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At least 217 records · Page 12Linked to original sources

PubMed2006

Validation of a chemical osteoarthritis model in rabbit temporomandibular joint: a compliment to biomechanical models.

To explore degenerative mechanisms occurring in the temporomandibular joint (TMJ), a chemical model of knee joint osteoarthritis using sodium mono-iodoacetate injection was transposed to the TMJ. Twelve New Zealand rabbits were used to document the effect of this drug on the TMJ. Eight rabbits underwent bilateral iodoacetate injection in the disco-condylar compartment while 4 served as controls. Rabbits were sacrificed at 10, 20, 30 and 40 days and joints studied by histology. Severity of the damage was time dependent and the use of iodoacetate allowed the observation, within a few weeks, of every osteoarthritic stage usually described in the literature. This study showed that the TMJ has a specific response to the degenerative process. This response was characterized by (i) thickening and fibrillation of the cartilage at the periphery of the lesion, tending to reduce mechanical stress in the lesional area and (ii) chondrocyte migration under areas where subchondral bone surface was locally destroyed. The extracellular matrix containing chondrocyte clusters and prechondrocytes dived around the bony defect and proceeded below the necrotic bone to promote the eviction of bony fragments into the joint cavity, pushing them up while the thickness of chondrocyte rows increased below. This could be interpreted as a repairing attempt due to the specific potential of fibrocartilage proliferative cells.

Alkylating Agents↗

PubMed2003

The use of mental models in chemical risk protection: developing a generic workplace methodology.

We adopted a comparative approach to evaluate and extend a generic methodology to analyze the different sets of beliefs held about chemical hazards in the workplace. Our study mapped existing knowledge structures about the risks associated with the use of perchloroethylene and rosin-based solder flux in differing workplaces. "Influence diagrams" were used to represent beliefs held by chemical experts; "user models" were developed from data elicited from open-ended interviews with the workplace users of the chemicals. The juxtaposition of expert and user understandings of chemical risks enabled us to identify knowledge gaps and misunderstandings and to reinforce appropriate sets of safety beliefs and behavior relevant to chemical risk communications. By designing safety information to be more relevant to the workplace context of users, we believe that employers and employees may gain improved knowledge about chemical hazards in the workplace, such that better chemical risk management, self-protection, and informed decision making develop over time.

Chemical Industry↗

PubMed1989

Thermodynamics of the various forms of the dodecamer d(ATTACCGGTAAT) and of its constituent hexamers from proton nmr chemical shifts and UV melting curves: three-state and four-state thermodynamic models.

Chemical shifts of base and H1' protons of the single-stranded hexamers d(ATTACC) and d(GGTAAT), of the 1:1 mixtures of these complementary hexamers, and of the self-complementary dodecamer d(ATTACCGGTAAT) were measured at various temperatures in aqueous solution. Four different sample concentrations were used in the case of the dodecamer and of the mixture of the complementary hexamers; the individual hexamers were measured at two different DNA concentrations. Absorbance temperature profiles at five different NaCl concentrations were measured for the dodecamer in order to quantify the effect of the ionic strength on the duplex formation. Under suitable conditions of nucleotide concentration, temperature, and ionic strength, the dodecamer adopts either a B-DNA duplex or a hairpin-loop structure. Chemical shift vs temperature profiles, constructed for all samples, were used to obtain thermodynamic parameters either for the various stacking interactions in the single strands or for the duplex or the hairpin-loop formation. In the analysis of the duplex formation of the hexamers, a two-state approach appeared too simple, because systematic deviations were revealed. Therefore, a new three-state model (DUPSTAK) was developed. In order to investigate the magnitude of error arising from the use of the two-state approach in cases where the DUPSTAK model appears more appropriate, a series of test calculations was made. The magnitude of error in the enthalpy and in the entropy of duplex melting is found to depend linearly upon the actual melting temperature and not upon the individual delta Hd degrees and delta Sd degrees values. Thermodynamic analysis of the chemical shift vs temperature profiles in D2O solution (no added salt) yields an average Tmd value of 341 K (1M DNA) and delta Hd degrees of - 121 kJ.mol-1 for the dimer/random-coil transition of the hexamer duplex d(ATTACC).d(GGTAAT). For the duplex in equilibrium random-coil transition of the 12-mer d(ATTACCGGTAAT) an average Tmd value of 336 K (1M DNA) and delta Hd degrees of -372 kJ.mol-1 are found. The hairpin/random-coil transition of d(ATTACCGGTAAT) is characterized by a rather large delta Hh degrees value, -130 kJ.mol-1, and an average Tmh value of 304 K.

