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An endogenous superantigen in the rat gut lumen as a model to study the role of human protein-Fv.

Protein-Fv (pFv) is a human B superantigen which can bind the variable domain (VH) of the heavy chain of immunoglobulins (Igs) and enhance the effector functions of secretory antibodies in the gut lumen. This study describes a rat molecule related to pFv by a similar specificity to the human VH3 domain. Investigation of the content of different gut segments shows that the rat pFv is usually hidden by its binding to local Igs to form macromolecular complexes similar to the immune fortresses described in normal humans. Furthermore, the pFv level generally increases from the jejunum to the colon in parallel with the decreasing water dilution, and finally a discontinuous presence can occur along the digestive tract. Detection of this molecule in the fetus proves its non-microbial origin. Variations of the release of pFv, according to the breeding and to littermating, suggest the influence of external factors. This animal model allows the development of a study of the functions of pFv in vivo using a current laboratory species and has already provided evidence that the synthesis of this important molecule of the secretory immune system is regulated by environmental factors.

Animals↗

The application of an artificial neural network and pharmacokinetic simulations in the design of controlled-release dosage forms.

The objective of this work is to use an artificial neural network (ANN) and pharmacokinetic simulations in the design of controlled-release formulations with predictable in vitro and in vivo behavior. Seven formulation variables and three other tablet variables (moisture, particle size and hardness) for 22 tablet formulations of a model sympathomimetic drug were used as the ANN model input, and in vitro dissolution-time profiles at ten different sampling times were used as output. An ANN model was constructed by selecting the optimal number of iterations and model structure (the number of hidden layers and number of hidden layer nodes). The optimized ANN model was used for prediction of formulations based on two desired target in vitro dissolution-time profiles and two desired bioavailability profiles. For three of the four predicted formulations there was very good agreement between the ANN predicted and the observed in vitro and simulated in vivo properties. This work illustrates the potential for an artificial neural network, along with pharmacokinetic simulations, to assist in the development of complex dosage forms.

Biological Availability↗

Hotelling's T2 multivariate profiling for detecting differential expression in microarrays.

The most widely used statistical methods for finding differentially expressed genes (DEGs) are essentially univariate. In this study, we present a new T(2) statistic for analyzing microarray data. We implemented our method using a multiple forward search (MFS) algorithm that is designed for selecting a subset of feature vectors in high-dimensional microarray datasets. The proposed T2 statistic is a corollary to that originally developed for multivariate analyses and possesses two prominent statistical properties. First, our method takes into account multidimensional structure of microarray data. The utilization of the information hidden in gene interactions allows for finding genes whose differential expressions are not marginally detectable in univariate testing methods. Second, the statistic has a close relationship to discriminant analyses for classification of gene expression patterns. Our search algorithm sequentially maximizes gene expression difference/distance between two groups of genes. Including such a set of DEGs into initial feature variables may increase the power of classification rules. We validated our method by using a spike-in HGU95 dataset from Affymetrix. The utility of the new method was demonstrated by application to the analyses of gene expression patterns in human liver cancers and breast cancers. Extensive bioinformatics analyses and cross-validation of DEGs identified in the application datasets showed the significant advantages of our new algorithm.

Algorithms↗

An artificial neural network for predicting the incidence of radiation pneumonitis.

