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PubMed2000

Globalization in road safety: explaining the downward trend in road accident rates in a single country (Israel).

A theoretical model is proposed in which road safety in a single country depends upon parochial considerations, such as police enforcement, and upon global considerations, such as international road safety technology. We show that there is a non-spurious relationship between the downward trend in the rate of road accidents in Israel and the road accident rate abroad. We suggest that this reflects the international propagation of road safety technology as it is embodied in motor vehicles and road design, rather than parochial road safety policy. Recent developments in the econometric analysis of time series are used to estimate the model using data for Israel. We make no direct attempt to explain the downward trend in the rate of road accidents outside Israel.

Accidents, Traffic↗

PubMed2000

Explaining two-lane highway crash rates using land use and hourly exposure.

This paper describes the estimation of Poisson regression models for predicting both single and multi-vehicle highway crash rates as a function of traffic density and land use, as well as ambient light conditions and time of day. The study focuses on seventeen rural, two-lane highway segments, each one-half mile in length with varying land use patterns and where actual hourly exposure values are available in the form of observed traffic counts. Land-use effects are represented by the number of driveways of various types on each segment. Hourly exposure is represented for single-vehicle crashes as the total vehicle miles traveled and volume/capacity ratio; for multi-vehicle crashes it is the product of the hourly volumes on the main highway and the roads intersecting it along the study segment. For single-vehicle crashes, the following variables were found to be significant, with a positive or negative effect as noted: daytime (06:00-19:00 h, negative effect), the natural log of the segment volume/capacity ratio (negative), percent of the segment with no passing zones (positive), shoulder width (positive), number of intersections (negative), and driveways (mixed effects by type). Good multi-vehicle crash prediction models had quite different variables: daylight conditions from 10:00-15:00 and 15:00-19:00 h (positive), number of intersections (negative), and driveways (positive for all types). The results show that traffic intensity explains differences in crash rates even when controlling for time of day and light conditions, and that these effects are quite different for single and multi-vehicle crashes. Suggestions for future research are also given.

Accidents, Traffic↗

PubMed1998

Can non-linear muscle dynamics explain the smoothness of handwriting movements?

The paper addresses the issue of the role of non-linear muscle dynamics in determining the smoothness and invariance of handwriting trajectories. In particular, a specific neuromuscular control model is described that has recently been shown to explain the detailed time course of hand stiffness during arm reaching movements. In the paper the model is applied to more complex handwriting trajectories, with the purpose of verifying to which extent the load compensation capabilities of the periphery can subserve motor equivalence. Simulations show the power of the mechanism for movements of "normal" speed. For quicker movements periphery alone is not enough and a central load compensation action is clearly required.

Handwriting↗

PubMed1999

A neural link to explain the "muscle hypothesis" of exercise intolerance in chronic heart failure.

BACKGROUND: In chronic heart failure the cause of exercise limitation is still unclear: ergoreceptors, muscle afferents sensitive to exercise metabolites, are proposed as a neural link between muscular abnormalities and the limited exercise responses in this syndrome. METHODS: In 92 stable patients with heart failure (34 in New York Heart Association class I, 27 in class II, and 31 in class III) and 28 age-matched normal controls, we assessed exercise tolerance (maximal upright bicycle) and ergoreflex activity (2 dynamic hand grips: one control and one followed by 3 minutes of local circulatory occlusion to isolate the ergoreflex component by metabolite trapping). RESULTS: Patients, with respect to the controls, showed reduced exercise tolerance (peak VO2: 20 vs 33 mL/kg/min), increased ergoreflex effects on ventilation (9 vs 4 L/min), systolic pressure (37 vs 13 mm Hg), and leg vascular resistance (45 vs 22 units) (all P <.005); with the progression of the symptoms, a progressive increase in ergoreflex contribution to the ventilatory response to exercise was observed. The indexes of exercise limitation during arm and leg exercise (ie, peak VO 2, V/VCO2 slope) correlated highly with the ergoreflex contribution to ventilatory response during handgrip test ( r </= 0.7, P <.0001) but weakly with left ventricular ejection fraction (r </= 0.5). CONCLUSION: In chronic heart failure, the overactivity of the ergoreflex is related to a degree of functional limitation and appears, through direct ventilatory and cardiovascular responses, to contribute to the abnormal responses to exercise, explaining the "muscle hypothesis."