Magnetic Resonance Spectroscopy↗

PubMed2002

T(2)-shortening by strongly magnetized spheres: a chemical exchange model.

It is shown that a chemical exchange model can reproduce nuclear magnetic relaxation caused by diffusion of water molecules near strongly magnetized particles. The agreement is based on the similarity (but not equivalence) of the respective "visit-limiting" mechanisms in the echo-limited regime. The model leads to a single equation that predicts relaxation behavior in both the motional-averaging and visit-limited regimes. When combined with the static-dephasing regime equation, the result is a simple theory (for spheres) that covers the entire range of diffusion times.

Diffusion↗

PubMed1989

The air pollutant 2-nitrofluorene as initiator and promoter in a liver model for chemical carcinogenesis.

2-Nitrofluorene (NF), a model substance for nitrated polycyclic aromatic hydrocarbons, is present in exhaust from diesel- and petrol-driven vehicles, in exhaust from kerosene heaters, and in urban air and river sediments. Therefore the possible consequences of human exposure are important to elucidate. In the present study the initiating and promoting activity of NF was studied in a liver model for chemical carcinogenesis in the rat. Furthermore, the in vivo metabolism and formation of genotoxic metabolites of NF were investigated. NF was found to be a moderate initiator and a weak promoter when compared to diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) respectively, both of which are potent carcinogens. Animals given NF excreted more urinary mutagenicity when compared to animals given AAF or DEN.

2-Acetylaminofluorene↗

PubMed2007

Unicorns in the world of chemical bonding models.

The appearance and the significance of heuristically developed bonding models are compared with the phenomenon of unicorns in mythical saga. It is argued that classical bonding models played an essential role for the development of the chemical science providing the language which is spoken in the territory of chemistry. The advent and the further development of quantum chemistry demands some restrictions and boundary conditions for classical chemical bonding models, which will continue to be integral parts of chemistry.

Hydrogen Bonding↗

PubMed1988

A chemical kinetic model for ligand binding to identical and independent binding sites in vivo.

In living systems, hormones bind to receptor proteins that are continuously synthesized and degraded. Since these systems cannot be described by equilibrium binding equations, we present a chemical kinetic model for the binding of a hormone to a receptor with identical and independent binding sites in which synthesis and degradation occur. We have derived, from the model, equations that can be used to calculate the bound ligand concentration and the total protein concentration as a function of the free ligand concentration and time. These results show that the methods for experimental measurements, parameter estimation, interpretation of the parameters, and error analysis that are commonly used for equilibrium binding to identical and independent binding sites can be adapted for the analysis of steady-state binding data. The equations we derived for the steady-state ligand binding permit determination of the total receptor protein concentration and the binding affinity from experimental data. In contrast, if an equilibrium model were used, the values of these parameters would not necessarily approximate the true values. A useful approximation to the total receptor concentration as a function of time was found that requires only three of the five rate constants required for exact description by the model. This approximation is shown to be accurate in the biologically relevant range by using previously published parameters estimated from steroid binding data, and adding perturbations to include experimental error and variations among biological systems. When complexities exist, such that the model does not describe the data, these analyses aid in assessing the types of additional components and interactions that may exist.

Binding Sites↗

PubMed2006

A "partitioned leaping" approach for multiscale modeling of chemical reaction dynamics.

