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PubMed2000

Network architectures and circuit function: testing alternative hypotheses in multifunctional networks.

Understanding how species-typical movement patterns are organized in the nervous system is a central question in neurobiology. The current explanations involve 'alphabet' models in which an individual neuron may participate in the circuit for several behaviors but each behavior is specified by a specific neural circuit. However, not all of the well-studied model systems fit the 'alphabet' model. The 'equation' model provides an alternative possibility, whereby a system of parallel motor neurons, each with a unique (but overlapping) field of innervation, can account for the production of stereotyped behavior patterns by variable circuits. That is, it is possible for such patterns to arise as emergent properties of a generalized neural network in the absence of feedback, a simple version of a 'self-organizing' behavioral system. Comparison of systems of identified neurons suggest that the 'alphabet' model may account for most observations where CPGs act to organize motor patterns. Other well-known model systems, involving architectures corresponding to feed-forward neural networks with a hidden layer, may organize patterned behavior in a manner consistent with the 'equation' model. Such architectures are found in the Mauthner and reticulospinal circuits, 'escape' locomotion in cockroaches, CNS control of Aplysia gill, and may also be important in the coordination of sensory information and motor systems in insect mushroom bodies and the vertebrate hippocampus. The hidden layer of such networks may serve as an 'internal representation' of the behavioral state and/or body position of the animal, allowing the animal to fine-tune oriented, or particularly context-sensitive, movements to the prevalent conditions. Experiments designed to distinguish between the two models in cases where they make mutually exclusive predictions provide an opportunity to elucidate the neural mechanisms by which behavior is organized in vivo and in vitro.

Animals↗
PubMed2000

Estimating hidden prevalence in Hansen's disease through diagnosis delay and grade of disability at time of diagnosis.

The objective of the present study was to propose a new method for the calculation of estimated hidden prevalence (EHP) in Hansen's disease (HD). We analyzed the records of 4142 HD patients diagnosed in the state of Rio Grande do Sul, Brazil, between 1970 and 1991. Out of these 4142 cases, 3291 patients had their grade of disability (GD) evaluated at the time of diagnosis and provided information about the time elapsed between the appearance of the symptoms and the moment when HD was identified by a physician (diagnosis delay, DD). Mean DD for the sample (in years) was 1.51 for disability grade 0, 2.14 for grade 1, 4.46 for grade 2, and 9.64 for grade 2. EHP was calculated taking into account only two strata of GD using the formula HP = [(NC-GD 0/1) x 2.0 + (CN-GD 2/3) x 5.0]/(CGE x PCP), where: NC-GD 0/1 = mean annual number of newly detected grades 0 or 1 cases; CN-GD 2/3 = mean annual number of newly detected grades 2 or 3 cases; CGE = proportion of newly detected cases with GD evaluated; PCP = proportion of the population covered by the state HD control program; 2.0 and 5.0 correspond to an approximation of the mean time in years of DD in each respective stratum of GD. Applying this model, we found an EHP of 529 cases which translates to an excess of 0.58 cases/10,000 population. We also conducted a multivariate analysis using a logistic regression model. This analysis revealed that, in addition to DD, other variables such as clinical form, age group, sex and mode of detection were independent risk factors for the presence of disabilities. We also found two significant effect modification factors: DD versus clinical form and DD versus age group. Taking these findings into consideration, a more complex model was used to calculate the EHP with 16 strata (defined by clinical form of the disease, age group, and GD from 0 to 3). An EHP of 502 cases (excess of 0.55/10,000) was obtained with this more complex model. This result differs only 5% from that of the simplified model. Therefore, we conclude that the simplified model is indicated to estimate hidden prevalence of HD in the field.

Adult↗
PubMed1996

On the dangers of adjusting the parameters values of mechanism-based mathematical models.