Aged↗

PubMed1996

Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients.

PURPOSE: To examine the mechanism of the decreased frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous intensive therapy. PATIENTS AND METHODS: Eight subjects with insulin-dependent diabetes mellitus (IDDM), enrolled in an implantable insulin pump study, were admitted to the General Clinical Research Center and on 2 separate days were given either a dose of preprandial insulin chosen to maintain normoglycemia for a standard (450 kcal, 50% carbohydrate) breakfast or 1.75 times the dose. The two doses were administered subcutaneously (by syringe or with an external pump) during one inpatient admission and by implantable pump (intraperitoneally, n=6; or intravenously, n=2) during a separate admission. Blood glucose, plasma-free insulin, and neurocognitive function were measured for 4 hours after the meal. RESULTS: Subcutaneous administration resulted in 7 episodes of hypoglycemia (2 with the usual dose and 5 with the 1.75-fold dose), defined as blood glucose less than 50 mg/dL; implantable pump treatment resulted in only 2 episodes, both with the 1.75-fold dose (P <0.05, Fisher's two-tailed test for implantable versus subcutaneous). Compared with subcutaneous delivery, implantable pump therapy provided significantly lower insulin levels during the final 2 hours after administration of the usual dose and the 1.75-fold dose (P <0.005). In addition to the decreased frequency of hypoglycemia, implantable pump therapy resulted in significantly lower area under the glycemia curve during the first 120 minutes with the 1.75-fold dose compared with subcutaneous administration. CONCLUSIONS: The lower frequency of severe hypoglycemia with intensive therapy administered by implantable pump therapy is explained by the more rapid clearance of insulin delivered intraperitoneally or intravenously compared with intensive subcutaneous injection regimens. The lower frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous therapy demonstrated in clinical trials is confirmed by this study, in which we attempted to induce hypoglycemia.

Adult↗

PubMed1999

Is the lack of concurrence of bacterial vaginosis and vaginal candidosis explained by the presence of bacterial amines?

OBJECTIVE AND STUDY DESIGN: We report for the first time an inhibitory effect on cell division and germ tube formation by Candida albicans and strains of other Candida species by putrescine and cadaverine. RESULTS: Both bacterial amines showed a dose-dependent inhibition of germ tube formation by C albicans, as well as budding (inhibition of cell division) of strains of other Candida species (ie, C glabrata, C krusei, and C tropicalis). CONCLUSIONS: We hypothesize that the presence of these and possibly other bacterial amines produced by anaerobes in the vaginal flora and seen in bacterial vaginosis, as in the healthy gut, may explain why candidosis is rarely seen in these instances.

Bacteria↗

PubMed2000

Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia.

Pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) remains a major therapeutic problem. Moreover, the pathogenesis of pulmonary hypoplasia in case of CDH is controversial. In particular, little is known about early lung development in this anomaly. To investigate lung development separate from diaphragm development we used an in vitro modification of the 2, 4-dichlorophenyl-p-nitrophenylether (Nitrofen) animal model for CDH. This enabled us to investigate the direct effects of Nitrofen on early lung development and branching morphogenesis in an organotypic explant system without the influence of impaired diaphragm development. Epithelial cell differentiation of the lung explants was assessed using surfactant protein-C and Clara cell secretory protein-10 mRNA expression as markers. Furthermore, cell proliferation and apoptosis were investigated. Our results indicate that Nitrofen negatively influences branching morphogenesis of the lung. Initial lung anlage formation is not affected. In addition, epithelial cell differentiation and cell proliferation are attenuated in lungs exposed to Nitrofen. These data indicate that Nitrofen interferes with early lung development before and separate from (aberrant) diaphragm development. Therefore, we postulate the dual-hit hypothesis, which explains pulmonary hypoplasia in CDH by two insults, one affecting both lungs before diaphragm development and one affecting the ipsilateral lung after defective diaphragm development.

Animals↗

PubMed2000

Openings between defective endothelial cells explain tumor vessel leakiness.

