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PubMedDate not supplied

The case for child development as a determinant of health.

The complex relationship between life course and social/economic-psychosocial conditions in a given society has a powerful determining effect on human health. The socioeconomic gradient emerges from a complex mixture of psychosocial and material influences operating at various levels of social aggregation and, also, a series of biological responses whose character and significance vary over the life course. Biological embedding and the "latency" and "pathways" model incorporate the notion of a critical period in development; the pathways model emphasizes the cumulative effect of life events and the ongoing importance of social/economic-psychosocial conditions throughout the life cycle. The models, although conceptually complementary, result in ideological conflict and lend themselves to different policy directions.

Child↗
PubMed2004

Pathway logic modeling of protein functional domains in signal transduction.

Protein functional domains (PFDs) are consensus sequences within signaling molecules that recognize and assemble other signaling components into complexes. Here we describe the application of an approach called Pathway Logic to the symbolic modeling signal transduction networks at the level of PFDs. These models are developed using Maude, a symbolic language founded on rewriting logic. Models can be queried (analyzed) using the execution, search and model-checking tools of Maude. We show how signal transduction processes can be modeled using Maude at very different levels of abstraction involving either an overall state of a protein or its PFDs and their interactions. The key insight for the latter is our algebraic representation of binding interactions as a graph.

Computational Biology↗
PubMed1998

Temporal architecture of violent incidents.

Five hundred five reports of violent incidents in British pubs and bars were studied by using logical pathway modeling to provide information on the processes underlying work-related violence. Logical pathway modeling is innovative in examining and mapping sequences in real incidents at a population level. The data reveal the most common pathway to be misbehavior by customers, intervention by staff (before any physically violent act), physical attack on staff, and injury to staff. The data also highlight the likelihood of further action after assailants have exited and identify stages in incidents at which most staff and customer injuries and damage to property occur. Results assist in the design of strategies to reduce the risk from future violence, particularly by training staff to recognize and to handle potentially violent situations and to maintain vigilance and security following problem incidents.

Accidents, Occupational↗
PubMed2002

Modeling the pathways of energy balance using the N1E-115 murine neuroblastoma cell line.

A good in vitro model within which to investigate molecular interactions between feeding relevant neuropeptide systems has been lacking. Consequently, we began using reverse transcriptase-polymerase chain reaction (RT-PCR) to screen various neuronal cell lines for the presence of feeding relevant neuropeptides and receptors. N1E-115 murine neuroblastoma cells have emerged as an attractive candidate for further analysis because they contain mRNA for a variety of key systems implicated in the regulation of energy homeostasis.

Agouti-Related Protein↗
PubMedDate not supplied

Differentiation of VEP intermodulation and second harmonic components by dichoptic, monocular, and binocular stimulation.

Modulation by two temporal frequencies differentiates visual processing at the fundamentals (1Fs), second harmonics (2Fs), and second-order intermodulation components (IMCs), the latter created neurally as the sum or difference of the two modulation frequencies. Steady-state VEPs were recorded while stereo-normal adults viewed luminance or grating stimuli modulated by up to three temporal frequencies under dichoptic, monocular, or ordinary (binocular) viewing conditions arranged using liquid crystal light shutters. In Experiment 1, modulation of luminance by a single temporal frequency produced strong 1F and 2F VEP components, but modulation of gratings produced only 2Fs. Modulation by two temporal frequencies resulted in IMCs, often in the absence of evoked activity in the EEG at the 1Fs. IMCs were generally larger during pattern as compared to luminance modulation. Amplitudes of 1Fs and IMCs were smaller, but 2Fs were larger, during dichoptic as compared to ordinary viewing. Although the 2F to a single modulation presented to one eye was not reduced when a second frequency was added to the opposite eye, monocular IMCs were diminished when a frequency was added to the opposite eye. We conclude that 2Fs and IMCs are associated with different neural substrates. Results are consistent with a two pathway model with one pathway having a nonlinear filter prior to binocular combination, the other pathway having a nonlinearity following binocular linear summation. Implications of these data for binocular function are discussed.

Adult↗
PubMed2004

In vivo metabolism of LDL subfractions in patients with heterozygous FH on statin therapy: rebound analysis of LDL subfractions after LDL apheresis.