Mechanism-based mathematical models describe systems in terms of identifiable physical processes, and the parameters are assumed to have fundamental physical significance. Ideally, the parameter values are measured independent of the system being modeled, but these values are often adjusted to give the best fit of model predictions to experimental data. A systematic investigation of the effects of such parameter adjustment was conducted by developing a model system comprising a known reaction mechanism and known rate constants. Simulations of experiments were run, and then attempts were made to model the system under a variety of problematic, but realistic, conditions. (1) When one rate constant was seriously in error, adjustment of a different rate constant gave the greatest improvement in the model fit. (2) When a contaminant was present in the experiment, the effects could be hidden by the adjustment of the rate constants. (3) When an incorrect reaction mechanism was assumed, the error could be hidden by parameter adjustment if the concentrations of only one of the reacting species were considered or if an unweighted fit was used for the optimization. (4) Parameter values adjusted for one set of experimental conditions gave a poorer fit than did the unadjusted parameter values when attempting to model a new set of experimental condition (addition of an inhibitor). These results show the potential dangers of adjusting parameter values and the importance of measuring as many variables as possible in a complex system.

Animals↗
PubMed2004

Model-based fitting of single-channel dwell-time distributions.

Single-channel recordings provide unprecedented resolutions on kinetics of conformational changes of ion channels. Several approaches exist for analysis of the data, including the dwell-time histogram fittings and the full maximal-likelihood approaches that fit either the idealized dwell-time sequence or more ambitiously the noisy data directly using hidden Markov modeling. Although the full maximum likelihood approaches are statistically advantageous, they can be time-consuming especially for large datasets and/or complex models. We present here an alternative approach for model-based fitting of one-dimensional and two-dimensional dwell-time histograms. To improve performance, we derived analytical expressions for the derivatives of one-dimensional and two-dimensional dwell-time distribution functions and employed the gradient-based variable metric method for fast search of optimal rate constants in a model. The algorithm also has the ability to allow for a first-order correction for the effects of missed events, global fitting across different experimental conditions, and imposition of typical constraints on rate constants including microscopic reversibility. Numerical examples are presented to illustrate the performance of the algorithm, and comparisons with the full maximum likelihood fitting are discussed.

Algorithms↗
PubMed1995

A standardized-patient assessment of a continuing medical education program to improve physicians' cancer-control clinical skills.

BACKGROUND: Although continuing medical education (CME) has long been used to inform physicians and teach specific skills, its efficacy in many areas is not well established. This randomized controlled trial assessed the effects of differing educational techniques on the cancer-control skills of 57 physicians. METHOD: The CME program was part of the Cancer Prevention in Community Practice Project in Hanover, New Hampshire, and was implemented in 1988. The program used several methods in its presentation, including interactive small-group discussion, role playing, videotaped clinical encounters, lecture presentations, and trigger tapes. Measurements included cross-sectional observations made by unannounced standardized patients (SPs) who, one year after the CME program, assessed 25 physicians who had participated in the program and 32 physicians who had not. To measure consistency in the SPs' performances and accuracy in assessing the physicians' performances, most interactions were audiotaped using a hidden microphone. Pearson chi-square, Fisher exact two-tailed test, and kappa coefficients were used for analysis. RESULTS: Significantly higher ratings were found for the CME physicians in two areas: breast cancer risk-factor determination (determined maternal history: 80% versus 52%, p = .03; determined age at first period: 16% versus 0%, p = .02), and smoking cessation counseling (providing written material: 32% versus 9%, p = .03). The CME physicians were rated higher on all 19 study variables in the target areas of early detection of breast cancer and smoking cessation. The results show that the physicians' performance were better in those areas where the CME program had used performance-based learning, such as role playing or viewing and discussing a videotaped role-play encounter. CONCLUSION: The educational techniques that rehearsed or portrayed clinical applications seem to have increased the physicians' performances of cancer-control clinical activities. The standardized-patient instrument seems to be particularly useful in evaluating interventions that address specific skills training.

Adult↗
PubMed1996

Identification of surface-exposed linear B-cell epitopes of the nonfimbrial adhesin CS31A of Escherichia coli by using overlapping peptides and antipeptide antibodies.