We present a novel multiscale simulation approach for modeling stochasticity in chemical reaction networks. The approach seamlessly integrates exact-stochastic and "leaping" methodologies into a single partitioned leaping algorithmic framework. The technique correctly accounts for stochastic noise at significantly reduced computational cost, requires the definition of only three model-independent parameters, and is particularly well suited for simulating systems containing widely disparate species populations. We present the theoretical foundations of partitioned leaping, discuss various options for its practical implementation, and demonstrate the utility of the method via illustrative examples.

Computer Simulation↗

PubMed1988

A new rhinitis model using chemical mediators in rats.

No good experimental model for studying rhinitis, has been hitherto available. In the present study, development of a new rhinitis model using chemical mediators was attempted, especially to establish an index of nasal congestion. Male Wistar rats were anesthetized with pentobarbital-Na. Nasal cavities were ventilated between both cannulae inserted into the nasopharynx and bilateral nostrils, with an artificial respirator. Intranasal resistance was recorded with a modification of a Konzett-Rössler apparatus as a change in ventilation overflow (VO). To provoke rhinitis, some mediators were inhaled into the nasal cavities with an ultrasonic nebulizer for 5 min. To assess the capillary permeability of the nasal mucosa, exudation of Evans blue was determined by injecting the dye before inhalations of mediators. Inhalation of histamine (0.01, 0.1, 0.3%), bradykinin (0.01, 0.1%) and ACh (0.3%) markedly increased VO, while inhalation of serotonin (0.01, 0.1, 0.3%) did not increase VO. Histamine, bradykinin and high concentration of ACh significantly increased the dye exudation in the nasal cavities, although serotonin did not. From the above results, it is concluded that 1) a new rhinitis model in which symptoms of nasal blockage and increased capillary permeability in nasal mucosa are quantitatively determined, was established, and 2) histamine- and bradykinin-inhalations can cause rhinitis-like symptoms, although serotonin-inhalation can not.

Airway Resistance↗

PubMed1982

Application of tumor, bacterial and parasite susceptibility assays to study immune alterations induced by environmental chemicals.

Model systems to study the effects of chemicals of environmental concern on bacterial and parasitic diseases as well as the immunosurveillance and destruction of transplantable tumor cells were described and evaluated. Studies were conducted in female B6C3F1 mice following adult or pre/postnatal exposure to several prototype chemicals. The prototype chemicals employed included the synthetic estrogen diethylstilbestrol (DES), the polycyclic aromatic hydrocarbon benzo(a)pyrene (B[a]P), and the carcinogenesis promoting agent 12-0-tetradecanoyl-phorbol-13-0-acetate (TPA). The host resistance models employed depend primarily on functional thymus-dependent immunity, although humoral immunity is suggested to have a role in the parasite model as well. These models include: subcutaneous challenge with a dose of PYB6 tumor cell causing a 10-20% incidence (TD(10-20)) of tumor; intravenous challenge with B16 melanoma cells; challenge with a dose of Listeria monocytogenes causing a 10-20% incidence of mortality (LD(10-20)); challenge with a dose of E. coli lipopolysaccharide endotoxin causing a 10-20% incidence of lethality (LD(10-20)); and challenge with larvae of Trichinella spiralis for parasite expulsion kinetic studies. Increased mortality was observed following Listeria monocytogenes challenge in DES-exposed mice. B(a)P and TPA exposure did not alter host resistance to this organism. The increased mortality observed following DES was associated with a significant increase in the number of viable Listeria in the spleens and livers at 4 days, a time when T-cell immunity is thought to be expressed, but bacterial counts were similar to control mice at day 1, a time when MPhi are thought to exert their greatest effect. These data suggest that the increased Listeria susceptibility found following DES exposure may result from a T-cell defect, although the intracellular killing capacity of DES-treated Mvarphi's has not been well examined. Tumor susceptibility studies following challenge with 5 x 10(3) viable syngeneic PYB6 tumor cells revealed that nontreated adult B6C3F1 mice resisted tumor formation, with only a 10-20% incidence of tumor formation. In contrast, mice exposed to DES or TPA as adults had a tumor frequency of from 70-100% following TPA and up to 90% following DES exposure. In all cases the tumors were progressive and resulted in death. B(a)P did not alter the frequency of tumor incidence from controls in this model. Preliminary data, using the B16 melanoma intravenous challenge model and (125)IUdR to quantitate tumor mass revealed this model was sensitive to non-specifically activated macrophage kill. DES treated mice with activated macrophages did not demonstrate increased tumor mass, while mice exposed to TPA or the potent immunosuppressive agent cyclophosphamide had a significantly increased tumor mass in their lungs. Expulsion of Trichinella spiralis adults from the gut also apparently required functional T-cells and possibly some element of humoral immunity. Mice exposed to DES and B(a)P exhibited increased numbers of adult worms in the gut at day 14. Sensitivity to gram-negative endotoxin (LPS) was apparently increased following exposure to DES or B(a)P. These data suggest that the detoxification of LPS is related to an intact Mvarphi population. The data presented here demonstrate the sensitivity of the host resistance assay panel proposed for detecting immune alteration. Alteration of T-cell function appeared to correlate with increased susceptibility to bacterial and tumor cell challenge.

