Logical Probability and Risk Assessment

A risk assessment is intended to provide a statement of current knowledge which is intended to inform a decision-maker of the current state of knowledge in response to a particular concern. Because answering the concerns of decision-makers often requires inferences to be drawn, doubt often arises over how the inference is to be drawn. In quantitative risk assessment, where a mathematical equation or model is used to draw the inference, this uncertainty is referred to as model uncertainty. A two-step process, which is referred to as logical probability, is proposed as a technique for representing model uncertainty in a risk assessment. The first step involves assigning model weights in which the degree of evidential support for each of the alternative models is considered. The second step involves assigning a unique interval in the range of 0 to 1 for each model which reflects the models' weight, to form a probability distribution. While the second step is straightforward, the first step is not. Assigning model weights requires consideration of any line of evidence that may reasonably impact the validity of the assertion of a model. While the development of a procedure for doing so may be expected to be a process which reflects the subjective preferences of whomever is involved in creating it, there are some historical precedents on which to build. Foremost among these are (1) the use of a correlation coefficient or other goodness-of-fit criteria to measure the degree of correspondence between a given model and a set of observations which are used as evidence to support it, and (2) preference given to models which are simpler, which may be ascertained as the number of adjustable parameters the model contains. Additional principles, which have little or no tradition to stand on, must be used to reflect the impact of other empirically supported beliefs on model preference. The procedure proposed is comparable to the procedure known as decision analysis, in which probabilities are assigned to alternative models based on expert or subjective input. The principal difference in the present case is that it is suggested that principles which transcend the decision at hand should be sought and articulated in order to generate a consistent measure of uncertainty arising from interpretation.     

MATCHING THE SHAPE OF TIME-INTENSITY CURVES1

Time-Intensity Curves are often summarized by average curves. From these curves TI-parameters are inferred. In this paper a different method is proposed in which the shape of the curves is the central concept. Isotropic scaling factors are computed for each curve. These factors can be tabled and inspected. Often a large number of scaling factors will be computed, which makes it hard to study them in a table. In such cases they can be represented in a plot, for which in this paper PCA is suggested. In this plot a structure in the scaling factors for the different TI-curves may become visible. It is also possible to make a plot in which the homogeneity of the panel of subjects can be studied.     

Estimating the Dilution Effect Due to Unreliability of Dichotomous Outcome Variables From Kappa

If category-specific reliabilities are constant across groups, the difference in group-specific "success" probabilities estimated from an unreliable dichotomous outcome variable can be shown to be diluted. Thus, although an intervention may truly have a sizable effect, this effect may not be detectable because of unreliability of the outcome variable. This article explores the dilution effect in a latent class analysis framework in which reliability is defined as the probability with which the manifest measure and the true state correspond. The size of the dilution effect will be related to the popular kappa coefficient, which is often used to assess the reliability of dichotomous variables. Conditions will be specified under which the magnitude of the dilution effect can be estimated from kappa.     

A simple matrix method for determining flux control coefficients in complex pathways

Flux control coefficients express in quantitative terms the extent to which the steady state flux through a metabolic pathway is controlled by a particular parameter. Enzyme flux control coefficients can be calculated using matrix algebra methods which express the control coefficients in terms of parameters which can be determined experimentally (enzyme elasticities, flux ratios, metabolite ratios). This paper describes an algorithm based on a 'constraint' matrix which enables expressions for enzyme control coefficients to be written for pathways of any complexity.     

Possible forms for dwell-time histograms from single-channel current records

Certain macromolecules embedded in the cell membranes of a variety of cells behave as gated ion-selective pores or channels. The length of time that a channel remains open or closed is not deterministic in nature and must be described in terms of relative probabilities. If channels act independently of each other and appropriate experimental conditions can be maintained, the behavior of a channel can be described by a homogeneous Markov process. Using this representation, the relative probability of observing openings (or closings) of various durations can be described by a sum of discrete components which are related to the underlying model of the kinetic behavior of the channel. Generally, these discrete components are taken to be simple decaying exponentials; however, exponentially decaying oscillatory components (as well as certain others which are discussed) are consistent with the Markov process representation. The presence of components other than simple decaying exponentials is shown to imply the violation of detailed balance in the steady-state (which requires energy), and thus, the presence of cyclic pathways in models which accurately represent the kinetic behavior of the channel. Oscillatory components, if present, will in general decay at a faster rate than the slowest decaying component, which, except under a very restricted set of conditions, will be a simple exponential.     