LDL can be subfractionated into buoyant (1.020-1.029 g/ml(-1)), intermediate (1.030-1.040 g/ml(-1)), and dense (1.041-1.066 g/ml(-1)) LDLs. We studied the rebound of these LDL-subfractions after LDL apheresis in seven patients with heterozygous familial hypercholesterolemia (FH) regularly treated by apheresis (58 +/- 9 years, LDL-cholesterol = 342 +/- 87 mg/dl(-1), triglycerides = 109 +/- 39 mg/dl(-1)) and high-dose statins. Apolipoprotein B (apoB) concentrations were measured in LDL subfractions immediately after and on days 1, 2, 3, 5, and 7 after apheresis. Compartmental models were developed to test three hypotheses: 1) that dense LDLs are derived from the delipidation of buoyant and intermediate LDLs (model A); 2) that dense LDLs are generated directly from LDL-precursors (model B); or 3) that a model combining both pathways (model C) is necessary to describe the metabolism of dense LDLs. In all models, it was assumed that apoB production and fractional catabolic rate (FCR) did not change with apheresis. Apheresis decreased buoyant, intermediate, and dense LDL-apoB by 60 +/- 12%, 67 +/- 5%, and 69 +/- 11%, respectively. Models B and C, but not model A, described the rebound data. The model with the greatest biological plausibility (model C) was used to estimate metabolic parameters. FCR was 1.05 +/- 0.86 d(-1), 0.48 +/- 0.11 d(-1), and 0.69 +/- 0.24 d(-1) for buoyant, intermediate, and dense LDLs, respectively. Dense LDL production was 17.3 +/- 0.2 mg/kg(-1)/d(-1), 58% of which was derived directly from LDL precursors (VLDL, IDL, or direct secretion), while 42% was derived from buoyant and intermediate LDLs. Thus, our data indicate that in statin-treated patients with heterozygous FH dense LDLs originate from two sources. Whether this is also valid in other metabolic situations (with predominant small, dense LDLs) remains to be determined.

Anticholesteremic Agents↗
PubMed1997

On the independence of chromatic and achromatic stereopsis mechanisms.

The extent to which the processing of stereoscopic depth information can take place separately in colour-contrast-sensitive and luminance-contrast-sensitive mechanisms has been investigated. Contrast thresholds for stereoscopic depth identification (front/back) were measured using 0.5 c/deg Gabor patches. The stimuli possessed different amounts of colour and luminance contrast ranging from isoluminance (red/green) to isochrominance (yellow/black) through intermediate values. Two models for combining chromatic and achromatic stereopsis information were tested. The first (single-pathway) model assumed colour and luminance contrast summation within a single luminance-contrast-sensitive mechanism before stereoscopic judgement. The second (dual-pathway) model assumed probability summation between independent chromatic and achromatic stereopsis mechanisms. The latter model provided the better fit to the data. In providing evidence in favour of an independent chromatic stereopsis mechanism, it was shown that luminance artifacts were unlikely to be the cause of maintained stereopsis at isoluminance. The possible neural substrates of chromatic stereopsis are discussed.

Color Perception↗
PubMed1997

Pulmonary lobectomy patient care pathway: a model to control cost and maintain quality.

BACKGROUND: Cost containment is a reality in thoracic surgery. Patient care pathways have proved effective in cardiac surgery to reduce length of stay and control costs. METHODS: A multidisciplinary team formulated a pulmonary lobectomy patient care pathway to standardize care, reduce length of stay and costs, and maintain quality. Variance codes were developed to collect data prospectively on reasons for prolonged stay. A patient satisfaction survey was instituted to learn patients' responses to their hospitalization. RESULTS: One hundred forty-seven patients underwent lobectomy in 1995 before institution of the pathway with a mean length of stay of 10.6 days and a mean cost of $16,063. The lobectomy pathway was instituted at the beginning of 1996. One hundred thirty patients underwent lobectomy in 1996 with a mean length of stay of 7.5 days (p = 0.03) and a mean cost of $14,792 (p = 0.47). Readmission and mortality rates were unchanged. Eighty-eight of 130 patients (68%) were able to be discharged by the target length of stay of 7 days in 1996 as opposed to 76 of 147 patients (52%) in 1995. The most common reason for delayed discharge was inadequate pain control. The majority of patients felt prepared for discharge by the seventh postoperative day (70 of 96 patients, 73%). CONCLUSIONS: The institution of a lobectomy patient care pathway appeared to reduce length of stay and costs. The pathway provided a framework to begin systematic quality control measures to enhance patient care.