Animals↗

PubMed1997

Detection of mutagenicity in Ames test using a metalloporphyrin/oxidant model system for cytochrome P450.

A chemical model system for cytochrome P450, a porphyrin and an oxidant, was used in Ames assay as a substitute for S9 mix. In the presence of tetrakis(pentafluorophenyl)porphyrinatoiron(III) chloride [Fe(F5P)Cl] and tert-butyl hydroperoxide (t-BuOOH), mutagenicity of N-nitrosodibutylamine (NDB) in Salmonella typhimurium TA1535 was detected. The mutagenicity depended on the pre-incubation period, and also on the concentration of an oxidant and of bacteria. In the chemical model system, pH affected the mutagenicity of NDB, which suggested that as observed in an enzymatic activating system, the mutagenicity was due to the labile alkylating species which was derived from NDB activated in the chemical activation system and was sensitive to pH. Under the optimum conditions; a higher concentration of an oxidant, a higher concentration of bacterial culture, and a weakly acidic medium, mutagenicity of N-nitrosodipropylamine in S. typhimurium TA1535 was also detected. Besides N-nitrosodialkylamines, 2-aminofluorene (2-AF) and benzo[a]pyrene (BaP) were also used as mutagens. Mutagenicity of 2-AF and BaP in S. typhimurium TA1538 were both detected in the same system as used in detecting the mutagenicity of N-nitrosodialkylamines. Ames test using a metalloporphyrin/oxidant model system makes it possible to detect mutagenicity derived from both base pair substitution mutagens and frameshift mutagens without using enzymatic activating system. These results demonstrate that the assay with the chemical model system is useful in detecting unstable unknown active mutagens or investigating the mechanisms of the metabolic pathway of mutagens or carcinogens in a protein-free medium.

Benzo(a)pyrene↗

PubMed2000

Effects of CEES on inflammatory mediators, heat shock protein 70A, histology and ultrastructure in two skin models.

