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PubMed1991

A graph-theoretic approach to modeling metabolic pathways.

The metabolic pathways of medazepam, oxazepam, and diazepam were modeled using graph-theoretic transforms which are incorporable into computer-assisted metabolic analysis programs. The information, represented in the form of a graph-theoretic transform kit, which was obtained from these pathways was then used to predict the metabolites of other benzodiazepine compounds. The transform kits gave statistically significant predictions with respect to a statistical method for evaluating the performance of the transform kits.

Anti-Anxiety Agents↗
PubMed2003

Assessing remedial effectiveness through the blood lead:soil/dust lead relationship at the Bunker Hill Superfund Site in the Silver Valley of Idaho.

The 21 square mile Bunker Hill Superfund Site in northern Idaho includes several thousand acres of contaminated hillsides and floodplain, a 365-acre abandoned lead/zinc smelter and is home to more than 7000 people in 5 residential communities. Childhood lead poisoning was epidemic in the 1970s with >75% of children exceeding 40 microg/dl blood lead. Health response activities have been ongoing for three decades. In 1991, a blood lead goal of 95% of children with levels less than 10 microg/dl was adopted. The cleanup strategy, based on biokinetic pathways models, was to reduce house dust lead exposure through elimination of soil-borne sources. An interim health intervention program, that included monitoring blood lead and exposures levels, was instituted to reduce exposures through parental education during the cleanup. In 1989 and 2001, 56% and 3% of children, respectively, exceeded the blood lead criteria. More than 4000 paired blood lead/environmental exposure observations were collected during this period. Several analyses of these data were accomplished. Slope factors derived for the relationship between blood lead, soil and dust concentrations are age-dependent and similar to literature reported values. Repeat measures analysis assessing year to year changes found that the remediation effort (without intervention) had approximately a 7.5 microg/dl effect in reducing a 2-year-old child's mean blood lead level over the course of the last ten years. Those receiving intervention had an additional 2-15 microg/dl decrease. Structural equations models indicate that from 40 to 50% of the blood lead absorbed from soils and dusts is through house dust with approximately 30% directly from community-wide soils and 30% from the home yard and immediate neighborhood. Both mean blood lead levels and percent of children to exceed 10 microg/dl have paralleled soil/dust lead intake rates estimated from the pathways model. Application of the IEUBK model for lead indicates that recommended USEPA default parameters overestimate mean blood lead levels, although the magnitude of over-prediction is diminished in recent years. Application of the site-specific model, using the soil and dust partitions suggested in the pathways model and an effective bioavailability of 18%, accurately predicts mean blood lead levels and percent of children to exceed 10 microg/dl throughout the 11-year cleanup period. This reduced response rate application of the IEUBK is consistent with the analysis used to originally develop the cleanup criteria and indicates the blood lead goal will be achieved.

Absorption↗
PubMed1996

Wound care clinical pathway: a conceptual model.

A clinical pathway is a written sequence of clinical processes or events that guides a patient with a defined problem toward an expected outcome. Clinical pathways are tools to assist with the cost-effective management of clinical outcomes related to specific problems or disease processes. The primary obstacles to developing clinical pathways for wound care are the chronic natures of some wounds and the many variables that can delay healing. The pathway introduced in this article was modeled upon the three phases of tissue repair: inflammatory, proliferative, and maturation. This physiology-based model allows clinicians to identify and monitor outcomes based on observable and measurable clinical parameters. The pathway design, which also includes educational and behavioral outcomes, allows the clinician to individualize the expected timeframe for outcome achievement based on individual patient criteria and expert judgement. Integral to the pathway are the "4P's" which help standardize the clinical processes by wound type: Protocols, Policies, Procedures, and Patient education tools. Four categories into which variances are categorized based on the cause of the deviation from the norm are patient, process/system, practitioner, and planning/discharge. Additional research is warranted to support the value of this clinical pathway in the clinical arena.

Cost-Benefit Analysis↗
PubMed1999

Neuroprotective effect of remacemide hydrochloride in a perforant pathway stimulation model of status epilepticus in the rat.

Previous studies have demonstrated that remacemide and its desglycinyl metabolite, AR-R 2495AA, reduce neuronal damage in animal models of ischemia, subarachnoid hemorrhage, and traumatic brain injury. The aim of the present study was to investigate whether remacemide hydrochloride also alleviates seizure-induced neuronal damage in a model of status epilepticus induced by the stimulation of the perforant pathway (PP) in the rat. Chronic oral remacemide treatment (3 x 25 mg/kg/day) was started either 2 days before or 2 h after the beginning of PP stimulation (2 mA, 20 Hz, 0.1 ms pulse duration for 60 min). The effects of remacemide treatment on the severity of seizures, electroencephalogram (EEG) parameters, seizure-induced neuronal damage in the temporal lobe regions, and memory impairment were compared to unstimulated and stimulated vehicle-treated controls, and carbamazepine-pre-treated (3 x 40 mg/kg/day) rats. Both remacemide and carbamazepine pretreatments, but not remacemide posttreatment, decreased pyramidal cell damage in the CA3 and CA1 subregions of the hippocampus (P < 0.05). In addition, overall neuronal damage in the extrahippocampal temporal lobe regions (the piriform cortex, entorhinal cortex, and the amygdaloid complex) was milder in remacemide-pretreated rats compared to stimulated control rats (P < 0.01). The neuroprotective effect was most evident on the side contralateral to stimulation. Remacemide or carbamazepine pretreatment had no evident effect on the number or duration of behavioral seizures during PP stimulation. Neither drug altered the spectral parameters of the baseline EEG or prevented status epilepticus-induced EEG slowing observed 2 weeks after PP stimulation. Nor did remacemide or carbamazepine treatment alleviate spatial memory impairment determined in a Morris water-maze task 2 weeks after PP stimulation. Our data provide evidence that pretreatment with remacemide has a moderate neuroprotective effect against status epilepticus-induced neuronal damage.

Acetamides↗
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↗
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↗
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↗