A method to predict radiation-induced pneumonitis (RP) using an artificial neural network (ANN) was investigated. A retrospective study was applied to the clinical data from 142 patients who have been treated with three-dimensional conformal radiotherapy for tumors in the thoracic region. These data were classified, based on their treatment outcome, into two patient clusters: with RP (Np=26) and without RP (Np= 116). An ANN was designed as a classifier. To perform the classification, a patient-treatment outcome with RP was assigned a value of 1, and a patient treatment outcome without RP was assigned a value of -1. The input of the ANN was limited to the patient lung dose-volume data only. A volume vector (VD) that describes patient lung subvolumes receiving more than a set of threshold doses was used as the network input variable. A zero value was used as the threshold to set the output value into -1 or 1. Three ANNs (ANN_1, ANN_2, and ANN_3), each with three layers, were trained to perform this classification function and to show the effect of training data on the ANN performance. Radial basis function was applied as the hidden layer neuron activation function and a sigmoid function was selected as the output layer neuron function. Backpropagation with a conjugate gradient algorithm was used to train the network. ANN_1 was trained and tested by using the leave-one-out method. ANN_2 was trained by randomly selecting 2/3 of the patient data, and tested by the remaining 1/3 of the data. ANN_3 was trained by a user selecting 2/3 of the patient data, and tested by the remaining 1/3 of the data. The predictive accuracy was verified as the area under a receiver operator characteristic (ROC) curve. The correct classification rates of 73% for RP cases, and 99% for non-RP cases were obtained from ANN_1. The corresponding correct classification rates of 44% for RP cases, and 89% for non-RP cases were obtained from ANN_2. From the ANN_3 test phase, the corresponding correct classification rates of 55% for RP cases, and 95% non-RP cases were achieved. The area under ROC curve was 0.85+/-0.05, 0.68+/-0.10, and 0.81+/-0.09 for ANN_1, ANN _2, and ANN_3, respectively, within its asymmetric 95% confidence interval. The sensitivity was 95%, 57%, and 71%, and the specificity was 94%, 88%, and 90% for ANN_1, ANN_2, and ANN_3, respectively. Preliminary results suggest that the ANN approach provides a useful tool for the prediction of radiation-induced lung pneumonitis, using the patient lung dose-volume information.

Algorithms↗

Additional faecal reservoirs or hidden constipation: a link between functional and organic bowel disease.

INTRODUCTION: The study was undertaken to test a hypothesis of coexistence and causality between abdominal and recto-anal symptoms and physical signs. MATERIAL AND METHODS: A random sample of 251 patients was drawn from 645 referred patients from 12th September 1988 to 19th January 1999. Nineteen selected symptoms were recorded; abdominal palpation and ano-rectoscopy were with special reference to identify faecal reservoirs. Barium enema was used to demonstrate colon pathology. After a combined prokinetic regimen, symptoms and signs were reassessed. The study was observational and factor analysis was used to explore the data together with testing after cross tabulations. RESULTS: One hundred and fifty-nine patients were female (63%); neither bloating (64%), abdominal pressure (60%) and pain (26%) nor right iliac fossa tenderness (58%) and faecal mass (42%) and meteorism (33%) were related to age. Patients with additional diverticula and haemorrhoids were significantly older than patients without these lesions. Bloating was found together with a reservoir of faeces in ano-rectum in 62% of patients and 51% had haemorrhoids grade 2 or more and 50% had bloating, faeces in rectum and a right sided palpable abdominal mass (additional faecal reservoir). Among 17 factors explaining 68% of the variance in 45 variables, frequent abdominal and ano-rectal symptoms and physical signs showed substantial correlations to nine factors, indicating that they belong to the same underlying condition. A malignant tumour was found in four patients, polyps in 20 patients, and in 105 patients left sided diverticula were present. After a prokinetic regimen was conducted the dominant symptoms and signs were reduced significantly. CONCLUSIONS: Collectively, the data showed significant correlations between abdominal and anorectal symptoms and signs. Additional faecal reservoirs were demonstrated in the right colon and the rectum, irrespective of defaecation daily. This hidden constipation (faecal retention) gives rise to bloating, pain and right iliac fossa tenderness and mass, and defaecation disorders (functional faecal retention) which was confirmed by a significant reduction in symptoms and physical signs after a propulsive regimen. Also, over the years, the state of hidden constipation seems to bear a cumulative risk of developing organic diseases like diverticula, polyps, haemorrhoids and malignancy.