As a first step toward the design of an epitope vaccine, by using the nonfimbrial adhesin CS31A of Escherichia coli as a carrier, a low-resolution topological and epitope map of the CS31A subunit was developed by using solid-phase peptide synthesis and polyclonal rabbit antibodies raised against both native and denatured proteins. Peptides constituting antigenic epitopes on the major subunit (ClpG) of the multimeric CS31A antigen were identified by examining the binding of the antibodies to 249 overlapping nonapeptides covering the amino acid sequence of ClpG. With antibodies raised against denatured ClpG subunit, seven major epitope regions, corresponding to residues 10 to 18, 45 to 58, 88 to 107, 148 to 172, 187 to 196, 212 to 219, and 235 to 241, were located. Most of the epitopes were hydrophilic and were located in variable regions, residing largely in loop regions at the boundaries of secondary structural elements of ClpG. In contrast, antibodies raised against native CS31A antigen reacted only with the peptide AVNPNA (positions 179 to 184), demonstrating that this peptide was the only linear B-cell epitope of the native protein. The different immunogenic profiles of native CS31A antigen and denatured ClpG indicated that the denaturation process resulted in marked conformational changes in the protein, which could expose epitopes hidden or absent in native CS31A. To identify the surface-exposed epitopes, nine peptides covering the dominant antigenic regions of ClpG were synthesized and used to prepare site-specific antibodies. Antipeptide antibodies were tested, in a competitive enzyme-linked immunosorbent assay (ELISA), for cross-reactivity with native CS31A and denatured ClpG subunit. Four of these antipeptide antibodies bound to the native protein in an accessibility ELISA, indicating that residues 44 to 56, 174 to 190, 185 to 199, and 235 to 249 were surface exposed on CS31A. These data indicate that an immunodominant surface-exposed linear epitope was present in the region from positions 179 to 184 of ClpG in the native CS31A antigen on intact bacterial cells and suggest that the four surface-exposed epitopes constitute potential sites for insertions or substitutions with heterologous peptides.

Adhesins, Bacterial↗
PubMed2026

Population heterogeneity in Helicobacter pylori PMSS1 shapes variable mouse infectivity: derivation of the homogeneous reference strain PMSS2.

UNLABELLED: Experimental infection models are widely used to investigate host-microbe interactions, often under the assumption that bacterial populations are genetically uniform. Here, we examined population heterogeneity in the widely used Helicobacter pylori strain PMSS1 and its relationship to variation in mouse infectivity. Single-colony isolates derived from PMSS1 displayed substantial differences in colonization efficiency, indicating that pre-existing variation within the population contributes to infection outcomes. To distinguish the effects of initial population heterogeneity from changes arising during infection, we analyzed PMSS2, a genetically homogeneous reference strain derived from PMSS1 that exhibited consistent infection phenotypes across independently isolated clones. Comparative genomic analysis of isolates recovered from infected mice revealed differences in the extent and patterns of genomic variation between PMSS1- and PMSS2-derived populations. These results demonstrate that variability in infection outcomes can arise from pre-existing heterogeneity within bacterial populations and highlight the importance of considering population composition when interpreting experimental infection studies. IMPORTANCE: Animal infection models are widely used to study how bacterial pathogens cause disease and change during infection. These studies often assume that the bacteria used for infection are genetically uniform. Our study shows that this assumption may not always hold. We found that a commonly used Helicobacter pylori strain contains hidden genetic diversity that leads to large differences in how well bacteria infect mice. By comparing this strain with a genetically uniform derivative, we show how differences present before infection can shape infection outcomes and influence the genetic changes observed during infection. Our findings highlight the importance of considering starting population diversity when interpreting experimental infection studies and are broadly relevant to research on microbial pathogenesis.

Helicobacter pylori↗
PubMed1992

Application of neural networks to the interpretation of laboratory data in cancer diagnosis.

Neural networks are a relatively new method of multivariate analysis. The purpose of this study was to investigate the ability of neural networks to differentiate benign from malignant breast conditions on the basis of the pattern of nine variables: patient age, total cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, albumin, the tumor marker CA15-3, and the Fossel index (measurement of methylene and methyl line-widths in proton NMR spectra). The laboratory analyses were made with blood plasma or serum specimens. The neural network was "trained" with 57 patients: 23 patients with breast malignancies and 34 patients with benign breast conditions. A neural network with nine input neurons, 15 hidden neurons, and two output neurons correctly classified all 57 patients. The ability of the network to predict the diagnoses of patients that it had no encountered in training was tested with a separate group (cross-validation group) of 20 patients. The network correctly predicted the diagnoses for 80% of these patients. For comparison we analyzed the same sets of 57 training patients and 20 cross-validation patients by quadratic discriminant function analysis. The quadratic discriminant function, calculated from the same 57 patients used to train the neural network, correctly classified 84% of the 57 patients, and correctly diagnosed 75% of the 20 cross-validation patients. The results suggest that neural networks are a potentially useful multivariate method for optimizing the diagnostic utility of laboratory data.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1985

Measuring dental students' ethical sensitivity.

