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PubMed2004

The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease.

Why do we get the stress-related diseases we do? Why do some people have flare ups of autoimmune disease, whereas others suffer from melancholic depression during a stressful period in their life? In the present review possible explanations will be given by using different levels of analysis. First, we explain in evolutionary terms why different organisms adopt different behavioral strategies to cope with stress. It has become clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population. The existence of these personality types (Hawks-Doves) is widespread in the animal kingdom, not only between males and females but also within the same gender across species. Second, proximate (causal) explanations are given for the different stress responses and how they work. Hawks and Doves differ in underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks preferentially adopt the fight-flight response when establishing a new territory or defending an existing territory, while cautious Doves show the freeze-hide response to adapt to threats in their environment. Thus, adaptive processes that actively maintain stability through change (allostasis) depend on the personality type and the associated stress responses. Third, we describe how the expression of the various stress responses can result in specific benefits to the organism. Fourth, we discuss how the benefits of allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and disease, thereby reinforcing a Darwinian concept of stress. Collectively, this provides some explanation of why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and non-aggressive Doves in a population. A conceptual framework is presented showing that Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and inflammation. In contrast, Doves, due to the greater release of mediators of allostasis (surplus), are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states and infection.

Adaptation, Physiological↗

PubMed2005

Mosaic monosomy of a neocentric ring chromosome maps brachyphalangy and growth hormone deficiency to 13q31.1-13q32.3.

We describe a boy with moderate intellectual disability associated with distinctive hand malformations (hypoplastic and angel-shaped middle phalanges) and partial growth hormone (GH) deficiency associated with mosaic deletion of 13q31.1-13q32.3. The deleted segment was mapped to a 20-Mb region bounded by BACs RP11-1143C2 and RP11-139C1, narrowing the previously described locus for hand malformations at this region and suggesting that a locus for GH deficiency is also present at this location. The deleted segment contains at least three candidate genes, glypican-5, FARP1 and SOX21, that may be contributing to the phenotype in this boy. In a significant proportion (approximately 50%) of cells, the deleted region is present as a supernumerary ring chromosome stabilized by the formation of a neocentromere at 13q31-q32, within a region with a known propensity for neocentromere formation. The ring chromosome appears to be prone to low-level misdivision and loss in vitro which, in vivo, must be countered by selection for the balanced karyotype because the level of mosaicism has remained stable over 13 years.

Abnormalities, Multiple↗

PubMed1998

Evolutionarily stable mutation rates.

I investigate the hypothesis that mutation rates in natural populations are determined by a balance between: (1) selection against deleterious mutations favouring lower mutation rates, and (2) selection opposing further reduction of the mutation rate, resulting from the costs incurred by more stringent proof-reading and repair (for example, a reduction in the rate of DNA replication). The influence of advantageous mutations is assumed to be negligible. In a previous paper, I analysed the dynamics of a modifier of the mutation rate in a large sexual population, where (infinitesimally rare) deleterious alleles segregate at an infinite number of unlinked loci with symmetric multiplicative fitness effects. A simple condition was obtained for a modifier allele to increase in frequency. Remarkably, this condition does not depend on the allele frequencies at the modifier locus. Here, I show that (as a consequence), given any set of possible values of the mutation rate (any set of possible modifier alleles), there always exists a single globally stable value of the mutation rate. This is an unusually strong form of "evolutionary stability" for a sexual population. Less surprisingly the optimum mutation rate in an asexual population has similar stability properties. Furthermore, in the case of an asexual population, it is not necessary to make any special assumptions about the selection acting against deleterious mutations, except that a deterministic mutation-selection equilibrium exists. I present a simple method for identifying the evolutionarily stable value of the mutation rate, given the function alpha(U) relating the value of the mutation rate to the fitness cost of maintaining this rate. I also argue that if there is a highly conserved relationship between the rate of replication per base, and the rate of mutation per base, and if this relationship has the form of a power law, then the remarkable uniformity of the per genome mutation rate in DNA based microbes can be explained.

Animals↗

PubMed1988

A combined regimen of subcutaneous lisuride and oral Madopar HBS in Parkinson's disease.