Cost Control↗
PubMed2003

Association chain graphs: modelling etiological pathways.

Multiple time-dynamic and interrelated risk factors are usually involved in the complex etiology of disorders. This paper presents a strategy to explore and display visually the relative importance of different association pathways for the onset of disorder over time. The approach is based on graphical chain models, a tool that is powerful but still under-utilized in most fields. Usually, the results of these models are displayed using directed acyclic graphs (DAGs). These draw an edge between a pair of variables whenever the assumption of conditional independence given variables on an earlier or equal temporal footing is violated to a statistically significant extent. In the present paper, the graphs are modified in that confidence intervals for the strengths of associations (statistical main effects) are visualized. These new graphs are called association chain graphs (ACGs). Statistical interactions cause 'edges' between the respective variables within the DAG framework (because the assumption of conditional independence is violated). In contrast they are represented as separate graphs within the subsample where the different association chains may work within the ACG framework. With this new type of graph, more specific information can be displayed whenever the data are essentially described only with statistical main- and two-way interaction effects.

Alcoholism↗
PubMed1978

Diffusion of water in cat ventricular myocardium.

The rates of diffusion of tritiated water (THO) and [14C]sucrose across cat right ventricular myocardium were studied at 23 degrees C in an Ussing-type diffusion cell, recording the time-course of increase in concentration of tracer in one chamber over 4--6 h after adding tracers to the other. Sucrose data were fitted with a model for a homogeneous sheet of uneven thickness in which the tissue is considered to be an array of parallel independent pathways (parallel pathway model) of varying length. The volume of the sucrose diffusion space, presumably a wholly extracellular pathway, was 23% of the tissue or 27.4 +/-1.7% (mean +/- SEM; n=11) of the tissue water. The effective intramyocardial sucrose diffusion coefficient, D8, was 1.51 +/- 0.19 X 10(-6)cm2.s-1 (n=11). Combining these data with earlier data, D8 was 22.6 +/- 1.1% (n=95) of the free diffusion coefficient in aqueous solution D degrees 8. The parallel pathway model and a dead-end pore model, which might have accounted for intracellular sequestration of water, gave estimates of DW/D degrees W (observed/free) of 15%. Because hindrance to water diffusion must be less than for sucrose (where D8/D degrees 8=22.6%), this showed the inadequacy of these models to account simultaneously for the diffusional resistance and the tissue water content. The third or cell-matrix model, a heterogeneous system of permeable cells arrayed in the extracellular matrix, allowed logical and geometrically reasonable interpretations of the steady-state data and implied estimates of DW in the cellular and extracellular fluid of approximately 25% of the aqueous diffusion coefficient.

Animals↗
PubMed1992

Sawtooth contrast sensitivity: effects of mean illuminance and low temporal frequencies.

Temporal contrast sensitivity was measured for mirror-image sawtooth (rapid-on and rapid-off) and sine waveforms for a 1.8 deg foveal target. In one experiment, contrast sensitivity was measured for 2-26 Hz stimuli at target mean illuminance levels of 5-1260 td. At 5 td, contrast sensitivity functions for sawtooth and sine waveforms, expressed in terms of the Fourier fundamental amplitude, are equivalent. At higher light levels, sawtooth sensitivity increasingly exceeds sine sensitivity and rapid-off (decremental) sawtooths show progressively greater sensitivity than rapid-on (incremental) sawtooths. This pattern of results was obtained for two color-normal observers and for a deuteranopic observer. In a second experiment, sawtooth and sine sensitivity was tested at 500 td with an extended low-frequency range, to 0.5 Hz. Rapid-off and rapid-on sensitivities declined only slightly at low temporal frequencies in contrast with sine sensitivity. To interpret our data, we evaluate two single-pathway models (last-stage asymmetric detector and compressive response-intensity non-linearity) and a dual-pathway model in which incremental and decremental waveforms are detected by separate ON and OFF visual mechanisms.

Adaptation, Ocular↗
PubMed2003

Convergent pathobiologic model of Parkinson's disease.

The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age-related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the identification of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.

Animals↗
PubMed2002

A theoretical analysis of low-frequency sonophoresis: dependence of transdermal transport pathways on frequency and energy density.