Leakiness of blood vessels in tumors may contribute to disease progression and is key to certain forms of cancer therapy, but the structural basis of the leakiness is unclear. We sought to determine whether endothelial gaps or transcellular holes, similar to those found in leaky vessels in inflammation, could explain the leakiness of tumor vessels. Blood vessels in MCa-IV mouse mammary carcinomas, which are known to be unusually leaky (functional pore size 1.2-2 microm), were compared to vessels in three less leaky tumors and normal mammary glands. Vessels were identified by their binding of intravascularly injected fluorescent cationic liposomes and Lycopersicon esculentum lectin and by CD31 (PECAM) immunoreactivity. The luminal surface of vessels in all four tumors had a defective endothelial monolayer as revealed by scanning electron microscopy. In MCa-IV tumors, 14% of the vessel surface was lined by poorly connected, overlapping cells. The most superficial lining cells, like endothelial cells, had CD31 immunoreactivity and fenestrae with diaphragms, but they had a branched phenotype with cytoplasmic projections as long as 50 microm. Some branched cells were separated by intercellular openings (mean diameter 1.7 microm; range, 0.3-4.7 microm). Transcellular holes (mean diameter 0.6 microm) were also present but were only 8% as numerous as intercellular openings. Some CD31-positive cells protruded into the vessel lumen; others sprouted into perivascular tumor tissue. Tumors in RIP-Tag2 mice had, in addition, tumor cell-lined lakes of extravasated erythrocytes. We conclude that some tumor vessels have a defective cellular lining composed of disorganized, loosely connected, branched, overlapping or sprouting endothelial cells. Openings between these cells contribute to tumor vessel leakiness and may permit access of macromolecular therapeutic agents to tumor cells.

Animals↗

PubMed2002

A direct-transfer polymerization model explains how the multiple profilin-binding sites in the actoclampin motor promote rapid actin-based motility.

The high actin-based motility rates observed in nonmuscle cells require the per-second addition of 400-500 monomers to the barbed ends of growing actin filaments. The chief polymerization-competent species is profilin.actin.ATP (present at 5-40 microM intracellular concentrations), whereas G-actin.ATP is much less abundant ( approximately 0.1-1 microM). While earlier studies unambiguously demonstrated that profilin.actin is highly concentrated within the polymerization zone, profilin-actin localization on the motile surface cannot increase the local solution-phase concentration of polymerizable actin. To explain these high rates of actin polymerization, we present and analyze a novel polymerization model in which monomers are directly transferred to growing filament ends in the actoclampin motor. This direct-transfer polymerization mechanism endows the polymerization zone with properties unavailable to bulk-phase actin monomers, and our model also indicates why profilin is the ideal mobile carrier for actin monomers.

Actins↗

PubMed1992

An amino acid change in the DNA-binding region of Sry, found in Mus musculus domesticus and other species, does not explain C57BL/6J-YDOM sex-reversal.

Sry is the testes determining factor gene located on the Y chromosome. We have performed dideoxy sequencing or restriction enzyme digestion of Sry sequences amplified by PCR from a variety of inbred strains and species of mice. A nonconservative replacement of Thr for Isoleu at position 61 was found in Sry from the Y chromosome of Mus musculus domesticus, Mus spretus, and Mus caroli. We demonstrate that this variation is not sufficient to explain the gradiation in the sex-reversal seen when different domesticus strains are bred to C57BL/6J females.

Animals↗

PubMed2001

Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils.

The elastic section of the giant muscle protein titin contains many immunoglobulin-like domains, which have been shown by single-molecule mechanical studies to unfold and refold upon stretch-release. Here we asked whether the mechanical properties of Ig domains and/or other titin regions could be responsible for the viscoelasticity of nonactivated skeletal-muscle sarcomeres, particularly for stress relaxation and force hysteresis. We show that isolated psoas myofibrils respond to a stretch-hold protocol with a characteristic force decay that becomes more pronounced following stretch to above 2.6-microm sarcomere length. The force decay was readily reproducible by a Monte Carlo simulation taking into account both the kinetics of Ig-domain unfolding and the worm-like-chain model of entropic elasticity used to describe titin's elastic behavior. The modeling indicated that the force decay is explainable by the unfolding of only a very small number of Ig domains per titin molecule. The simulation also predicted that a unique sequence in titin, the PEVK domain, may undergo minor structural changes during sarcomere extension. Myofibrils subjected to 1-Hz cycles of stretch-release exhibited distinct hysteresis that persisted during repetitive measurements. Quick stretch-release protocols, in which variable pauses were introduced after the release, revealed a two-exponential time course of hysteresis recovery. The rate constants of recovery compared well with the refolding rates of Ig-like or fibronectin-like domains measured by single-protein mechanical analysis. These findings suggest that in the sarcomere, titin's Ig-domain regions may act as entropic springs capable of adjusting their contour length in response to a stretch.