At the first stage of a pilot study involving 14 parkinsonians with motor fluctuations, treatment with standard Madopar was substituted by a sustained-release form, Madopar HBS, which attenuated fluctuations in patients with end-of-dose impairment, but achieved only moderate improvement in patients with on-off phenomena. In a second phase of the trial, 4 parkinsonians exhibiting the most severe fluctuations of mobility and the poorest response to Madopar HBS (Hydrodynamically Balanced System) were selected for treatment with a combined regimen utilizing subcutaneous lisuride infusions as the additional component. The sequence of the trial was as follows: 1. standard Madopar, 2. Madopar HBS, 3. standard Madopar combined with lisuride infusions and 4. Madopar HBS combined with lisuride infusions. Steady improvement was observed along the lines of this schedule, but the best results were obtained when Madopar HBS was combined with lisuride infusions. Subsequently motor fluctuations were less marked or disappeared, early-morning Parkinson symptoms decreased and dystonia was not recorded any longer. Even better results could be accomplished in an extended trial attempting to establish the best dosage ratio of the combination, possibly admitting increased dosage. The tolerance of the combined regimen was excellent, except in one patient who transiently exhibited delusions and postural hypotension. The combination of sustained-release Madopar and continuous infusions of the dopaminergic agonist lisuride seems to prove a more physiological and effective regimen for the treatment of severe motor fluctuations.

Administration, Oral↗

PubMed1995

Intravenous dopexamine in the treatment of acute congestive heart failure: results of a multicenter, double-blind, placebo-controlled withdrawal study.

Acute hemodynamic effects of intravenous infusion of dopexamine were evaluated by a placebo-controlled withdrawal study in patients with acute congestive heart failure. Twenty patients were enrolled at 10 centers in Japan. All patients had a pulmonary capillary or diastolic pressure of 15 mmHg or greater and a cardiac index of 2.5 l/min/m2 or less. Phase I: Intravenous dopexamine was introduced in a single-blind, uncontrolled fashion at the rate of 0.5 micrograms/kg/min and was titrated up to achieve a 30% or more increase in the cardiac index. Two patients withdrew from the study due to sinus tachycardia and ventricular ectopy or exacerbation of heart failure. Phase II: The remaining 18 responders who were free of limiting side effects were randomized in double-blind fashion to continue dopexamine or to switch to placebo for an additional 60 minutes. At the end of phase II, the hemodynamic improvement obtained in phase I of the study disappeared completely after substitution of placebo but was maintained in dopexamine-treated patients. Our findings suggest that dopexamine, when given in appropriate doses to selected patients, shows balanced vasodilator action suitable for the treatment of acute congestive heart failure.

Acute Disease↗

PubMed1998

A DICOM document-oriented approach to PACS infrastructure.

The need for long-term storage requires the future migration of image data from a PACS to its successor system. This paper considers the cost of such migration It is proposed that storage of data as "documents" in DICOM Part 10 formats on industry-standard media could reduce the time and cost of data migration relative to on-line DICOM transfer. The relation to present efforts in developing document-oriented electronic patient records is discussed. DICOM Part 10 files are found to be a sufficient representation of image documents, but additional software tools will be needed to reach its full potential. There is a significant cost benefit of the document storage method, but it is one of many factors which must be balanced in the selection of a PACS.

Costs and Cost Analysis↗

PubMed2004

Fractures of the proximal humerus in osteoporotic bone.

The purpose of this article was to review critically the current treatment options for fractures of the proximal humerus in patients with severe osteoporosis. The main difficulties lie in correctly diagnosing the fracture and hence selecting the most appropriate method of treatment. The reliability of the diagnosis can be increased by systematically appending additional information to a basic fracture classification. Classification is best carried out on a morphological basis, whereby a descriptor of bone quality can be added in order to introduce the degree of osteoporosis into the decision-making algorithm. Any classification system that claims to provide both treatment and prognosis is inappropriate, because prognosis will depend hopefully on the treatment. Approaches to treatment differ widely amongst centers and surgeons. It is still unclear as to what would be the optimal treatment. Factors such as the individual's functional requirements and ability to cooperate should be given careful consideration. At our institution, hemiarthroplasty is the method of choice for ischemic humeral heads and/or when anatomic reconstruction cannot be obtained. In all other displaced fractures, the main objective is preservation of the head since the best functional results can generally be obtained with internal fixation. Selection of a balanced osteosynthesis, adapted to the weak bone, is mandatory. Bulky, stiff implants are inadequate and may cause additional damage. Load sharing, not load bearing, compound constructions are the aim. Obtaining metaphyseal elastic buttressing is the key element in achieving the necessary load-sharing fixation. The system should allow controlled impaction and be forgiving towards occasional load peaks that will occur and are beyond patient control. Thin and flexible implants are required to realize this type of fixation. Given the polypragmatic approach that is current in clinical practice there is room for further improvement of techniques and implants.

