Anti-retinal Autoantibodies in Hydroxychloroquine Eye Toxicity.

Objective: Autoimmune retinopathy and hydroxychloroquine (HCQ)-related retinal toxicity share many similarities, raising the possibility autoimmunity plays a role in HCQ retinopathy. The objective of this study is to determine whether patients diagnosed with HCQ retinal toxicity are more likely to have circulating antiretinal autoantibodies (AAbs) compared to controls.

Methods: We tested plasma samples for the presence of anti-retinal AAbs by immunoblotting in 270 patients with systemic lupus erythematosus (SLE) receiving HCQ.

Qualitative theory of compartmental systems with lags.

Dynamic models of many processes in the biological and physical sciences give systems of ordinary differential equations called compartmental systems. Often, these systems include time lags; in this context, continuous probability density functions (pdfs) of lags are far more important than discrete lags. There is a relatively complete theory of compartmental systems without lags, both linear and non-linear [SIAM Rev.

Density functions of residence times for deterministic and stochastic compartmental systems.

A significant consideration in modeling systems with stages is to obtain models for the individual stages that have probability density functions (pdfs) of residence times that are close to those of the real system. Consequently, the theory of residence time distributions is important for modeling. Here I show first that linear deterministic compartmental systems with constant coefficients and their corresponding stochastic analogs (stochastic compartmental systems with linear rate laws) have the same pdfs of residence times for the same initial distributions of inputs.

Fisher's randomization test and Darwin's data -- a footnote to the history of statistics.

In the presentation of his randomization test for paired data, Fisher used Darwin's data on the relative growth rates of cross- and self-fertilized corn to motivate the development. On reading Darwin's description of his experiment, it appears clear that the experiment did not use true paired comparisons. Although the statistical foundation of Fisher's randomization test is sound, it is of historical interest that it does not suit the design of the motivating experiment.

Mother-to-child transmission of HIV-1.

After reviewing the evidence on the relation of vertical transmission of HIV to stage of infection in the mother, I developed a stochastic model of transmission in which the probability of transmission per week is proportional to the virus load in the mother. The virus load in different stages of the infection is measured by viral RNA levels or tissue culture infectious virus levels in plasma. The constant of proportionality is assumed to be different for transmission during pregnancy, during parturition, and during breast-feeding.

The role of early HIV infection in the spread of HIV through populations.

The combination of two factors gives early HIV infection an especially strong influence on transmission dynamics: (a) increased transmission probabilities and (b) increased transmission potential of partners infected during this period. Most attention has been focused on the first factor because it fits the way we usually think about risk factors affecting individuals. The second factor acts not on individuals, but across chains of transmission.

Use of parallel Erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs.

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model.

Parameter identifiability is required in pooled data methods.

In pooled data methods such as naive pooled data methods and NONMEM, the number of sample points per individual may be less than the number of unknown parameters so that the values of the parameters are not estimable in individuals. However, for the moments of the distributions of the parameters to be estimable, the basic parameters must be identifiable.

Hypoglycemia counterregulation in elderly humans: relationship to glucose levels.

This study was designed to define the effect of human aging on hypoglycemia counterregulatory mechanisms. A hyperinsulinemic (2 mU.kg-1.

The stochastic SI model with recruitment and deaths. I. Comparison with the closed SIS model.

We compare the stochastic and deterministic versions of an SI model with recruitment, background deaths, and deaths due to the disease. For the stochastic version, analysis of the mean number of susceptibles, mx, and infecteds, m(y), and of the means conditioned on nonextinction of the infection, m*x and m*y, shows that (1) if R0 < or = 1, the disease dies out monotonically for the deterministic and stochastic models, and (2) if R0 > 1, the disease dies out early with a probability close to (1/R0)a, where a is the number of infecteds introduced, or m(y) rises to a peak and then dies out slowly. For small populations, N, the peak is an obvious maximum.

Theory of production rate calculations in steady and non-steady states and its application to glucose metabolism.

I present a review and synthesis of the basic theory, steady state, and non-steady state for the calculation of metabolite production rates for systems that have a central well-mixed compartment that is the site of tracer input and sampling. The theory is then applied to the calculation of glucose production. If the only inputs are into the central compartment, an experimental design that involves varying tracer infusion rates to maintain constant specific activity in the central compartment and the same constant specific activity in the peripheral compartments allows calculation of the endogenous production.

Reproduction numbers and thresholds in stochastic epidemic models. I. Homogeneous populations.

We compare threshold results for the deterministic and stochastic versions of the homogeneous SI model with recruitment, death due to the disease, a background death rate, and transmission rate beta cXY/N. If an infective is introduced into a population of susceptibles, the basic reproduction number, R0, plays a fundamental role for both, though the threshold results differ somewhat. For the deterministic model, no epidemic can occur if R0 less than or equal to 1 and an epidemic occurs if R0 greater than 1.