Amino Acid Sequence↗

PubMed2004

Dynamic receptor team formation can explain the high signal transduction gain in Escherichia coli.

Evolution has provided many organisms with sophisticated sensory systems that enable them to respond to signals in their environment. The response frequently involves alteration in the pattern of movement, either by directed movement, a process called taxis, or by altering the speed or frequency of turning, which is called kinesis. Chemokinesis has been most thoroughly studied in the peritrichous bacterium Escherichia coli, which has four helical flagella distributed over the cell surface, and swims by rotating them. When rotated counterclockwise the flagella coalesce into a propulsive bundle, producing a relatively straight "run," and when rotated clockwise they fly apart, resulting in a "tumble" which reorients the cell with little translocation. A stochastic process generates the runs and tumbles, and in a chemoeffector gradient, runs that carry the cell in a favorable direction are extended. The cell senses spatial gradients as temporal changes in receptor occupancy and changes the probability of counterclockwise rotation (the bias) on a fast timescale, but adaptation returns the bias to baseline on a slow timescale, enabling the cell to detect and respond to further concentration changes. The overall structure of the signal transduction pathways is well characterized in E. coli, but important details are still not understood. Only recently has a source of gain in the signal transduction network been identified experimentally, and here we present a mathematical model based on dynamic assembly of receptor teams that can explain this observation.

Bacterial Physiological Phenomena↗

PubMed1993

Explaining glomerular pores with fiber matrices. A visualization study based on computer modeling.

The extracellular space of the glomerular capillary wall is occupied by a complex meshwork of fibrous molecules. Little is understood about how the size, shape, and charge recognition properties of glomerular ultrafiltration arise from this space-filling fiber matrix. We studied the problem of size recognition by visualizing the void volume accessible to hard spheres in computer-generated three-dimensional homogeneous random fiber matrices. The spatial organization of the void volume followed a complex "blob-and-throat" pattern in which circumscribed cavities of free space within the matrix ("blobs") were joined to adjacent cavities by narrower throats of void space. For sufficiently small solutes, chains of blobs and throats traversed the matrix, providing pathways for trans-matrix permeation. The matrices showed threshold or gating properties with respect to permeation: solutes whose radius exceeded a critical value, at which a throat on the last connected trans-matrix pathway pinched off, could not cross, whereas smaller solutes had nonzero permeability. The thresholds may give the glomerular fiber matrix porelike response properties and explain why pore models have been such a useful means of treating permselectivity.

Capillaries↗

PubMed1995

A cross-bridge model that is able to explain mechanical and energetic properties of shortening muscle.

The responses of muscle to steady and stepwise shortening are simulated with a model in which actin-myosin cross-bridges cycle through two pathways distinct for the attachment-detachment kinetics and for the proportion of energy converted into work. Small step releases and steady shortening at low velocity (high load) favor the cycle implying approximately 5 nm sliding per cross-bridge interaction and approximately 100/s detachment-reattachment process; large step releases and steady shortening at high velocity (low load) favor the cycle implying approximately 10 nm sliding per cross-bridge interaction and approximately 20/s detachment-reattachment process. The model satisfactorily predicts specific mechanical properties of frog skeletal muscle, such as the rate of regeneration of the working stroke as measured by double-step release experiments and the transition to steady state during multiple step releases (staircase shortening). The rate of energy liberation under different mechanical conditions is correctly reproduced by the model. During steady shortening, the relation of energy liberation rate versus shortening speed attains a maximum (approximately 6 times the isometric rate) for shortening velocities lower than half the maximum velocity of shortening and declines for higher velocities. In addition, the model provides a clue for explaining how, in different muscle types, the higher the isometric maintenance heat, the higher the power output during steady shortening.

Actins↗

PubMed1996

Small segmental rearrangements in the myosin head can explain force generation in muscle.

