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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↗
PubMed2006

Physicochemical modelling of cell signalling pathways.

Physicochemical modelling of signal transduction links fundamental chemical and physical principles, prior knowledge about regulatory pathways, and experimental data of various types to create powerful tools for formalizing and extending traditional molecular and cellular biology.

Algorithms↗
PubMed2005

Context enrichment of health risk surveillance data for use and application: conceptual considerations from an Australian perspective.

Increasing the relevance of health surveillance data for use and application remains a critical issue among users and stakeholders. However methods for displaying and communicating health risk data could do more to enrich these data for use and application. There is too much focus on developers, users and stakeholders and not enough focus on pathway models of disease and health. A greater focus on pathway models would help detail a wider explanation of the health problems across sectors and encourage better acceptance of responsibility for their occurrence within other sectors. Contextual enrichment of health data would encourage a shared theory among these players that would permit greater use and application. Better use of data and its translation into information and increased policy traction are likely to be achieved through processes that effectively: (1) establish a shared theoretical base for risk behaviour surveillance; (2) deliver data about the health and developmental status of individuals living in contexts over time; (3) maintain a systems approach to monitoring and surveillance that builds capacity for development, ownership, access to and dissemination of the data outside of the health system and (4) achieve sustainable partnerships that produce more intersectoral engagement.

Adult↗
PubMed2005

Disruption of the TGF-beta pathway and modeling human cancer in mice.

There is considerable complexity underlying the mechanisms through which the TGF-beta signaling pathway regulates the initiation and progression of cancer. Analysis of this pathway and the role that it plays in human malignancy continues to elucidate novel mechanisms through which various genetic and epigenetic events subvert the controls that TGF-beta exerts over cell growth, differentiation, and malignant transformation. Modeling these events in the mouse represents an important goal, as the relevant preclinical models are essential not only for improving our understanding of the role of the TGF-beta pathway in the molecular pathogenesis of cancer, but also as tools for evaluating the impact of novel therapeutics on TGF-beta signaling and the role they may play in the prevention and treatment of malignancies. Here, we consider highlights from a number of in vivo murine model systems and relate a few of the significant observations to what we know about TGF-beta signaling in human cancer.

Animals↗
PubMed2004

Evidence for multiple cycles of strand invasion during repair of double-strand gaps in Drosophila.

DNA double-strand breaks (DSBs), a major source of genome instability, are often repaired through homologous recombination pathways. Models for these pathways have been proposed, but the precise mechanisms and the rules governing their use remain unclear. In Drosophila, the synthesis-dependent strand annealing (SDSA) model can explain most DSB repair. To investigate SDSA, we induced DSBs by excision of a P element from the male X chromosome, which produces a 14-kb gap relative to the sister chromatid. In wild-type males, repair synthesis tracts are usually long, resulting in frequent restoration of the P element. However, repair synthesis is often incomplete, resulting in internally deleted P elements. We examined the effects of mutations in spn-A, which encodes the Drosophila Rad51 ortholog. As expected, there is little or no repair synthesis in homozygous spn-A mutants after P excision. However, heterozygosity for spn-A mutations also resulted in dramatic reductions in the lengths of repair synthesis tracts. These findings support a model in which repair DNA synthesis is not highly processive. We discuss a model wherein repair of a double-strand gap requires multiple cycles of strand invasion, synthesis, and dissociation of the nascent strand. After dissociation, the nascent strand may anneal to a complementary single strand, reinvade a template to be extended by additional synthesis, or undergo end joining. This model can explain aborted SDSA repair events and the prevalence of internally deleted transposable elements in genomes.

Animals↗
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↗
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↗
PubMed2006

Computational neurogenetic modelling: a pathway to new discoveries in genetic neuroscience.

The paper presents a methodology for using computational neurogenetic modelling (CNGM) to bring new original insights into how genes influence the dynamics of brain neural networks. CNGM is a novel computational approach to brain neural network modelling that integrates dynamic gene networks with artificial neural network model (ANN). Interaction of genes in neurons affects the dynamics of the whole ANN model through neuronal parameters, which are no longer constant but change as a function of gene expression. Through optimization of interactions within the internal gene regulatory network (GRN), initial gene/protein expression values and ANN parameters, particular target states of the neural network behaviour can be achieved, and statistics about gene interactions can be extracted. In such a way, we have obtained an abstract GRN that contains predictions about particular gene interactions in neurons for subunit genes of AMPA, GABAA and NMDA neuro-receptors. The extent of sequence conservation for 20 subunit proteins of all these receptors was analysed using standard bioinformatics multiple alignment procedures. We have observed abundance of conserved residues but the most interesting observation has been the consistent conservation of phenylalanine (F at position 269) and leucine (L at position 353) in all 20 proteins with no mutations. We hypothesise that these regions can be the basis for mutual interactions. Existing knowledge on evolutionary linkage of their protein families and analysis at molecular level indicate that the expression of these individual subunits should be coordinated, which provides the biological justification for our optimized GRN.

Algorithms↗
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↗