Adolescent↗

Nutrition guidance by primary-care physicians: LISREL analysis improves understanding.

BACKGROUND: When determinants of nutrition guidance practices for primary care physicians (PCPs) are identified, the key question remains: what is the mechanism of action? This knowledge is essential in order to understand how PCPs practice nutrition guidance. METHODS: Mail questionnaires (result of focus-group discussions and in-depth interviews) were sent to a nationwide random sample of 1,000 PCPs in the Netherlands, who had been in practice for between 5 and 15 years (633 respondents). The mechanism of action of determinants of nutrition guidance practices of PCPs was identified by means of linear structural relationship analysis (LISREL) using a postulated model. RESULTS: The postulated model on the mechanism of action was confirmed. The model demonstrates that nutrition guidance practices of PCPs are directly and significantly based on a few predisposing factors; driving forces and perceived barriers may act as significant intermediary variables. The predisposing factors, driving forces, and perceived barriers were identified. CONCLUSION: Policies to improve nutrition guidance practices of PCPs may, in the future, benefit from a LISREL model analysis of determinants of these practices to become more effective. Using multiple regression analysis to ascertain the determinants of these practices could result in missing important predisposing factors and "hidden" intermediary factors and lead, therefore, to an incomplete understanding of the mechanism of action.

Adult↗

Diagnosis and initial management of laryngotracheal injuries associated with facial fractures.

INTRODUCTION: Laryngotracheal injuries are uncommon with an estimated incidence of 1 per thousand (1-6 patients per 15000-42500 trauma victims). They may be associated with fractures of the facial skeleton. Their symptoms are variable ranging from obvious airway obstruction to minor or almost missing symptoms. Early diagnosis and proper initial management may sometimes be difficult or delayed. PATIENTS: Three patients with maxillofacial fractures and concomitant laryngotracheal injuries are presented. The diagnostic procedures used and the management of these injuries are reported. DISCUSSION AND CONCLUSION: Due to their low incidence and their hidden nature laryngotracheal injuries may pose diagnostic problems, especially in polytraumatized or intubated patients. Subcutaneous emphysema is the chief clinical sign. Fibreoptic endoscopy is the most important and informative diagnostic examination. Radiographic evaluation by CT scan provides additional information about the extent of the injury and the indication for surgery. A coordinated team approach is necessary for proper management of these injuries.

Adult↗

Modeling markers of disease progression by a hidden Markov process: application to characterizing CD4 cell decline.

Multistate models have been increasingly used to model natural history of many diseases as well as to characterize the follow-up of patients under varied clinical protocols. This modeling allows describing disease evolution, estimating the transition rates, and evaluating the therapy effects on progression. In many cases, the staging is defined on the basis of a discretization of the values of continuous markers (CD4 cell count for HIV application) that are subject to great variability due mainly to short time-scale noise (intraindividual variability) and measurement errors. This led us to formulate a Bayesian hierarchical model where, at a first level, a disease process (Markov model on the true states, which are unobserved) is introduced and, at a second level, the measurement process making the link between the true states and the observed marker values is modeled. This hierarchical formulation allows joint estimation of the parameters of both processes. Estimation of the quantities of interest is performed via stochastic algorithms of the family of Markov chain Monte Carlo methods. The flexibility of this approach is illustrated by analyzing the CD4 data on HIV patients of the Concorde clinical trial.

Algorithms↗

Optimal control by least squares support vector machines.