Assessing risk factors for transmission of infection.

Commonly used measures of effect, such as risk ratios and odds ratios, may be quite biased when used to assess the effect of factors that alter transmission risks given exposure to infected individuals. This is demonstrated in a simulation model involving a higher-risk behavior and a lower-risk behavior affecting the sexual transmission of human immunodeficiency virus. The bias arises because population contact patterns between higher-risk and lower-risk persons change their relative probabilities of exposure to an infected individual as an epidemic progresses.

Identifiability and parameter estimation.

In experiments on biological systems one often cannot measure all state variables (compartments). Given a particular experiment of that type, a basic kinetic parameter may have no effect on the observations; such a parameter is an insensible parameter for that experiment. A parameter may influence the observations and not be uniquely determinable; such a parameter is nonidentifiable for that experiment.

The effects of population structure on the spread of the HIV infection.

A model for the spread of human immunodeficiency virus (HIV) in a population of male homosexuals is presented. The population is divided into five groups on the basis of degree of sexual activity. Within each group, the individuals are classified as 1) susceptible; 2) infective; or 3) removed because of a lack of sexual activity associated with advanced acquired immunodeficiency disease (AIDS).

Parameter estimation: local identifiability of parameters.

For biological systems one often cannot set up experiments to measure all of the state variables. If only a subset of the state variables can be measured, it is possible that some of the system parameters cannot influence the measured state variables or that they do so in combinations that do not define the parameters' effects separately. Such parameters are unidentifiable and are in theory unestimable.

A resource facility for kinetic analysis: modeling using the SAAM computer programs.

Kinetic analysis and integrated system modeling have contributed significantly to understanding the physiology and pathophysiology of metabolic systems in humans and animals. Many experimental biologists are aware of the usefulness of these techniques and recognize that kinetic modeling requires special expertise. The Resource Facility for Kinetic Analysis (RFKA) provides this expertise through: (1) development and application of modeling technology for biomedical problems, and (2) development of computer-based kinetic modeling methodologies concentrating on the computer program Simulation, Analysis, and Modeling (SAAM) and its conversational version, CONversational SAAM (CONSAM).

Inhibition of adenylate cyclase is mediated by the high affinity conformation of the alpha 2-adrenergic receptor.

The functional significance of high affinity agonist binding to receptors that interact with guanine nucleotide regulatory proteins has remained controversial. Preincubation of human platelet membranes with the full alpha 2-agonist UK 14,304 in the absence of GTP increases the potency of the agonist to inhibit adenylate cyclase in a pre-steady state (15-sec) assay. The EC50 after preincubation (6 +/- 1 nM) is within a factor of 2 of the high affinity Kd for [3H]UK 14,304 binding determined under identical conditions (2.

Effect of sodium-restricted diet and posture on norepinephrine kinetics in humans.

We used compartmental analysis to analyze the kinetics of distribution and metabolism of norepinephrine (NE) and to determine whether the increase in plasma norepinephrine concentration (PNE) during sodium restriction in humans is due to sympathetic nervous system (SNS) activation. [3H]-NE infusion and postinfusion decay were measured in young subjects in the supine position and during 60 min of standing during normal sodium (NS) diet and after 7 days of 10 meq/day sodium-restricted (SR) diet. The mean supine PNE was greater during SR diet compared with NS diet (154 +/- 9 vs.

Sexual partner selectiveness effects on homosexual HIV transmission dynamics.

Deterministic simulation models are used to show that HIV transmission dynamics in homosexual populations can be strongly affected by sexual partner selectiveness. The type of selectiveness or biased mixing examined is where individuals with similar new partnership formation rates are more likely to form a pair than would be expected by chance. The effect of such selectiveness could be strong even when the total number and distribution of new sexual partnerships and sex acts remains constant.

Norepinephrine metabolism in humans. Kinetic analysis and model.

The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [3H]NE infusion and postinfusion plasma disappearance of [3H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [3H]NE disappearance curves of each subject studied in the supine (r = 0.

Identifiability: the first step in parameter estimation.

The observations in an experiment define a set of observational parameters that are functions of the basic kinetic parameters of the model of the system. The problem of identifiability is concerned with whether the observational parameters uniquely specify the basic kinetic parameters. As such, it depends only on the functional relation between the two levels of parameters and not on errors of observation and the estimation procedure.

Does myoglobin contribute significantly to diffusion of oxygen in red skeletal muscle?

We have examined the role of myoglobin to facilitate O2 diffusion to active mitochondria in skeletal muscle by constructing computer-simulation experiments. Steady-state mitochondrial O2 consumption under different conditions of supply partial pressure of O2 (PO2) in a system with and without myoglobin were examined for a one-dimensional slab of tissue. O2 consumption by mitochondria was saturable with the mitochondria located in bands at uniform intervals throughout the tissue.