Poisson-Boltzmann calculations of the distribution of electrostatic potentials around an actin filament in physiological-strength solutions show that negative isopotential surfaces protrude into the solvent. Each protrusion follows the actin two-start helix and is located on the sites implicated in the formation of the actomyosin complex. Molecular dynamic calculations on the S1 portion of the myosin molecule indicate that in the presence of ATP the crystallographically invisible loops (comprising residues 624-649 and 564-579) remain on the surface, whereas in the absence of ATP they can move toward the actin-binding sites and experience electrostatic forces that range from 1 to 10 pN. The molecular dynamics calculations also suggest that during the ATP cycle there exist at least three states of electrostatic interactions between the loops and actin. Every time a new interaction is formed, the strain in the myosin head increases and the energy of the complex decreases by 2kT to 5kT. This can explain muscular contraction in terms of a Huxley-Simmons-type mechanism, while requiring only rearrangements of small mobile S1 segments rather than the large shape changes in the myosin molecule postulated by the conventional tilting head model.

Actins↗

PubMed1998

The adsorption of phloretin to lipid monolayers and bilayers cannot be explained by langmuir adsorption isotherms alone.

Phloretin and its analogs adsorb to the surfaces of lipid monolayers and bilayers and decrease the dipole potential. This reduces the conductance for anions and increases that for cations on artificial and biological membranes. The relationship between the change in the dipole potential and the aqueous concentration of phloretin has been explained previously by a Langmuir adsorption isotherm and a weak and therefore negligible contribution of the dipole-dipole interactions in the lipid surface. We demonstrate here that the Langmuir adsorption isotherm alone is not able to properly describe the effects of dipole molecule binding to lipid surfaces--we found significant deviations between experimental data and the fit with the Langmuir adsorption isotherm. We present here an alternative theoretical treatment that takes into account the strong interaction between membrane (monolayer) dipole field and the dipole moment of the adsorbed molecule. This treatment provides a much better fit of the experimental results derived from the measurements of surface potentials of lipid monolayers in the presence of phloretin. Similarly, the theory provides a much better fit of the phloretin-induced changes in the dipole potential of lipid bilayers, as assessed by the transport kinetics of the lipophilic ion dipicrylamine.

Adsorption↗

PubMed1977

The 'Jack Stone' or 'Mercedes Benz' sign--anew theory to explain the presence of gas within fissures in gallstones.

Gas within clefts of fissures in gallstones is not a very common finding, but when it occurs is, characteristic and indicates the presence of one or more calculi. It closely resembles the appearance of a 'Jack Stone' but has previously been termed the 'Mercedes Benz' sign. Only a few cases have previously been recognised in the U.K. Most reported cases have been associated with biliary colic or cholecystitis. Various theories have been put forward to explain the presence of gas, but the author believes that the gas is released from solution by negative pressure within cholesterol stones undergoing internal fissuring due to their crystalline structure, i.e. the gas is released from solution from the small amount of fluid trapped in the calculus, in the same way that gas may be 'pulled' out of solution in a joint, a degenerate intervertebral disc or the fibro-cartilage of the symphysis pubis.

Aged↗

PubMed1997

Explaining human movements and actions: children's understanding of the limits of psychological explanation.

Human actions and movements can be caused by psychological states (e.g. beliefs and desires), physical forces (e.g. gravity) and biological processes (e.g. reflexes). In three studies we explored young children's understanding of the causes of human movements in order to examine their ability to differentiate and coordinate psychological, physical and biological reasoning to account for the activities of one single entity--a human being. In Study 1, 4-year-olds explained characters' voluntary actions, mistakes, physically-caused and biologically-caused behaviors and movements. Children gave psychological explanations for the intended actions and mistakes, but biological and physical explanations for the biologically-caused and physically-caused movements. Studies 2 and 3 extended the investigation to younger children (3-year-olds), encompassed a greater variety of items, and used several converging methods in order to examine children's judgments and explanations. Consistently, 3- and 4-year-olds gave appropriately different responses and explanations to the different item types. These findings show that far from viewing people in strictly psychological terms, young children evidence multiple causal-explanatory construals of human behavior. We discuss the implications of these findings for children's everyday psychological, physical, and biological theories. One implication of the findings is that young children do not assume a match between entities and theories (persons-psychology, objects-physics). If they do not, this raises the question of what information they use to decide which explanatory system fits which events.

Age Factors↗