The pharmacology of a new nitric oxide donor: B-NOD

We describe here a new compound, B-NOD, which, in vitro and in situ, releases nitric oxide (NO). Its activity in situ persists for more than 7 h, it does not cause a fall in blood pressure or an increase in heart rate and can be orally administered. It increases cyclic guanosine monophosphate (cGMP) and prevents platelet aggregation. In vitro, its release of NO is augmented by the presence of living cells (blood platelets). B-NOD may be useful in a number of clinical conditions in which prolonged release of NO without hemodynamic effects are desirable. A combination of aspirin with B-NOD could be formulated in which the individual concentrations of aspirin and B-NOD may be useful in the long-term treatment of coronary artery disease and in clinical situations in which long-term release of NO may be beneficial.     

The relationship between light scattering and chlorophyll a fluorescence during oscillations in photosynthetic carbon assimilation

Light scattering, which can be taken as an indicator of the transthylakoid proton gradient, and the 518-nm rise, which can be regarded as a measure of the transthylakoid membrane potential, have been followed during oscillations in chlorophyll a fluorescence, which are known to be associated with corresponding changes in photosynthetic carbon assimilation. Both components oscillated in a manner which was broadly reciprocal to chlorophyll a fluorescence. However, there was a phase shift such that the light-scattering change usually anticipated fluorescence and often also the 518-nm shift. It is concluded that the proton motive force rises and falls slightly in advance of rises and falls in carbon assimilation. The relationship of these changes to a possible underlying mechanism is discussed.     

A NEW SIMPLIFIED METHOD OF MAMMAPLASTY

Abnormally large breasts, which may be a factor in psychic disturbance from an esthetic point of view and which appear to be related to habitual abortion and sterility, can be reduced in size and reshaped by a simpler operative procedure than those now in use. The operation takes considerable less time than others used heretofore. It avoids the need for marking the skin beforehand as a guide to the reshaping procedure and then trying to abide by a preconceived plan, which may be difficult, and it permits the ultimate site of the nipples to be selected after the reshaping is done and even after the skin over the entire breast is completely closed.     

A new procedure for refining force constants in normal coordinate calculations on large molecules

We develop a force-constant refinement procedure which we believe capable of being used in problems of large molecules and biopolymers. The procedure is based on a Green-function expression which relates changes in frequency to changes in force constants. The method does not require that assignments be made before refinment (although they may be). An expansion of this expression gives rise to a set of linear algebraic equations for the force-constant corrections, rather than an equation involving residuals to minimize. The resulting calculations are considerably simpler. This approximate is iterated to find the final refined force-constants. We discuss several methods of improving the convergence of the procedure which take into account the experimental information which may be available. Of particular interest is a scheme to select the force constants to be refined by imposing a criterion for selecting those which will fit the experimental data with the smallest changes of the force constants from their expected values. We discuss some limitations which occur for all methods of refinement applied to large molecules.     

Testing hypotheses in case-control studies--equivalence of Mantel-Haenszel statistics and logit score tests.

The two approaches in common use for the analysis of case-control studies are cross-classification by confounding variables, and modeling the logarithm of the odds ratio as a function of exposure and confounding variables. We show here that score statistics derived from the likelihood function in the latter approach are identical to the Mantel-Haenszel test statistics appropriate for the former approach. This identity holds in the most general situation considered, testing for marginal homogeneity in mK tables. This equivalence is demonstrated by a permutational argument which leads to a general likelihood expression in which the exposure variable may be a vector of discrete and/or continuous variables and in which more than two comparison groups may be considered. This likelihood can be used in analyzing studies in which there are multiple controls for each case or in which several disease categories are being compared. The possibility of including continuous variables makes this likelihood useful in situations that cannot be treated using the Mantel-Haenszel cross-classification approach.     