Support vector machines have been very successful in pattern recognition and function estimation problems. In this paper we introduce the use of least squares support vector machines (LS-SVM's) for the optimal control of nonlinear systems. Linear and neural full static state feedback controllers are considered. The problem is formulated in such a way that it incorporates the N-stage optimal control problem as well as a least squares support vector machine approach for mapping the state space into the action space. The solution is characterized by a set of nonlinear equations. An alternative formulation as a constrained nonlinear optimization problem in less unknowns is given, together with a method for imposing local stability in the LS-SVM control scheme. The results are discussed for support vector machines with radial basis function kernel. Advantages of LS-SVM control are that no number of hidden units has to be determined for the controller and that no centers have to be specified for the Gaussian kernels when applying Mercer's condition. The curse of dimensionality is avoided in comparison with defining a regular grid for the centers in classical radial basis function networks. This is at the expense of taking the trajectory of state variables as additional unknowns in the optimization problem, while classical neural network approaches typically lead to parametric optimization problems. In the SVM methodology the number of unknowns equals the number of training data, while in the primal space the number of unknowns can be infinite dimensional. The method is illustrated both on stabilization and tracking problems including examples on swinging up an inverted pendulum with local stabilization at the endpoint and a tracking problem for a ball and beam system.

Feedback↗

Optimisation of the monitoring strategy of macroinvertebrate communities in the river Dender, in relation to the EU Water Framework Directive.

The Dender basin in Flanders (Belgium) was used as a case study to implement the European Union (EU) Water Framework Directive. During the last 5 years, ample research on pollution loads and ecological water quality has been done on the Dender River. In addition to biological sampling of macroinvertebrates and fish, automated measurement stations were also used to investigate the spatial-temporal variability of the physical-chemical water quality. This research revealed that the pollution of the Dender River is highly variable. The high nutrient loads result in severe algae blooms during summer, leading to very complex diurnal processes. In this paper, the monitoring strategy for the assessment of the biological water quality in the Dender basin has been reviewed in relation to the EU Water Framework Directive. For this, seasonal macroinvertebrate data were collected and assessed. General trends and hidden structures in these data were analysed by means of classification trees, using different inputs (seasons, river types, and subbasins). Validation of the results was obtained by applying statistical methods. Analysis about the presence and abundance of the macroinvertebrates revealed that there is a distinct difference between the biological water quality in the Dender stem river and its tributaries. There are also seasonal differences between the macroinvertebrate communities when the Dender and its tributaries are examined separately. An optimised monitoring strategy is proposed based on these results and the EU Water Framework Directive. This includes two monitoring campaigns in summer and winter every 3 years. Furthermore, a cyclic monitoring scheme was developed to minimise sampling efforts.

Animals↗

Population genetic structure of and inbreeding in an insular cattle breed, the Jersey, and its implications for genetic resource management.

The Jersey is a ubiquitous and successful breed of cattle that originates from the UK Channel Island of Jersey. While the breed has been exported extensively, no imports have taken place to the island since 1789, leading to a concern regarding possible losses of genetic diversity and increased inbreeding. We have conducted the first large-scale genetic analysis of the Jersey cattle using only samples from the island. A total of 223 cattle from all parishes except one were genotyped for 12 microsatellite loci. The average number of alleles per locus and expected heterozygosity were found to be comparatively high (n(A)=4, H(e)=0.64) with respect to that observed in a number of continental breeds. Only breeds that have been upgraded and are therefore the result of admixture are clearly more variable than the Jersey. We also found a significant but limited amount of genetic differentiation between parishes (F(st)=0.013), or even between farms (F(st)=0.035) despite an apparent lack of movement. This is confirmed by the application of two recent statistical methods. A Bayesian partition analysis shows that the most probable value of K, the number of possible hidden partitions, is 1 (P approximately 0.98). K=2 has a much lower probability (P approximately 0.02) while other values are essentially zero. Similarly, we were able to show that there was no support for departure from panmixia other than due to population structure, and thus that there is sufficient background gene flow across the island to overcome local drift. Overall, it appears that the current level of genetic diversity and its distribution within the island means it is unnecessary to import unrelated genetic material to the island for management purposes.

Alleles↗

In vitro study on passive fit in implant-supported 5-unit fixed partial dentures.