Arthroplasty↗

PubMed2001

Evolution of Mhc class II B genes in Darwin's finches and their closest relatives: birth of a new gene.

The 15 extant species of Darwin's finches on the Galápagos and Cocos Islands are the products of an unfinished adaptive radiation from a founder flock of birds related to the South American species Tiaris obscura. Molecular characterization of their major histocompatibility complex ( Mhc) class II B genes has revealed the existence of several related groups of sequences (presumably encoded in distinct loci) from which one (group 5) stands out because of its low divergence over extended time periods. Analysis of group 5 exon 2 and intron 2 sequences has revealed that the encoding locus apparently arose 2-3 million years ago in the Tiaris group of South and Central American Thraupini. The locus shows no evidence of inactivation, but displays a very low degree of polymorphism, both in terms of number of alleles and genetic distances between alleles. Some of the polymorphism, however, appears to be trans-specific. All the observed intergenic differences can be explained by point mutations and most of the exon 2 changes represent non-synonymous substitutions, although the rate of non-synonymous and synonymous substitutions appears to be the same. The origin of the new locus is explained by the birth-and-death model of Mhc evolution with two important extensions. First, the ancestor of the group 5 genes may have arisen without new gene duplication and second, the birth of the new group may have been brought about by a switch from balancing to directional selection. The ancestor of the group 5 genes may have been a classical class II B allele (one of many) which directional selection fixed in the ancestral population and drove into the category of nonclassical genes.

Animals↗

PubMed2000

Adaptive walks by the fittest among finite random mutants on a Mt. Fuji-type fitness landscape. II. Effect of small non-additivity.

We examined properties of adaptive walks by the fittest on "rough Mt. Fuji-type" fitness landscapes, which are modeled by superposing small uncorrelated random component on an additive fitness landscape. A single adaptive walk is carried out by repetition of the evolution cycle composed of (1) mutagenesis process that produces random d-fold point mutants of population size N and (2) selection process that picks out the fittest mutant among them. To comprehend trajectories of the walkers, the fitness landscape is mapped into a (x, y, z)-space, where x, y and z represent, respectively, normalized Hamming distance from the peak on the additive fitness landscape, scaled additive fitness and scaled nonadditive fitness. Thus a single adaptive walk is expressed as the dynamics of a particle in this space. We drew the "hill-climbing" vector field, where each vector represents the most probable step for a walker in a single step. Almost all of the walkers are expected to move along streams of vectors existing on a particular surface that overlies the (x, y)-plane, toward the neighborhood of a characteristic point at which a mutation-selection-random drift balance is reached. We could theoretically predict this reachable point in the case of random sampling search strategy.

Biological Evolution↗

PubMed1994

Effect of a cafeteria diet on energy intake and balance in Wistar rats.

The energy balance and nutrient selection strategies of 30-day-old Wistar rats offered a reference pellet and a seven-item cafeteria diet were studied in two consecutive 15-day periods: 30-45 and 45-60 days after birth. Cafeteria-fed rats grew faster, incorporating more fat and water, but a similar amount of protein to reference-fed animals. In the second 15 days all rats ate less and produced less heat than in the first 15 days. Reference-fed rats also deposited less energy in their bodies, in contrast to the tendency towards higher carcass energy deposition in cafeteria-fed rats. Cafeteria-fed rats selected much more fat and sugars than controls, with similar protein and less starch; in the second period studied, cafeteria-fed rats significantly increased their sugar consumption, with no change in fat or protein. It is suggested that the switch to selecting more sugars may be an essential factor in the shift towards increased fat deposition at the expense of heat production in cafeteria-fed rats.

Animals↗

PubMed1984

Evolution and intraspecific exploitative competition. II. A two-locus model for additive gene effects.