Chimpanzees in AIDS research: A biomedical and bioethical perspective

The present article represents a consensus view of the appropriate utilization of chimpanzees in AIDS research arrived at as a result of a meeting of a group of scientists involved in AIDS research with chimpanzees and bioethicists. The paper considers which types of studies are scientifically justifiable in this species, the conditions under which such studies should be carried out, and the conditions which should be encouraged for post-experimental retirement of these animals.     

Single-salt behavior of a symmetrical 4-site channel with barriers at its middle and ends

The theory of a symmetrical 3-barrier, 4-site, single-filing ionic channel is developed. The model goes beyond earlier models by including additional sites, as well as barriers which need not be symmetrical in the applied field, and contains the earlier models as special cases. It is itself a special case of the most general 4-site model, which has 5 barriers. By considering the barriers at the mouth and middle of the channel to be sufficiently larger than the barriers separating the sites in each channel half, these barriers can be neglected; thus this case reduces to a 3-barrier model where the sites in each channel half can then be assumed to be in equilibrium with each other. The alternative 3-barrier, 4-site case, where the barrier between the sites is considered to be larger than that at the mouth of the channel, is considered elsewhere. Pure cation permeation is considered and only single-salt properties of the system are analyzed, namely occupancy, conductance, flux ratio exponent and current-voltage relation. The concentration dependences of these properties are computed and interrelated and, where possible, also given in analytical form. The mathematical relations are obtained for a channel which is symmetrical around its middle, which is the appropriate assumption for the gramicidin channel. However, the barriers themselves are allowed to be asymmetric with respect to the potential dependence, which has been found to be essential for gramicidin. Mathematically, a straight-forward matrix formulation is used; but a general theoretical method is presented for reducing a complex model (with more than 2 sites) to a simpler cases when equilibrium exists across one or several barriers, as is often the cases. This method is a prototype which makes analytical solutions of complex barrier models possible in many cases.     

Multistep entry of rotavirus into cells: a Versaillesque dance

Rotavirus entry into a cell is a complex multistep process in which different domains of the rotavirus surface proteins interact with different cell surface molecules, which act as attachment and entry receptors. These recently described molecules include several integrins and a heat shock protein, which have been found to be associated with cell membrane lipid microdomains. The requirement during viral entry for several cell molecules, which might be required to be present and organized in a precise fashion, could explain the selective cell and tissue tropism of these viruses. This review focuses on recent data describing the virus-receptor interactions, the role of lipid microdomains in rotavirus infection and the mechanism of rotavirus cell entry.     

Microspectrophotometric quantitation of the diaminobenzidine reaction for histochemical demonstration of cytochrome oxidase activity.

Polyacrylamide models in which an extract of cattle heart mitochondria was incorporated, as well as cryostat sections of tongue muscle and epithelium, were used to set up the conditions under which the histochemical reaction for the demonstration of cytochrome oxidase can be quantitated. Using diaminobenzidine in a concentration of 5.5 mM, cytochrome C in a fixed concentration of 76 micron and keeping the incubation medium away from direct light action, enzyme activity can be evaluated by means of direct microphotometry on tissue sections. Each biologic model requires previous individual determination of the measurement limits. These limits can be readily established by using a small chamber for the incubation medium, which can be placed in the microphotometer, allowing the reaction rate to be following using a single section.     

Nonvulnerability of ecosystems in unpredictable environments

One way to bracket the effects of a real environment on an ecosystem during a finite time interval is to use the concept of vulnerability. If a deterministic model ecosystem has a good Lyapunov function, it may be possible to derive simple and useful tests for the system to be nonvulnerable. For a subset of Lotka-Volterra models, the system is nonvulnerable if the smallest eigenvalue of a certain matrix is not only positive, but is greater than a positive number, which depends on a priori estimates for the bounds on the unpredictable forcing functions. The bounded but unknown functions which act on the Lotka-Volterra equations also can be interpreted as errors in the system's equations which can be tolerated without a qualitative change in the behaviour of its solutions.     

