Functional consequences of ultrastructural geometry in "backwards" fluid-transporting epithelia.

Many fluid-transporting epithelia possess dead-end, long, and narrow channels opening in the direction to which fluid is being transported (basal infoldings, lateral intercellular spaces, etc.). These channels have been thought to possess geometrical significance as standing-gradient flow systems, in which active solute transport into the channel makes the channel contents hypertonic and permits water-to-solute coupling. However, some secretory epithelia (choroid plexus, Malpighian tubule, rectal gland, etc.) have "backwards" channels opening in the direction from which fluid is being transported. It is shown that these backwards channels can function as standing-gradient flow systems in which solute transport out of the channel makes the channel contents hypotonic and results in coupled water flow into the channel mouth. The dependence of the transported osmolarity (isotonic or hypertonic) on channel radius, length, and other parameters is calculated for backwards channels for values of these parameters in the physiological range. In addition to backwards channels' being hypotonic rather than hypertonic, they are predicted to differ from "forwards" channels in that some restrictions are imposed by the problem of solute exhaustion, and in the presence of a sweeping-in effect on other solutes which limits the solutes that may be transported.

A definition of proximal and distal tubular compliance. Practical and theoretical implications.

Micropuncture studies were carried out in the rat to evaluate the in situ distensibility characteristics of the proximal and distal tubules under a variety of experimental conditions. In the first phase, we determined the response of tubular diameter (D) to changes in tubular pressure (P) induced by partially obstructing single tubules. The response observed under these conditions (i.e., when interstitial pressure is presumed to be constant) has been defined as the compliance of the tubule. Over the range of tubular pressures studied (10-35 mm Hg for the proximal tubule, 5-25 mm Hg for the distal tubule) the compliance characteristics of the proximal and distal tubule were found to be markedly different; the proximal tubular pressure-diameter relationship was linear, DeltaD/DeltaP = 0.45 mum/mm Hg, whereas the distal pressure-diameter relationship was curvilinear, DeltaD/DeltaP = c(-0.1xP+2.2). In the second phase we used the compliance data to construct a series of theoretical pressure-diameter curves that define the response of the tubule to increments in interstitial as well as intratubular pressure. These curves indicate that changes in distal diameter should provide a sensitive index of a rise in interstitial pressure under conditions in which the transtubular pressure gradient is increased by a small amount, but that proximal diameter should provide a more sensitive index of changes in interstitial pressure when the transtubular pressure gradient is increased by a large amount. In subsequent experiments in which furosemide was administered, we observed that the pressure-diameter relationships for both the proximal and distal tubule were indistinguishable from the compliance curves, a finding consistent with the interpretation that interstitial pressure was not appreciably changed from control. By contrast, when mannitol was administered, both proximal and distal tubular pressure-diameter relationships were significantly altered in a fashion consistent with a large increase in interstitial pressure. Neither with furosemide nor mannitol administration did it appear likely that significant changes in tubular compliance could account for the observed behavior of the tubule.Finally, we propose that a knowledge of tubular compliance will be useful in exploring the interrelationships between tubular and peritubular pressures, tubular anatomy, and transtubular ionic permeability. Recent studies linking changes in the geometry of lateral intercellular spaces of the tubule to changes in passive ion movement suggest that an investigation of such anatomical-functional correlates should be productive.

Standing-gradient osmotic flow. A mechanism for coupling of water and solute transport in epithelia.

At the ultrastructural level, epithelia performing solute-linked water transport possess long, narrow channels open at one end and closed at the other, which may constitute the fluid transport route (e.g., lateral intercellular spaces, basal infoldings, intracellular canaliculi, and brush-border microvilli). Active solute transport into such folded structures would establish standing osmotic gradients, causing a progressive approach to osmotic equilibrium along the channel's length. The behavior of a simple standing-gradient flow system has therefore been analyzed mathematically because of its potential physiological significance. The osmolarity of the fluid emerging from the channel's open end depends upon five parameters: channel length, radius, and water permeability, and solute transport rate and diffusion coefficient. For ranges of values of these parameters encountered experimentally in epithelia, the emergent osmolarity is found by calculation to range from isotonic to a few times isotonic; i.e., the range encountered in epithelial absorbates and secretions. The transported fluid becomes more isotonic as channel radius or solute diffusion coefficient is decreased, or as channel length or water permeability is increased. Given appropriate parameters, a standing-gradient system can yield hypertonic fluids whose osmolarities are virtually independent of transport rate over a wide range, as in distal tubule and avian salt gland. The results suggest that water-to-solute coupling in epithelia is due to the ultrastructural geometry of the transport route.