This paper describes the development of stimulus materials and scoring procedures to measure an individual's ability to recognize the ethical issues often hidden within the dentist's professional problems. The importance of this ability is discussed as it relates to other abilities thought to be necessary conditions for ethical or moral behavior. Dental students completed the ethical sensitivity test and Rest's test of moral reasoning. The sensitivity test requires transcribing verbal responses to audio dramas, a technique that: (1) elicits sufficient data for making inferences about ethical sensitivity, (2) produces good interjudge agreement and interrater reliability, and (3) measures variability in student performance. Data indicate high internal consistency compared with previous efforts to measure components of sensitivity (e.g., empathy), acceptable test-retest reliability for a subsample. and the distinctiveness of sensitivity and reasoning scores. The results have broad application for the teaching of ethics and suggest new directions for the study of professional socialization.

Dentist-Patient Relations↗
PubMed2005

Patterns of polydrug use among ketamine injectors in New York City.

Polydrug use is an important public health issue since it has been linked to significant adverse health outcomes. Recently, club drugs, including ketamine and other drugs used in dance/rave scenes, have been identified as key substances in new types of polydrug using patterns. While seemingly a self-explanatory concept, "polydrug" use constitutes multiple drug using practices that may impact upon health risks. Ketamine, a club drug commonly administered intranasally among youth for its disassociative properties, has emerged as a drug increasingly prevalent among a new hidden population of injection drug users (IDUs). Using an ethno-epidemiological methodology, we interviewed 40 young (<25 years old) ketamine injectors in New York during 2000-2002 to describe the potential health risks associated with ketamine and polydrug use. Findings indicate that ketamine was typically injected or sniffed in the context of a polydrug using event. Marijuana, alcohol, PCP, and speed were among the most commonly used drugs during recent ketamine using events. Polydrug using events were often quite variable regarding the sequencing of drug use, the drug combinations consumed, the forms of the drug utilized, and the modes of administrating the drug combinations. Future research should be directed towards developing a more comprehensive description of the risks associated with combining ketamine with other drugs, such as drug overdoses, the transmission of bloodborne pathogens, such as HIV and HCV, the short- and long-term effects of drug combinations on cognitive functioning, and other unanticipated consequences associated with polydrug use.

Adolescent↗
PubMed2003

Computer-assisted detection of colonic polyps with CT colonography using neural networks and binary classification trees.

Detection of colonic polyps in CT colonography is problematic due to complexities of polyp shape and the surface of the normal colon. Published results indicate the feasibility of computer-aided detection of polyps but better classifiers are needed to improve specificity. In this paper we compare the classification results of two approaches: neural networks and recursive binary trees. As our starting point we collect surface geometry information from three-dimensional reconstruction of the colon, followed by a filter based on selected variables such as region density, Gaussian and average curvature and sphericity. The filter returns sites that are candidate polyps, based on earlier work using detection thresholds, to which the neural nets or the binary trees are applied. A data set of 39 polyps from 3 to 25 mm in size was used in our investigation. For both neural net and binary trees we use tenfold cross-validation to better estimate the true error rates. The backpropagation neural net with one hidden layer trained with Levenberg-Marquardt algorithm achieved the best results: sensitivity 90% and specificity 95% with 16 false positives per study.

Algorithms↗
PubMed1992

Hidden costs of mobile mammography: is subsidization necessary?