Models of Repression of Transposition in P-M Hybrid Dysgenesis by P Cytotype and by Zygotically Encoded Repressor Proteins

By analytical theory and computer simulation the expected evolutionary dynamics of P transposable element spread in an infinite population are investigated. The analysis is based on the assumption that, unlike transposable elements which move via RNA intermediates, the harmful effects of P elements arise primarily in the act of transposition, and that this causes their evolutionary dynamics to be unusual. It is suggested that a situation of transposition-selection balance will be superceded by the buildup of a cytoplasmically inherited repression or by the elimination of active transposase-encoding elements from the chromosomes, a process which may be accompanied by the evolution of elements which encode proteins which repress transposition.     

Melting experiment concerning the topological structure of closed circular double-stranded DNA

A melting experiment was performed on the whole set of populations of the replicative form of ?X174 DNA, which can be obtained treating this DNA with rat liver nicking-closing enzyme in the presence of ethidium bromide. Gel electrophoresis performed by loading the DNA samples at neutral and alkaline pH allows separation of these populations in discrete sets of bands, which can then be compared. The outcome of the experiments indicates that in the range of electrophoretic mobilities which can be explored, no band is formed exclusively by circular complementary strands which can be separated by alkaline denaturation. These results are compared with what would be expected if double-stranded closed circular DNA had structures other than the canonical double helix. Under nonrestrictive hypotheses, the experiments reported allow one to obtain a minimum estimate of the absolute value of the linking number of a closed circular double-stranded DNA: for native ?X174 RF DNA, the linking number appears to be greater than 12 (in absolute value). Some data on the electrophoretic mobility of denatured closed circular duplexes are reported, which still wait for a physicochemical interpretation.     

The shape of the mandible in the domestic sheep: a biomechanical analysis using EMG as an estimator of muscle force

Analysis of the maximal loads to which a skeletal element is subjected in vivo offers attractive possibilities of explaining the shape of the element. The underlying assumption is that the element will be constructed in such a way that deformations (strains) which result from mechanical stress will not exceed certain limits and that stresses will be evenly distributed. The sheep mandible shows a number of characteristic morphological features that invite this kind of explanation. We investigated the patterns of activity of the masticatory musculature by multichannel electromyography, expressing the activity of any particular muscle during a given interval as a percentage of the highest activity recorded for the muscle in question. In combination with data on the physiological cross sections of the muscles, which provide indications of the maximal forces which can be exerted by the muscles, three-dimensional patterns of relative muscular forces acting on the mandible can be constructed for successive stages of a masticatory cycle. No absolute forces can be measured or even estimated by this technique. A two-dimensional finite element model of the mandible was designed, by means of which predictions of stress and strain resulting from the muscular loading can be made. Calculations were based on the highest loads that occurred, during the power stroke of rumination. It is concluded that mechanical loading of the mandible provides a partial explanation of the form, and that a more satisfactory model should include other than purely mechanical influences.     

Characterization of proteins by means of their buffer capacity, measured with an ISFET-based coulometric sensor—actuator system

Proteins form the specific selector in many biochemical sensors. A change in one of the properties of such a protein has to be detected by an appropriate transducer, which completes the biochemical sensor. One of these properties is the buffer capacity of a protein. If the binding of a substance to a protein can significantly change the proton binding, which accounts for the buffer capacity of proteins, the detection of this changed buffer capacity enables the construction of a new type of biosensor.

It will be shown that the buffer capacity can be measured with an ISFET-based sensor—actuator device. The alternating generation of protons and hydroxyl ions by alternating current coulometry at a porous noble metal actuator electrode causes an associated small pH perturbation, which is detected by the underlying pH-sensitive ISFET. The amplitude of the measured signal is a function of the buffer capacity of the solute, in which proteins can be present (or these proteins can be adsorbed in the porous actuator electrode of the device). A model describing the transfer function from the electrical input signal of the actuator to the resulting chemical output, which is subsequently detected by the ISFET pH sensor, is presented. Preliminary results of the measured buffer capacity of ribonuclease and lysozyme are presented.