Chemical warfare threats require the development of diverse models for the assessment of countermeasures. Human skin products, Skin2 (differentiating keratinocytes on a fibroblast-collagen matrix) and EpiDerm (differentiating keratinocytes) were exposed (2 h) to the sulfur mustard 2-chloroethyl ethyl sulfide (CEES, 1-2 mg l(-1) min(-1)) in humidified air or to humidified air alone. Tissues were evaluated histologically, ultrastructurally and for viability 22 h later; media and tissues were also analyzed for inflammatory mediators. Histology showed that CEES induced the separation of dermal and epidermal regions in Skin2 with severe damage to basal keratinocytes. Histology and electron microscopy of both products revealed condensation of nuclear chromatin, retraction of spinous processes, collapse of the tonofibrillar network and cytoplasmic vacuolization and blebbing in those cells with loss of pseudobasement membrane integrity. Exposure of Skin2 to CEES increased extracellular interleukin-1alpha (IL-1alpha), prostaglandin-E2 (PGE2) and especially IL-1 receptor antagonist (IL-1Ra) release (56,334 vs 84,614 pg ml(-1)), but decreased interleukin-6 (IL-6, 4,755 vs 351 pg ml(-1)). Exposure of EpiDerm to CEES led to unaffected extracellular and reduced intracelluar IL-1alpha (371 vs 92 pg ml(-1)). Extracellular IL-1Ra greatly increased (2,375 vs 24,875 pg ml(-1)), whereas cellular levels decreased (16,5425 vs 96,625 pg ml(-1)). Extracellular (224 vs 68 pg ml(-1)) and intracellular (485 vs 233 pg ml(-1)) soluble interleukin-1 receptor H (sIL-1RII) decreased. Prostanglandin E2 increased (1,835 vs 2,582 pg ml(-1)), whereas heat shock protein 70A (Hsp70A) remained statistically unchanged (57,000 vs 96,000 pg ml(-1)). Failure to obtain a heat shock response to CEES may contribute to the susceptibility of tissue to the alkylating agent. Consistent and marked responses of cellular and extracellular IL-1Ra to CEES suggest a potential for use as a tissue status marker and primary antiinflammatory regulator in skin.

Biomarkers↗

PubMed1997

Structure-activity model of chemicals that cause human respiratory sensitization.

We report a structure-activity model of chemicals with the potential to cause respiratory allergy developed through the CASE/MultiCASE systems. Chemicals documented to elicit a decrease in FEV1 of > or = 20% within 24 h of inhalation provocation challenge were used to form a learning set. Additional requirements for inclusion in the learning set were that chemicals had at least two contiguous nonhydrogen atoms and were nonmetallic. Forty chemicals met these criteria. The model identified several "structural alerts" including the isocyanate functionality (N = C = O), primary and secondary amines, substituted aromatic moieties, and distance descriptors. An external data-withholding exercise used to validate the model yielded a sensitivity of 0.95 and a specificity of 0.95. This model is applicable to initial prediction of the sensitizing ability of untested chemicals and may provide mechanistic insight into the process(es) of respiratory sensitization.

Administration, Inhalation↗

PubMed1993

Model of chemically excitable membranes generating autonomous chaotic oscillations.

A simple mathematical model of the chemically excitable membranes leading to autonomous chaotic oscillations is presented. The model assumes two kinds of autocatalytic ion channels, one is for cations and the other is for anions. Self-consistency between the ion distributions and the electric potentials is taken into account by including the counter ions explicitly. Cations and anions pass through their own channels with their permeabilities changing nonlinearly with the densities of ions at the surfaces of the membrane. Cation and anion transport systems then form two subsystems that oscillate and interact with each other through the membrane potential. When the coupling strength between the two ion systems and adsorption rate of ions to channels are varied, various types of chaotic oscillations are generated autonomously, i.e., without a stimulating periodic force. Experimental evidence to the present model is discussed. It is suggested that endogenous chaos in biological systems may appear from the electric coupling among different kinds of ion transport systems.

Catalysis↗

PubMed2001

Predicting toxicity: a mechanism of action model of chemical mutagenicity.

The increasing importance of theoretical studies for predicting toxicology has aroused the interest of many computational chemists. A new approach has been developed, based on studying at the molecular level two potential mechanisms of action that are related to compound mutagenicity. This approach is the first example that considers both the toxicant and the biological target molecules involved in the interaction. Using some calculated descriptors and a simulation of the interaction chemical, compounds can be classified. More important, the approach helps in understanding and explaining both the correct and the incorrect results, and gives a deeper understanding of the toxic mechanisms. The model has been applied to many compounds and the results are compared with experimental results reported for the corresponding Salmonella tests.

Algorithms↗

PubMed2006

Dynamic modeling of chemical fate and transport in multimedia environments at watershed scale-I: theoretical considerations and model implementation.