Two major impediments to an effective mammography program are inaccessibility and cost. This article itemizes the expenses associated with providing a mobile screening program accredited by the American College of Radiology (ACR) during a 3-year period. Mobile Diagnostics Inc. established a mobile mammography service in April 1987. A 36-ft (11-m) van is staffed by two registered technologists. The unit includes on-board processing and educational videotapes. Analysis of expenses for the years 1988, 1989, and 1990 does not include interpretation fees. A total of 3522 patients were examined in 1988, 4232 in 1989, and 5005 in 1990. Fixed operating expenses in 1988 were $70/examination and variable expenses were $13/examination, resulting in an average total cost per examination of $83. Fixed costs in 1989 were $63, variable costs were $15, and total costs were $78 per examination. Fixed costs in 1990 were $55, variable costs were $14, and total costs were $69 per examination. Many third parties, including Medicare, are contemplating a global screening fee in the $50-$60 range. An average payment of $55 would require examination of more than 6500 patients a year or 28 patients a day to break even. Our experience suggests that some form of subsidization may be necessary to sustain a mobile mammography service at those reimbursement levels.

Costs and Cost Analysis↗
PubMed2005

Phase-space analysis of acoustics fields and its application to waveguide.

A description of two-dimensional acoustic fields by means of a joint "space-wave number" representation is discussed. A function defined in the phase-space domain (x,y,k(x),k(y)) is associated with a signal which is a function of spatial coordinates (x,y). This paper presents two methods to realize it. The first is to associate with each point (x,y) of the wave field a two-dimensional wave number spectrum (k(x),k(y)), called local spectrum. The second is to process by other coordinates the wave field along an arbitrary direction, introduced in quantum mechanics for the study of classical billiards, and provided by the Birkhoff variables (s,cos phi). Phase-space diagrams are given by quadratic phase-space distributions. Simulations are presented for wave fields in a 2D planar waveguide for a pedagogical point of view with Gaussian beam or point-source excitation, and nonuniform waveguides as a sudden area expansion chamber and an open billiard with a single incoming mode at the entrance of each of them. In these problems, local spectrum and Birkhoff analysis are used in order to identify the structures hidden in the field. The result is the contribution of different wave vectors which contribute to the field value at the analysis point or at a certain section of the boundary, and show complicated structure of the acoustic field like whispering gallery or diffracted waves.

Journal Article↗
PubMed1991

Ultrastructural and cytoarchitectural features of lymphoreticular organs in the colon and rectum of adult BALB/c mice.

The structure and function of colonic mucosal lymphoid organs remain largely unexplored, especially in the rectum hidden within the pelvic vault. Two-month-old female BALB/c mice were anesthetized, and the entire colon was removed from cecum to anus. Distal colonic patches were then prepared for electron microscopy or were quick-frozen and sectioned for immunoperoxidase localization of B cells and T cell subsets. Aggregated lymphoid follicles were distributed irregularly along the entire colon with an average of 1.4 patches per centimeter of colon length. There were large collections of follicles opposite the ileocecal valve (cecal patches), variable numbers of patches throughout the colon, and at least one patch within 10 mm of the anus (rectal patch). Follicles were adjacent to branching crypts lined by epithelium infiltrated by lymphoid cells and containing few goblet cells. In electron micrographs, M cells were identified by their short, irregular microvilli; intraepithelial lymphoid cells; reduced lysosomal dense bodies; and an expanded tubulovesicular network. Small germinal centers were seen. Cytoarchitectural components of colonic lymphoid follicles and Peyer's patch follicles were remarkably similar, despite differences in surrounding mucosa and luminal microbial exposure. The presence of organized lymphoid tissue with M cells and germinal centers suggests that transepithelial particle transport and antigen recognition can take place in the rectum. Whether such tissue has the capacity for uptake of luminal microorganisms is of particular interest, not only because colonic follicles may be sites for local initiation of immune responses but also because they may be important entry points for systemic infection.

Animals↗
PubMed1992

Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats.

Rats were subjected to either right proximal middle cerebral artery (MCA) occlusion or sham operation, and examined for an extended period on a battery of tests designed to measure simple motor function, sensorimotor integration and cognitive function. Rats with MCA occlusion showed extensive neuronal loss in the dorsolateral striatum and variable neuron loss in the parietal, temporal and frontolateral neocortex. MCA occluded animals exhibited significant impairments in tests of postural reflex, visual and tactile forelimb placing, locomotor coordination, and a test of simultaneous bilateral tactile extinction. The reflex and sensorimotor function deficits recovered to pre-operative levels by Day 30 post-ischemia. Five weeks following surgery, rats were tested in 2 versions of the Morris water task. Rats with MCA occlusion demonstrated significant impairments in their ability to navigate to a hidden platform, but were not significantly impaired on the visible (cued) version of the task. This general pattern of transient sensorimotor and reflex deficits, but with more persistent cognitive impairments, is similar to that seen in humans following MCA infarcts.