The effect of the unstirred layer on human red cell water permeability.

A study has been made of water entry into human red blood cells under an osmotic pressure gradient. The measurements were made using a rapid reaction stop flow apparatus, whose construction, calibration, and performance are described in detail. Red cell volume changes were determined from 90 degrees scattered light. The permeability coefficient for water entry under a relative isosmolar concentration of 1 to 1.5 was found to be 0.22 +/- 0.01 cm(4)/sec osmol, which agrees well with our previously published value. The experiments were also designed to measure the thickness of the unstirred layer around the6 red cells. This was found to be 5.5 +/- 0.8 micro under the present experimental conditions. It is concluded that our previously measured permeability coefficient for water entrance under a diffusion gradient does not require correction on account of the unstirred layer.

Meiotic recombination, cross-reactivity, and persistence in Plasmodium falciparum.

We incorporate a representation of Plasmodium falciparum recombination within a discrete-event model of malaria transmission. We simulate the introduction of a new parasite genotype into a human population in which another genotype has reached equilibrium prevalence and compare the emergence and persistence of the novel recombinant forms under differing cross-reactivity relationships between the genotypes. Cross-reactivity between the parental (initial and introduced) genotypes reduces the frequency of appearance of recombinants within three years of introduction from 100% to 14%, and delays their appearance by more than a year, on average. Cross-reactivity between parental and recombinant genotypes reduces the frequency of appearance to 36% and increases the probability of recombinant extinction following appearance from 0% to 83%. When a recombinant is cross-reactive with its parental types, its probability of extinction is influenced by cross-reactivity between the parental types in the opposite manner; that is, its probability of extinction after appearance decreases. Frequencies of P. falciparum outcrossing are mediated by frequencies of mixed-genotype infections in the host population, which are in turn mediated by the structure of cross-reactivity between parasite genotypes. The three leading hypotheses about how meiosis relates to oocyst production lead to quantitative, but no qualitative, differences in these results.

A target for intervention in Plasmodium falciparum infections.

We present a set of simple mathematical models to investigate interactions between malaria parasites and the human immune system and the differentiation of parasites from asexual, pathogenic into sexual, transmissible blood stages. Each model represents a different combination of empirically based hypotheses, and salient behaviors of each fit criteria developed from clinical data. In all models, however, higher gametocyte conversion rates result in lower peak asexual-form densities. Therefore, to the extent that asexual-form densities are associated with disease symptoms, interventions that stimulate gametocytogenesis should produce unexpected clinical benefits.

Mixed-species Plasmodium infections of Anopheles (Diptera:Culicidae)

Mixed-pathogen infections of vectors rarely are considered in the epidemiological literature, although they may occur in nature. A review of published reports shows that many Anopheles species are capable of carrying sporozoites of > 1 Plasmodium species, of doing so simultaneously in field conditions, and of acquiring and transmitting these in experimental situations. Mixed-species infections in mosquito populations occur at frequencies greater than or equal to the product of the constituent species prevalences, whereas human populations have apparent mixed-species infections at frequencies less than or equal to their corresponding expected values. We present a model for the accumulation of parasite infections over the lifespan of a mosquito that explains this surplus of mixed-species infections. However, the expected frequencies of mixed infections on the basis of our model are greater than those found in nature, indicating that the sampling by mosquitoes of Plasmodium species from human malaria infections may not be random.

Mixed-species Plasmodium infections of humans.