A two-locus model corresponding to the model of Christiansen and Loeschcke (1980, theoret, Popul. Biol. 18, 297-313) is analysed. The two loci each have two alleles, and the loci influences a character which determines the utilization of resources in a one-dimensional continuum. The analysis of the model is supported by numerical iterations of the recurrence equations. The previous prediction of high linkage disequilibrium for small allele contributions to the character and close linkage between the loci is confirmed. For larger allele contributions results comparable to those for the symmetric viabilities model are obtained. The model degenerates when the allele contributions at the two loci are equal, i.e., in the most symmetric situation. The results are discussed as the outcome of a balance between optimizing selection and disruptive selection. For small allele contributions the results are virtually independent of which genotype is most favoured by the optimizing aspect of the selective forces.

Alleles↗

PubMed1992

Antagonist muscle inhibition before rapid voluntary movements of the human wrist.

When a fast voluntary movement is performed from a background condition of sustained antagonist muscle activation, there is often a decrease in antagonist muscle activity before the onset of the first agonist muscle burst (AG1) that continues until the onset of the antagonist muscle burst (ANT). We studied how controlling the peak velocity, movement size, and the magnitude of antagonist muscle loading affected antagonist muscle inhibition (AntI). AntI was more pronounced during movements with lower velocity and greater size, and when performed in the direction of heavier background loads, but its variation could not be related to any single kinematic or kinetic variable in all circumstances. When AntI was larger, ANT was smaller, suggesting that AntI does not play a role similar to the premotor silence of the agonist seen before AG1 when the movement is made from a background of sustained agonist contraction. When AntI was larger, the size of AG1 was also smaller, showing that, according to the motor task, different levels of reciprocal inhibition and coactivation occur at the onset of the movement. Both AG1 and AntI produce force in the direction of the desired movement, and the central nervous system selects an appropriate balance between the two, using AntI when possible.

Adult↗

PubMed2005

Using models of nucleotide evolution to build phylogenetic trees.

Molecular phylogenetics and its applications are popular and useful tools for making comparative investigations in genetics; however, estimating phylogenetic trees is not always straightforward. Some phylogenetic estimators use an explicit model of nucleotide evolution to estimate evolutionary parameters such as branch lengths and tree topology. There are many models to choose from, and use of the optimal model for a particular data set is important to avoid a loss of power and accuracy in phylogenetic estimations. Here, we review some molecular evolutionary forces and the parameters included in some common models of evolution used to interpret resulting patterns of molecular variation. We present some statistical methods of selecting a particular model of nucleotide evolution, and provide an empirical example of model selection. Statistical model selection strikes a balance between the bias introduced by some models and the increased variance of parameter estimates that results from using other models.

Animals↗

PubMed2005

Immunogenetics of killer cell immunoglobulin-like receptors.

The killer cell immunoglobulin receptor locus (KIR) on human chromosome 19 encodes activating and inhibitory receptors that are expressed principally by NK cells but also by subpopulations of T cells. For some of the KIR the ligands are known to be MHC class I molecules, for others ligands are elusive. In humans the KIR locus is highly diverse. KIR haplotypes differ in gene content and the individual genes exhibit allelic polymorphism; these two components work together to diversify haplotypes, which in pairwise combination diversify human KIR genotypes. The divergence of KIR between different human populations, as well as between closely related hominoid species, seem likely to be the products of balancing and directional selection upon the functions of KIR-expressing lymphocytes. Consistent with this model are the results of several studies associating KIR differences with disease susceptibility, immune responsiveness and events following allogeneic transplantation.

Bone Marrow Transplantation↗

PubMedDate not supplied

Vitamin and mineral status: effects on physical performance.

Public health recommendations encourage the selection of a balanced diet and increasing physical activity to foster health and well-being. Whereas the adverse effects of restricted intakes of protein, fat, and carbohydrate on physical performance are well known, there is limited information about the impact of low intakes of vitamins and minerals on the exercise capacity and performance of humans. Physically active people generally consume amounts of vitamins and minerals consistent with the recommendations for the general public. However, when intakes are less than recommendations, some noticeable functional impairments occur. Acute or short-term marginal deficiencies, identified by blood biochemical measures of vitamin B status, had no impacts on performance measures. Severe deprivation of folate and vitamin B12 result in anemia and reduce endurance work performance. Evidence of vitamin A and E deficiencies in athletic individuals is lacking apparently because body storage is appreciable. In contrast to vitamins, marginal mineral deficiencies impair performance. Iron deficiency, with or without anemia, impairs muscle function and limits work capacity. Magnesium deprivation increases oxygen requirements to complete submaximal exercise and reduces endurance performance. Use of vitamin and mineral supplements does not improve measures of performance in people consuming adequate diets. Young girls and individuals participating in activities with weight classifications or aesthetic components are prone to nutrient deficiencies because they restrict food intake and specific micronutrient-rich foods. This information will be useful to professionals who counsel physically active people and scientific groups who make dietary recommendations to improve health and optimize genetic potential.