Animals↗
PubMed2006

No evidence for the use of DIR, D-D fusions, chromosome 15 open reading frames or VH replacement in the peripheral repertoire was found on application of an improved algorithm, JointML, to 6329 human immunoglobulin H rearrangements.

Antibody diversity is created by imprecise joining of the variability (V), diversity (D) and joining (J) gene segments of the heavy and light chain loci. Analysis of rearrangements is complicated by somatic hypermutations and uncertainty concerning the sources of gene segments and the precise way in which they recombine. It has been suggested that D genes with irregular recombination signal sequences (DIR) and chromosome 15 open reading frames (OR15) can replace conventional D genes, that two D genes or inverted D genes may be used and that the repertoire can be further diversified by heavy chain V gene (VH) replacement. Safe conclusions require large, well-defined sequence samples and algorithms minimizing stochastic assignment of segments. Two computer programs were developed for analysis of heavy chain joints. JointHMM is a profile hidden Markow model, while JointML is a maximum-likelihood-based method taking the lengths of the joint and the mutational status of the VH gene into account. The programs were applied to a set of 6329 clonally unrelated rearrangements. A conventional D gene was found in 80% of unmutated sequences and 64% of mutated sequences, while D-gene assignment was kept below 5% in artificial (randomly permutated) rearrangements. No evidence for the use of DIR, OR15, multiple D genes or VH replacements was found, while inverted D genes were used in less than 1 per thousand of the sequences. JointML was shown to have a higher predictive performance for D-gene assignment in mutated and unmutated sequences than four other publicly available programs. An online version 1.0 of JointML is available at http://www.cbs.dtu.dk/services/VDJsolver.

Algorithms↗
PubMed1995

Design and evaluation of a flow phantom.

RATIONALE AND OBJECTIVES: We constructed a near-anatomically correct large-vessel phantom to perform repeatable flow dynamics research examinations by angiography, magnetic resonance (MR) angiography, and computed tomography (CT) angiography. METHODS: An internal carotid artery was constructed within a head phantom. The internal carotid artery branches into a middle and an anterior cerebral artery; the former trifurcates and ends in the superior sagittal sinus, and the latter ends in the inferior sagittal sinus. A transverse and sigmoid sinus drains the model. All four vessels connecting the arterial and venous vessels have variable flow-constricting ligatures placed around them. These ligatures are accessible on the skull surface. The skull cavity is filled with a silicone polymer that is isodense to brain on CT scans and isointense on most MR images. RESULTS: The flow in the phantom's vessels may be varied in a repeatable manner. Multiple scan sequences may be performed without the image degradation caused by patient motion. The homogeneity of the filler polymer allows visualization of flow-related artifacts that may be hidden by complex human anatomy. CONCLUSION: Preliminary images of each modality show promise for use of the phantom in imaging research on large-vessel flow dynamics.

Cerebral Angiography↗
PubMed1979

The ratio of body haematocrit to venous haematocrit in open heart surgery and estimation of the blood volume in the large and small vessels.

Double tracer blood volume technique revealed in open heart surgery patients a wide variability of Fcells-value in about 11 per cent of cases investigated, from the "normal" 0.91 value. The possible calculational error of blood volume measurements by single-isotopic--haematocrit methods in the normal or subnormal LVH-ranges point to the superiority of plasma volume determinations in the calculation of the total blood volume. The calculation of the volume of the blood-component actually not-labelled during single-isotopic--haematocrit procedures can be so highly inaccurate because of the hidden deviation of Fcells-value, that such misleading arithmetics has no real value and therefore should be omitted. Estimation of the large vessel and small vessel volumes and haematocrits in patients showed a rough 70 per cent---30 per cent distribution of the circulating blood volume between large and small vessels and an LVH tosmall vessel haematocrit ratio of 2:1 to 2:1.5. This offers a possibility to divide the circulating blood volume into a haemodynamically active (large vessel area) and a metabolically active (small vessel area) part, which can have important diagnostic and prognostic implications.

Blood Volume↗