We analyzed point-prevalence data from 35 recent studies of human populations in which Plasmodium falciparum and one other Plasmodium species were the reported causes of malaria infections. For the P. falciparum-Plasmodium vivax pair, higher overall prevalence in a human population is associated with fewer mixed-species infections than expected on the basis of the product of individual species prevalences. This is not true for P. falciparum-Plasmodium malariae.

Multispecies Plasmodium infections of humans.

We analyzed point-prevalence data from 19 recent studies of human populations in which either Plasmodium ovale or Plasmodium vivax co-occur with Plasmodium falciparum and Plasmodium malariae. Although the only statistical interactions among, sympatric congeners are pairwise, the frequencies of mixed-species infections relative to standard hypotheses of species sampling independence show no strong relation to overall malaria prevalence. The striking difference between the P. falciparum-P. malariae-P. ovale and the P. falciparum-P. malariae-P. vivax data is that the first typically shows a statistical surplus of mixed-species infections and the second a deficit. This suggests that the number of Plasmodium species present in a human population may be less important in determining the frequencies of mixed-species infections than is the identity of those species.

Social evaluation with variable population size: an alternative concept.

This paper deals with some consequences of certain population changes on social welfare considerations. In particular, a general concept for expressing value judgments about how the addition of 1 further agent to some given society should affect social welfare and a replication invariance condition are introduced and discussed. An axiomatic framework for welfare orderings based on a generalized averaging procedure applied to individual utilities is provided.

Leximin population ethics.

This paper concerns the ethical issues that arise when policy decisions have to be taken that affect population size and characteristics. Such policies include social security systems, intertemporal resource allocation decisions, and policies designed to influence fertility rates. The authors provide characterizations of Leximin principles for social evaluation in an intertemporal framework, so that they can be used to compare social alternatives with different population sizes. "The main axioms used in our characterizations are Hammond Equity together with Independence of the Utilities of the Dead (a plausible intertemporal consistency requirement) for the Critical-Level Leximin principles, and Positional Leximin Consistency (an axiom that allows non-constant critical levels) for the Positional-Extension Leximin principle. The performance of these principles is compared in the pure population problem and we argue that the Critical-Level Leximin principles are ethically more attractive than Positional-Extension Leximin."

Intertemporal population ethics: critical-level utilitarian principles.

"This paper considers the problem of social evaluation in a model where population size, individual lifetime utilities, lengths of life, and birth dates vary across states. In an intertemporal framework, we investigate principles for social evaluation that allow history to matter to some extent. Using an axiom called independence of the utilities of the dead, we provide a characterization of critical-level generalized utilitarian rules. As a by-product of our analysis, we show that social discounting is ruled out in an intertemporal welfarist environment. A simple population-planning example is also discussed."

The dynamics of Plasmodium falciparum blood-stage infection.

We develop a system of ordinary differential equations to model the dynamics of the blood-stages of the malaria parasite, Plasmodium falciparum. Variants of the model allow the study of a set of hypotheses about the interaction of the parasite with the host immune system, in particular with regard to the stimulation of the immune response and the regulation of the rate of conversion from the pathogenic, asexual to the transmissible, sexual blood stage. The values of several parameters of our models can be estimated from previous empirical work. Although the dynamics of the variants differ somewhat, in each variant some set of values of the three unconstrained parameters, different from one variant to the next, produces a range of behaviours quantitatively consistent with those reported from clinical studies. Some parameter values produce infections which quickly terminate, while others approach a chronic equilibrium level or produce oscillations, with repeated severe peaks separated by periods of undetectable parasitemia. We examine these and several other distinctions that might be used to assess model variants and focus further empirical research.

[Analysis of health care needs and evaluation five years after severe brain injuries]. / Bedürfnisanalyse und Bilanz 5 Jahre nach schweren Hirnverletzungen.

Five years after severe head injury with persistent and extensive deficits of brain functions and loss of working capacity, an assessment and analysis of demand was performed with 31 patients and their relatives. The main impairments consist in the severe changes of personality and in cognitive deficits; they contrast with the spare physical handicaps. A main demand of the relatives are local family groups which are still lacking in many parts of the country.