Ascorbic Acid↗

PubMed2000

Relations between variable rates of growth, metabolic costs and growth efficiencies in individual Sydney rock oysters (Saccostrea commercialis).

Rock oysters from a mass selection trial were compared with wild-caught (control) oysters of the same age to determine the physiological basis for faster growth rates amongst the selected individuals, and to describe the associated flexibility in phenotypic traits of feeding, metabolism and growth. In confirmation of earlier studies, fast growth was associated with faster rates of feeding, reduced metabolic rates and lower metabolic costs of growth. Selected individuals deposited more protein, at a lower metabolic cost, than the controls. Control oysters, however, deposited more lipid than the selected oysters, though the unit costs of lipid deposition did not differ between categories. The results indicated a wide plasticity of physiological rates and efficiencies and demonstrated how, by selection, interactions between physiological traits can serve to enhance growth. If differences in lipid deposition observed here were indicative of different rates of gametogenesis, then the results also suggest that selection alters the balance between growth and reproduction. Whether these differences can be termed compensatory with respect to the life history of the species remains to be determined, but the results indicate some of the ways in which physiological flexibility may be expressed to effect different patterns of energy allocation.

Journal Article↗

PubMed2003

Thermodynamical interpretation of an adaptive walk on a Mt. Fuji-type fitness landscape: Einstein relation-like formula holds in a stochastic evolution.

We have theoretically studied the statistical properties of adaptive walks (or hill-climbing) on a Mt. Fuji-type fitness landscape in the multi-dimensional sequence space through mathematical analysis and computer simulation. The adaptive walk is characterized by the "mutation distance" d as the step-width of the walker and the "population size" N as the number of randomly generated d-fold point mutants to be screened. In addition to the fitness W, we introduced the following quantities analogous to thermodynamical concepts: "free fitness" G(W) is identical with W+T x S(W), where T is the "evolutionary temperature" T infinity square root of d/lnN and S(W) is the entropy as a function of W, and the "evolutionary force" X is identical with d(G(W)/T)/dW, that is caused by the mutation and selection pressure. It is known that a single adaptive walker rapidly climbs on the fitness landscape up to the stationary state where a "mutation-selection-random drift balance" is kept. In our interpretation, the walker tends to the maximal free fitness state, driven by the evolutionary force X. Our major findings are as follows: First, near the stationary point W*, the "climbing rate" J as the expected fitness change per generation is described by J approximately L x X with L approximately V/2, where V is the variance of fitness distribution on a local landscape. This simple relationship is analogous to the well-known Einstein relation in Brownian motion. Second, the "biological information gain" (DeltaG/T) through adaptive walk can be described by combining the Shannon's information gain (DeltaS) and the "fitness information gain" (DeltaW/T).

Animals↗

PubMed2001

Transmission bottlenecks and the evolution of fitness in rapidly evolving RNA viruses.

We explored the evolutionary importance of two factors in the adaptation of RNA viruses to their cellular hosts, size of viral inoculum used to initiate a new infection, and mode of transmission (horizontal versus vertical). Transmission bottlenecks should occur in natural populations of viruses and their profound effects on viral adaptation have been previously documented. However, the role of transmission mode has not received the same attention. Here we used a factorial experimental design to test the combined effects of inoculum (bottleneck) size and mode of transmission in evolution of vesicular stomatitis virus (VSV) in tissue culture, and compared our results to the predictions of a recent theoretical model. Our data were in accord with basic genetic principles concerning the balance between mutation, selection and genetic drift. In particular, attenuation of vertically transmitted viruses was a consequence of the random accumulation of deleterious mutations, whereas horizontally transmitted viruses experiencing similar bottlenecks did not suffer the same fitness losses because effective bottleneck size was actually determined by the number of host individuals. In addition, high levels of viral fitness in horizontally transmitted populations were explained by competition among viral variants.

Animals↗