A geo-referenced environmental fate model was developed for analyzing unsteady-state dispersion and distribution of chemicals in multimedia environmental systems. Chemical transport processes were formulated in seven environmental compartments of air, canopy, surface soil, root-zone soil, vadose-zone soil, surface water, and sediment. The model assumed that the compartments were completely mixed and chemical equilibrium was established instantaneously between the sub-compartments within each compartment. A fugacity approach was utilized to formulate the mechanisms of diffusion, advection, physical interfacial transport, and transformation reactions. The governing equations of chemical mass balances in the environmental compartments were solved simultaneously to reflect the interactions between the compartments. A geographic information system (GIS) database and geospatial analysis were integrated into the chemical transport simulation to provide spatially explicit estimations of model parameters at watershed scale. Temporal variations of the environmental properties and source emissions were also considered in the parameter estimations. The outputs of the model included time-dependent chemical concentrations in each compartment and its sub-compartments, and inter-media mass fluxes between adjacent compartments at daily time steps.

Computer Simulation↗

PubMed2003

Botulinum toxin type A may improve bladder function in a rat chemical cystitis model.

The purpose of this study was to investigate the effect of botulinum toxin type A on bladder function and histology in a rat chemical cystitis model. The study included 41 female Sprague-Dawley rats with chemical cystitis induced by intravesical instillation of hydrochloric acid. The acid instillation was repeated monthly to maintain chronic inflammation. The treatment group (n=21) received 2-3 units of botulinum toxin type A injected into the bladder detrusor at the 3, 6, 9 and 12 o'clock positions, and the control group (n=20) underwent saline injection into the bladder detrusor at the same positions. Urodynamic studies were performed in all rats before the treatment and at death. The rats were killed at 1 week, 2 weeks, 1 month and 2 months after treatment. The bladders were removed and examined histologically for mast cells and inflammatory changes. The cystometric findings showed that, at the beginning and end of the experiment, the increases in the maximum bladder capacity and compliance were significantly higher in the treatment group than in the control group (P=0.000 and P=0.025, respectively). The histological studies revealed similar mast cell counts and leukocyte infiltration for the treatment and control groups. In conclusion, in this rat chemical cystitis model, botulinum toxin type A injected into the bladder detrusor led to a functional improvement. Thus, botulinum toxin type A injection may be an alternative, minimally invasive choice to other surgical treatment options in the treatment of a chronic inflammatory condition to improve deteriorated bladder function.

Animals↗

PubMed1986

A chemically explicit model for the molecular mechanism of the F1F0 H+-ATPase/ATP synthases.

A general hypothesis for the molecular mechanism of membrane transport based on current knowledge of protein structure and the nature of ligand-induced protein conformational changes has recently been proposed [Scarborough, G. A. (1985) Microbiol. Rev. 49, 214-231]. According to this hypothesis, the essential reaction undergone by all proteinaceous transport catalysts is a ligand-induced hinge-bending-type conformational change that results in the transposition of binding-site residues from access on one side of the membrane to access on the other side. Subsequent release and/or alteration of the ligand or ligands that induce the conformational change facilitates the converse conformational change, which returns the binding-site residues to their original position. With this simple cyclic ligand-dependent gating process as a central feature, biochemically orthodox mechanisms for virtually all known transporters are readily conceived. In this article, a chemically explicit model for the molecular mechanism of the F1F0 H+-ATPase/ATP synthases of mitochondria, bacteria, and chloroplasts, formulated within the guidelines of this general transport paradigm, is presented. At least three points of potential interest arise from this exercise. First, with the aid of the model, it is possible to visualize how energy transduction catalyzed by these enzymes might proceed, with no major events left unspecified. Second, explicit possibilities as to the molecular nature of electric field effects on the transport process are raised. And finally, it is shown that enzyme conformational changes, energy-dependent binding-affinity changes, and several other related phenomena as well, need not be taken as evidence of "action at a distance" or indirect energy coupling mechanisms, as is sometimes assumed, because such events are also integral features of the mechanism presented, even though all of the key reactions proposed for both ATP-driven proton translocation and proton translocation-driven ATP synthesis occur at the enzyme active site.

Animals↗