Uncertainty and critical-level population principles.

PIP: The authors explore social evaluation with a variable population size in the presence of uncertainty using a timeless framework based upon individual lifetime utilities rather than utilities during a single period. Some standard fixed-population axioms are complemented with an axiom termed the "independence of the utilities of unconcerned individuals," a variable-population version of "separability with respect to unconcerned individuals." Characterizations of expected-utility versions of critical-level generalized utilitarian rules are provided. The principles evaluate lotteries over possible states of the world on the basis of the sum of the expected values of differences between transformed utility levels and a transformed critical level, conditional upon the agents being alive in the states being considered. At the same time, the critical-level utilitarian value functions applied to weighted individual expected utilities can be used. Weights are determined by the anonymity axiom.^ieng

Birth-date dependent population ethics: critical-level principles.

"This paper investigates birth-date dependent principles for social evaluation in an intertemporal framework in which population size may vary. We weaken the strong Pareto principle in order to allow individuals' birth dates to matter in establishing a social ordering. Using the axiom independence of the utilities of the dead, we characterize population principles with a recursive structure. If the individual substitution principle and an individual intertemporal equivalence axiom are added, birth-date dependent generalizations of the critical-level generalized utilitarian principles result. Stationarity leads to the special case of geometric discounting."

The optimal production of gametocytes by Plasmodium falciparum.

We use a simple model of the blood-stage infection dynamics of the malaria parasite Plasmodium falciparum to consider the adaptive significance of different rates of conversion from its pathogenic, asexual stages to its transmissible, sexual forms. We find that maximize transmissivity in single-strain infections are generally greater than the highest rates reported for in vitro cultures and are several times those for which the behavior of the model is consistent with clinical profiles of infection dynamics. When two strains that share a common immune agent coinfect a host through simultaneous inoculation or sequential superinfection, however, a strain with a lower, clinically-consistent value of the conversion rate inhibits the transmissivity of one with the higher value optimal for single-strain infection. Hence we suggest that "apparent" competition by way of a common immune response might be responsible for selection of the former.

The blood-stage dynamics of mixed Plasmodium malariae-Plasmodium falciparum infections.

We present the first mathematical model of the within-host dynamics of a mixed-species malaria infection in a human: the blood-stage population dynamics of a dual infection with Plasmodium malariae and Plasmodium falciparum. Our results reproduce several important features of such infections in nature, including the asymmetry of species asexual-form densities, inter-specific suppression through interactions with the human immune system, and seasonal alternations in species prevalence. Most importantly, our results suggest that an existing P. malariae infection can reduce the peak parasitemia of a subsequent P. falciparum superinfection by as much as 50%. This result integrates numerous empirical observations and supports the hypothesis that clinical outcomes of P. falciparum infections may be influenced by the presence of a congener.

Ventilatory response to chronic metabolic acidosis and alkalosis in the dog.

Systematic data are not available with regard to the anticipated appropriate responses of arterial PCO2 to primary alterations in plasma bicarbonate concentration. In the present study, we attempted to rigorously characterize the ventilatory response to chronic metabolic acid-base disturbances of graded severity in the dog. Animals with metabolic acidosis produced by prolonged HCl feeding and metabolic alkalosis of three different modes of generation, i.e., diuretics (ethacrynic acid or chlorothiazide), gastric drainage, and administration of deoxycorticosterone acetate (alone or in conjunction with oral sodium bicarbonate), were examined. The results indicate the existence of a significant and highly predictable ventilatory response to chronic metabolic acid-base disturbances. Moreover, the magnitude of the ventilatory response appears to be uniform throughout a wide spectrum of chronic metabolic acid-base disorders extending from severe metabolic acidosis to severe metabolic alkalosis; on average, arterial PCO2 is expected to change by 0.74 Torr for a 1-meq/l chronic change in plasma bicarbonate concentration of metabolic origin. Furthermore, the data suggest that the ventilatory response to chronic metabolic alkalosis is independent of the particular mode of generation.