PURPOSE: Fabrication and retention methods have an influence on the passivity of superstructure fit. The objective of the study was to quantify the strain development of various cemented and screw-retained fixed partial dentures (FPDs). MATERIALS AND METHODS: Forty samples of 4 different types of FPDs (10 of each type) were investigated. Each sample had 3 ITI implant abutments and 2 pontics. The 3 implants were anchored in a straight-line configuration in a measurement model simulating a real-life patient situation. Strain gauges were mounted close to the implants and on the pontics. The developing strains were recorded during cement setting and screw fixation. For statistical analysis, multivariate 2-sample tests were performed, with the level of significance set at P = .1. RESULTS: All FPDs investigated revealed a considerable amount of strain, with no significant difference between cement and screw retention. Furthermore, no significant difference was found between the conventional fabrication modes for screw-retained FPDs. The lowest strains were found in prostheses that were intraorally bonded onto gold cylinders. DISCUSSION: Because bonding of the superstructure in the oral cavity may compensate for impression and laboratory variables, restorations with the best possible passive fit can result from this retention technique. Before this technique can be recommended, the long-term stability of the adhesive layer should be investigated. CONCLUSIONS: As an absolute passive fit of superstructures is not possible using conventional clinical and laboratory procedures, and as clinical fit-evaluation methods often do not detect "hidden" inaccuracies, the more sensitive strain-gauge technique should be utilized for an objective accuracy test. Reference strain values from implant-supported prostheses that have served without complications could help define a "biologically acceptable fit.

Aged↗

Cross-cultural aspects of the somatization trait.

Studies using a variety of diagnostic rating scales have identified much higher levels of somatic symptoms in Hispanic psychiatric patients, particularly those with a diagnosis of schizophrenia or depression, than in their Anglo counterparts. However, this cultural difference cannot be generally demonstrated by using DSM-III somatoform disorders criteria. Many patients with "unfounded" somatic symptoms have another DSM-III primary diagnosis that is often assumed to cause or explain the somatic symptoms. In addition, the true prevalence of unfounded somatic symptoms is hidden because of the strict criteria required for a DSM-III primary diagnosis of somatization disorder. The author believes a more inclusive notion of somatization should be developed that would substantiate the presence of this trait among different populations and, if operationalized, would facilitate research on this important phenomenon. This is relevant not only because of the cross-cultural variability of somatization traits but also because they may become a salient feature of the primary syndrome and determine the use of clinical services. He proposes a new operational definition of somatization that encompasses the trait concept.

Cross-Cultural Comparison↗

Dynamic monitoring system for full-scale wastewater treatment plants.

This paper proposes a new process monitoring method using dynamic independent component analysis (ICA), ICA is a recently developed technique to extract the hidden factors that underlie sets of measurements, whereas principal component analysis (PCA) is a dimensionality reduction technique in terms of capturing the variance of the data. Its goal is to find a linear representation of non-Gaussian data so that the components are statistically independent. PCA aims at finding PCs that are uncorrelated and are linear combinations of the observed variables, while ICA is designed to separate the ICs that are independent and constitute the observed variables. The dynamic ICA monitoring method is applying ICA to the augmenting matrix with time-lagged variables. The dynamic monitoring method was applied to detect and monitor disturbances in a full-scale biological wastewater treatment (WWTP), which is characterized by a variety of dynamic and non-Gaussian characteristics. The dynamic ICA method showed more powerful monitoring performance on a WWTP application than the dynamic PCA method since it can extract source signals which are independent of time and cross-correlation of variables.

Algorithms↗

Firing patterns of pallidal cells in parkinsonian patients correlate with their pre-pallidotomy clinical scores.

