a non-profit-oriented organization aimed at reducing animal experimentation in the biomedical sciences by computational approaches (cf. http://www.biograf.ch).

Computer Simulation↗

Predicting the subject-specific primary stability of cementless implants during pre-operative planning: preliminary validation of subject-specific finite-element models.

Pre-operative planning help the surgeon in taking the proper clinical decision. The ultimate goal of this work is to develop numerical models that allow the surgeon to estimate the primary stability during the pre-operative planning session. The present study was aimed to validate finite-element (FE) models accounting for patient and prosthetic size and position as planned by the surgeon. For this purpose, the FE model of a cadaveric femur was generated starting from the CT scan and the anatomical position of a cementless stem derived by a skilled surgeon using a pre-operative CT-based planning simulation software. In-vitro experimental measurements were used as benchmark problem to validate the bone-implant relative micromotions predicted by the patient-specific FE model. A maximum torque in internal rotation of 11.4 Nm was applied to the proximal part of the hip stem. The error on the maximum predicted micromotion was 12% of the peak micromotion measured experimentally. The average error over the entire range of applied torques was only 7% of peak measurement. Hence, the present study confirms that it is possible to accurately predict the level of primary stability achieved for cementless stems using numerical models that account for patient specificity and surgical variability.

Biomechanical Phenomena↗

Nasogastric intubation after abdominal surgery: a meta-analysis of recent literature.

OBJECTIVE: To determine whether refraining from nasogastric intubation (NGI) in patients after abdominal surgery will result in the same therapeutic effectiveness as using NGI. Data Source We identified randomized trials from the Cochrane Central Register of Controlled Trials published between January 1990 and January 2005. STUDY SELECTION: Two of us independently selected trials based on randomization, abdominal surgery in patients, early vs late removal of the NGI, and reporting at least 1 of the following end points: hospital stay, gastrointestinal function, and postoperative complications. DATA EXTRACTION: Two of us independently performed trial quality assessment and data extraction. Trials were judged using a structured list that included factors relating to internal and external validity. Data were entered and analyzed by means of dedicated software from the Cochrane Collaboration. DATA SYNTHESIS: Seventeen randomized trials met the inclusion criteria. Meta-analysis showed that NGI does not offer any clinically relevant benefits for patients after abdominal surgery, such as recovery of gastrointestinal function or reduction of postoperative complications (relative risk, 1.18; 95% confidence interval, 0.98-1.42). Moreover, NGI showed some undesired effects, such as discomfort (in 60% of the NGI patients) and a later return to a liquid diet (weighted mean difference, 0.65 days; 95% confidence interval, 0.38-0.92 days) or a regular diet, whereas hospital stay was not shortened. CONCLUSIONS: Routine NGI seems to serve no beneficial purpose and may even be harmful in patients after modern abdominal surgery; also, it is uncomfortable. Therefore, NGI is recommended only as a therapeutic approach.

Digestive System Surgical Procedures↗

Object-oriented image analysis for high content screening: detailed quantification of cells and sub cellular structures with the Cellenger software.

BACKGROUND: Detailed image analysis still is a considerable bottleneck for many cellular assays, and automated solutions to the problem are desirable. However, dealing with the complexity and variability of structures in cellular images makes detailed and reliable analysis a nontrivial task. METHODS: Therefore, based on the object-oriented image analysis approach, a novel image analysis technology, a flexible and reliable system for image analysis in cellular assays was developed. It contains a library of predefined, adaptable modules, each of them developed for a specific analysis task. The system can be configured easily by combining appropriate modules and adapting them interactively to the specific image data, if necessary. By representing cells and sub cellular structures within a network of interlinked image objects, a large number of parameters can be derived that describe shape, intensity, and relevant structural and relational aspects of any chosen class of structures. RESULTS: Thus, multi-parameter analysis and multiplexing are supported. A sample application based on this approach demonstrates that GFP signals can be distinguished based on their properties and the relative location within the cell.

Cell Membrane↗

Optimal design for linear interpolation of curves.

Non-parametric procedures are often used for the analysis of pharmacokinetic trials. Fewer design procedures are available for non-parametric estimation than for parametric estimation. Linear interpolation is widely used for curve estimation in pharmacokinetic trials, where often only sparse sampling is feasible. Current design procedures for smoothing or local fit are not suitable as they are based on asymptotic properties and the bias of the estimate is ignored. This paper proposes optimal designs that minimize the mean squared error of linear interpolation. Optimal designs for three situations are considered. The first situation is single curve estimation based on an ordinary non-linear model. The second is estimating several curves in a non-linear mixed model setting using an average mean squared error as the design criterion. The third situation is destructive sampling where estimating the average curve is the main purpose. In the first situation, the design results in the best linear interpolation when the variance is constant. For the destructive sampling design, an algorithm based on approximations is proposed. This algorithm can be programmed in a common statistical package. Numerical examples are used to illustrate the design procedure.