PURPOSE: Application of low-frequency ultrasound has been shown to increase skin permeability, thereby facilitating delivery of macromolecules (low-frequency sonophoresis). In this study, we seek to determine the dependence of transport pathways during low-frequency sonophoresis on ultrasound parameters. METHODS: Pig skin is exposed to low-frequency ultrasound over a range of frequencies to achieve different skin resistivities. The porous pathway model is used to study the dependence of average pore size, porosity, and tortuosity on ultrasound parameters. Imaging experiments are also carried out to visualize the transport pathways created by ultrasound. RESULTS: The data show that the average pore size, determined from the porous pathway model, does not depend on application frequency. Both in the presence and absence of ultrasound the average pore size determined from mannitol delivery is the same (28 +/- 12 A). With the application of ultrasound the skin porosity could be increased by up to 1700-fold. The effect of ultrasound on skin is heterogeneous thereby creating localized transport pathways (LTP). The porosity of these transport pathways is of the same order of magnitude as that of the dermis. CONCLUSIONS: With this study it is shown that low-frequency ultrasound increases skin permeability by increasing skin porosity rather than by increasing the size of the pores that are responsible for permeant delivery.

Administration, Cutaneous↗
PubMed1987

Activation of multiple oncogene pathways: a model for experimental carcinogenesis.

Evidence from experimental animal tumor models suggests that in many instances, the identity and mechanism of activation of cellular oncogenes is a function of both carcinogen and tissue specificity. In addition, the activation of no single oncogene has yet been found to be either sufficient or necessary for tumorigenesis in any particular experimental system. A hypothesis to account for these and other molecular and biological observations of experimental tumorigenesis has been developed. The hypothesis is based on the premise that multiple tissue specific groups or pathways of oncogenes exist in each cell, and that activation of all the oncogenes in any of these alternative pathways leads to transformation. It is assumed that each oncogene (which may be a member of one or more pathways) has a spontaneous and a carcinogen specific probability of activation. The latter value will vary from carcinogen to carcinogen. By modelling the spontaneous and carcinogen specific probabilities of activation of each gene, the number and identity of genes in each pathway, and the number of pathways in a particular cell type, it is possible to calculate the relative potency of carcinogens, the percentage of tumors containing each activated oncogene, the dose-response relationship, and other parameters. Use of this hypothetical model gives results consistent with experimental observations on oncogene activation in carcinogen-induced animal tumors.

Animals↗
PubMed1994

NASPE Young Investigator Awardee-1993. Computer model of the atrioventricular node predicts reentrant arrhythmias.

INTRODUCTION: Following atrial premature beats, the AV node may exhibit sustained reentrant tachyarrhythmias, isolated echo beats, or discontinuities in the recovery curve (the plot of conduction time versus atrial cycle length). A computer model was used to examine the hypothesis that spatial variation of AV nodal passive electrical resistance may account for these phenomena. METHODS AND RESULTS: A computer model of a rectangular lattice of electrotonically linked elements whose ionic kinetics simulated nodal ionic flux was developed. The model showed that there exists a resistance value that minimizes the effective refractory period, because high resistance prevents depolarization of distal elements, while low resistance allows leakage of depolarizing current by electrotonic transmission, preventing activation of proximal elements. High resistances stabilized reentry by slowing conduction. Simulations incorporating equal resistance values between elements predicted increased AV nodal conduction times with increasing prematurity of atrial impulses. A model with a gradual change in resistance between fibers produced discontinuities and tachycardia, but not both simultaneously. Uniform anisotropy produced preferential transverse block, leading to echo beats and "fast-slow" tachycardia, but not recovery curve discontinuities. Nonuniform anisotropy could produce reentry, but tachycardia often occurred without discontinuities. Dividing the lattice into two electrotonically linked parallel pathways with different resistance values ("dual pathway model") predicted recovery curve discontinuities, echo beats, and tachycardia. At critical atrial cycle lengths, only the (high resistance) slow pathway conducted antegradely, while the fast pathway conducted retrogradely, to generate the typical "slow-fast" tachycardia. Responses of the dual pathway model to ablation were consistent with clinical data, including the previous observation of a decrease in fast pathway effective refractory period after slow pathway ablation. CONCLUSION: Differences in passive electrical resistance of electronically linked dual pathways within the AV node may account for functional longitudinal dissociation, reentrant arrhythmias, and responses to catheter ablation therapy.

Awards and Prizes↗