It is unclear how the disordered activity of cells in the basal ganglia contributes to the symptoms of Parkinson's disease (PD). We recorded from single neurons extracellularly in 3 regions of the globus pallidus (GPe, GPie and GPii) in patients undergoing pallidotomy for PD. Movement-related cell firing patterns, analysed using hidden Markov models, were significantly correlated with patients' preoperative clinical scores (off drugs). Responses of cells in GPii correlated best with the scores for specific motor tasks, rather than general ones related to activities of daily living, but the reverse was true for responses from GPe. In both GPii and GPe, a higher score (i.e. greater parkinsonian severity) was associated with greater variability in cell firing rather than an increase in firing rate itself.

Activities of Daily Living↗

Pattern recognition and associative memory as dynamical processes in a synergetic system. I. Translational invariance, selective attention, and decomposition of scenes.

We consider a model for associative memory and pattern recognition which was devised by Haken (1987b). This model treats the activity of the neurons as continuous variables and exploits an analogy with pattern formation in synergetic systems. The capability of such a system to act as associative memory is demonstrated by the reconstruction of faces which are partially offered to the system, and which are restored by the corresponding dynamical process. We demonstrate how this model can be cast into a form which is translation invariant and how partially hidden faces in scenes can be recognized by means of the control of attention parameters of specific patterns.

Cybernetics↗

Human immunoglobulin variable region genes: V kappa polymorphisms suggest variation in V-gene repertoires.

The present study characterizes four potentially informative polymorphic bands of 5.2, 2.3, 1.9, and 1.2 kb, detected by Southern blot hybridization of Eco RI digests of human DNA using HK101/80 (an immunoglobulin V kappa I probe). These restriction fragment length polymorphisms (RFLP) show Mendelian segregation and they are linked to each other and to Km(1), the allotypic marker on the kappa constant region. There is strong linkage disequilibrium between the 2.3 and 1.2 kb polymorphisms. A 0.7 kb Pst I polymorphic band and a 2.9 kb Sac I polymorphic band were also identified; the latter may reflect a region of tandem repeats in the V kappa region. No bands representing the alternative forms of any of the polymorphic restriction sites were identified. This implies either that genes are missing from the V kappa repertoire or that such bands are hidden because of comigration of fragments due to conservation of restriction sites. Evidence for comigration of fragments was obtained from independent V kappa clones and suggests that dark bands on Southern blots of Pst I digests must often represent several superimposed genes which have conserved restriction sites. The demonstration of RFLP within the V kappa region provides circumstantial evidence for polymorphic variation in the repertoire of V kappa structural genes. The RFLP reported here should be useful as genetic markers in future studies on the immune response and disease susceptibility in man.

Genes↗

The effect of visual targeting on ground reaction force and temporospatial parameters of gait.

BACKGROUND: Visual targeting has been cited as a confounding factor for gait analysis in which measures of ground reaction force and plantar pressure are obtained. OBJECTIVE: To investigate the effect of visual targeting on temporospatial and kinetic aspects of gait when small targets, such as pressure platforms, have to be used. DESIGN: A within subjects repeated measure design was used to measure step parameters and ground reaction forces of 11 healthy volunteers. METHODS: Subjects were required to walk over a 10 m walkway at a self-selected pace. A 30x24 cm(2) target area was superimposed over a hidden Kistler force plate (60x90 cm(2)) mounted at the midpoint of the walkway. Step parameters and ground reaction forces were measured with and without the presence of the target. Ground reaction forces were analysed within the time-domain. RESULTS: Subjects used visual control strategies when approaching targets of similar dimensions to a pressure platform. These strategies were manifested by an increase in the variability of the step length onto the target (P<0.05). However, targeting was observed to have no affect on the magnitude, timing and variability of ground reaction forces when measured within the time-domain and averaged over five trials (P>0.05). CONCLUSIONS: Visual control strategies employed while walking toward a target area have no affect on ground reaction force parameters when measured within the time-domain. RELEVANCE: These findings demonstrate that targeting a 30x24 cm(2) target does not affect ground reaction force parameters, when a gait protocol that fine-tunes the start position is employed. The findings are relevant to gait research in which small force or pressure platforms are used to assess gait kinetics.

Adult↗