Algorithms↗

Simple measures of progress and outcome in the evaluation of mental health services.

There is a tautology regarding the use of progress and outcome measures. Such measures are easy to use in a reliable and valid fashion if the language of the measures is used as an integral part of (a) treatment planning and progress review, (b) clinical supervision, and (c) program management. The paper describes example guidelines and uses of measures in each of these functions. Also included are listings of scales with documented reliability and validity (by target population) and some sources for finding computer software for scoring some of the scales.

Evaluation Studies as Topic↗

Quantitative assessment of apolipoprotein E genotypes by image analysis of PCR-RFLP fragments.

Apolipoprotein E (APOE) genotyping usually involves polymerase chain reaction (PCR) and assessment of restriction fragment length polymorphism (RFLP) by gel electrophoresis. We made determination of HhaI restriction endonuclease digestive patterns more objective and improved diagnostic accuracy with a quantitative approach using sensitive DNA stain (SYBR Green) and image analysis of gel patterns. For distinguishing true and partially-digested restriction fragments, band ratios were calculated for the staining intensity of gel patterns from 116 sample runs of 63 human blood specimens. Each of these specimens was independently genotyped for APOE by at least two (and most of them by three) different PCR-RFLP methods. Based on the distribution of band ratios, decision levels were established and used for developing a program for computer-aided interpretation of APOE genotypes (Microsoft Excel software). Appropriateness of the decision levels for band ratios was validated by APOE genotyping of additional 61 specimens. The approach described here is applicable to a variety of other molecular diagnostic techniques that are based on PCR-RFLP or sequence-specific signal amplifications.

Apolipoproteins E↗

Prediction of intestinal absorption: comparative assessment of GASTROPLUS and IDEA.

We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery.

Intestinal Absorption↗

Monitoring universal leucodepletion performance: the current issues within components production and testing.

The UK NBS completed the introduction of universal leucodepletion in November 1999. This involved the implementation of new methods of production, testing and monitoring, the development of which is still ongoing. Whilst important lessons have been learnt, much remains to be achieved in respect of quality improvement through standardisation of procedures, processes and product modifications to improve safety/efficacy of therapeutic blood components. Since the introduction of universal leucodepletion, many changes in component production and testing have occurred. The primary goal of this report is to review the level of standardisation and harmonisation currently achieved for low leucocyte counting within the NBS and discuss remedial actions undertaken to improve the standard of blood component production and quality monitoring and to highlight some of the related issues which are currently being worked on. The following issues are discussed.

Blood Component Removal↗

Control of dental prosthesis system with microcontroller.

In this study, a microcontroller-based electronic circuit was designed and implemented for dental prosthesis curing system. Heater, compressor and valve were controlled by 8-bit PIC16C64 microcontroller which is programmed using MPASM package. The temperature and time were controlled automatically by preset values which were inputted from keyboard while the pressure was kept constant. Calibration was controlled and the working range was tested. The test results showed that the system provided a good performance.

Algorithms↗

Design strategy for a simultaneous nitrification/denitrification of a slaughterhouse wastewater in a Sequencing Batch Reactor: ASM2d modeling and verification.

Sequencing Batch Reactor (SBR) was used to treat slaughterhouse wastewater which contains average Chemical Oxygen Demand (COD) concentration of 5000 mg l(-1) and ammonium of 360 mgN l(-1). Nitrification/denitrification process was conducted for nitrogen removal. The influent wastewater as internal carbon source and sodium acetate as an external one was used for completing denitrification to achieve the simultaneous organic matter removal (95-96%) and nitrogen removal (95-97%). In addition, the dynamic SBR simulation model for biological nitrogen removal based on the Activated Sludge Model No. 2d (ASM2d) and GPS-X software is presented. The experimental study for the calibration and validation of the model was carried out using laboratory SBR. The study showed that the model provides a powerful tool to reduce the experimental expenditure and time to find the optimum strategy.

Abattoirs↗

Evaluation of personal digital assistant software for drug interactions.

PURPOSE: The accuracy, comprehensiveness, and ease of use of drug interaction software used with personal digital assistants (PDAs) were studied. METHODS: Each program was assessed for accuracy using 40 clinically important and 40 clinically unimportant drug interaction pairs. Accuracy was scored through the summation of software sensitivity, specificity, and positive and negative predictive values. The comprehensiveness of each program was determined by the number of components in the drug interaction monograph. Time needed to identify the management of five important drug interactions defined each program's ease of use. The aggregate scores for accuracy, comprehensiveness, and ease of use were calculated. RESULTS: Scoring 777 and 756 out of a possible 800 points, iFacts and Lexi-lnteract, respectively, provided the most competent, complete, use-friendly compendia for assessment of drug interactions. Mosby's Drug Consult and Mobile Micromedex ranked third and fourth, scoring 688 and 655 points, respectively, while ePocrates Rx v. 6.0 rated seventh, with a score of 559. All drug interaction resources suffer from limitations in the quality or relevance of evidence for the interaction, an absence of identifiable patient and medication risk factors, and a lack of standardization in assigning significance to the interaction. Consequently, clinicians must interpret the importance of the interaction based on all available evidence. Discussion of such evidence was available for only iFacts and Lexi-Interact. CONCLUSION: Both iFacts and Lexi-Interact excelled as PDA pharmacopoeia for assessing drug interactions. However, clinicians should understand the limitations of all current drug interaction resources and exercise vigilance in prevention and recognition of interactions relevant to their patients.

Computers, Handheld↗

Transposable element annotation of the rice genome.

MOTIVATION: The high content of repetitive sequences in the genomes of many higher eukaryotes renders the task of annotating them computationally intensive. Presently, the only widely accepted method of searching and annotating transposable elements (TEs) in large genomic sequences is the use of the RepeatMasker program, which identifies new copies of TEs by pairwise sequence comparisons with a library of known TEs. Profile hidden Markov models (HMMs) have been used successfully in discovering distant homologs of known proteins in large protein databases, but this approach has only rarely been applied to known model TE families in genomic DNA. RESULTS: We used a combination of computational approaches to annotate the TEs in the finished genome of Oryza sativa ssp. japonica. In this paper, we discuss the strengths and the weaknesses of the annotation methods used. These approaches included: the default configuration of RepeatMasker using cross_match, an implementation of the Smith-Waterman-Gotoh algorithm; RepeatMasker using WU-BLAST for similarity searching; and the HMMER package, used to search for TEs with profile HMMs. All the results were converted into GFF format and post-processed using a set of Perl scripts. RepeatMasker was used in the case of most TE families. The WU-BLAST implementation of RepeatMasker was found to be manifold faster than cross_match with only a slight loss in sensitivity and was thus used to obtain the final set of data. HMMER was used in the annotation of the Mutator-like element (MULE) superfamily and the miniature inverted-repeat transposable element (MITE) polyphyletic group of families, for which large libraries of elements were available and which could be divided into well-defined families. The HMMER search algorithm was extremely slow for models over 1000 bp in length, so MULE families with members over 1000 bp long were processed with RepeatMasker instead. The main disadvantage of HMMER in this application is that, since it was developed with protein sequences in mind, it does not search the negative DNA strand. With the exception of TE families with essentially palindromic sequences, reverse complement models had to be created and run to compensate for this shortcoming. We conclude that a modification of RepeatMasker to incorporate libraries of profile HMMs in searches could improve the ability to detect degenerated copies of TEs. AVAILABILITY: The Perl scripts and TE sequences used in construction of the RepeatMasker library and the profile HMMs are available upon request.

Algorithms↗

A memory-efficient algorithm for multiple sequence alignment with constraints.

MOTIVATION: Recently, the concept of the constrained sequence alignment was proposed to incorporate the knowledge of biologists about structures/functionalities/consensuses of their datasets into sequence alignment such that the user-specified residues/nucleotides are aligned together in the computed alignment. The currently developed programs use the so-called progressive approach to efficiently obtain a constrained alignment of several sequences. However, the kernels of these programs, the dynamic programming algorithms for computing an optimal constrained alignment between two sequences, run in (gamman2) memory, where gamma is the number of the constraints and n is the maximum of the lengths of sequences. As a result, such a high memory requirement limits the overall programs to align short sequences only. RESULTS: We adopt the divide-and-conquer approach to design a memory-efficient algorithm for computing an optimal constrained alignment between two sequences, which greatly reduces the memory requirement of the dynamic programming approaches at the expense of a small constant factor in CPU time. This new algorithm consumes only O(alphan) space, where alpha is the sum of the lengths of constraints and usually alpha << n in practical applications. Based on this algorithm, we have developed a memory-efficient tool for multiple sequence alignment with constraints. AVAILABILITY: http://genome.life.nctu.edu.tw/MUSICME.

Algorithms↗