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Modifiers of mutation rate: Evolutionary optimum with complete selfing.

It often has been assumed that, for infinite random mating populations in a constant environment, natural selection will favor genotypes at a neutral modifier locus that minimize the mutation rate. Mathematical modeling of this process confirms this assertion, independent of the selection regime. The same model under conditions of complete selfing can produce, under certain nondegenerate overdominance conditions, an optimum mutation rate below which increased mutation is favored and above which decreased mutation is favored. This occurs with unidirectional mutation models and a class of reversible mutation models with fitness overdominance. This is the first time that such a modifier optimum has been produced analytically for an infinite population in a constant environment.

Journal Article↗

Sex and the evolution of intrahost competition in RNA virus phi6.

Sex allows beneficial mutations that occur in separate lineages to be fixed in the same genome. For this reason, the Fisher-Muller model predicts that adaptation to the environment is more rapid in a large sexual population than in an equally large asexual population. Sexual reproduction occurs in populations of the RNA virus phi6 when multiple bacteriophages coinfect the same host cell. Here, we tested the model's predictions by determining whether sex favors more rapid adaptation of phi6 to a bacterial host, Pseudomonas phaseolicola. Replicate populations of phi6 were allowed to evolve in either the presence or absence of sex for 250 generations. All experimental populations showed a significant increase in fitness relative to the ancestor, but sex did not increase the rate of adaptation. Rather, we found that the sexual and asexual treatments also differ because intense intrahost competition between viruses occurs during coinfection. Results showed that the derived sexual viruses were selectively favored only when coinfection is common, indicating that within-host competition detracts from the ability of viruses to exploit the host. Thus, sex was not advantageous because the cost created by intrahost competition was too strong. Our findings indicate that high levels of coinfection exceed an optimum where sex may be beneficial to populations of phi6, and suggest that genetic conflicts can evolve in RNA viruses.

Adaptation, Physiological↗

A multidisciplinary team approach to preservation of quality of life for patients following oral cancer surgery.

Knowledge of the etiology and pathophysiology of, and risk factors contributing to oral cavity cancer facilitates patient assessment and diagnosis. If untreated, oral cavity cancer can be disabling and potentially fatal. Even when treated, using the modalities discussed in this article, the patient experiences significant changes in body image and quality of life. The patient's physical and psychosocial needs must be identified pre-operatively and assessed throughout the post-operative period. By providing programs as described at the Toronto General Hospital utilizing a coordinated multidisciplinary team approach that encourages, supports, and nurtures patients and their significant others, an optimum quality of life may be established for this population. From the outset, patient education describing oral cancer and the course of treatment to follow, may contribute to the preservation and/or early return of optimum quality of life. Increased public knowledge and awareness of oral cavity cancer regarding risk factors and their potential effects may contribute to healthier life styles.

Body Image↗

Case gender and severity in cerebral palsy varies with intrauterine growth.

BACKGROUND: There is an unexplained excess of cerebral palsy among male babies. There is also variation in the proportion of more severe cases by birth weight. It has recently been shown that the rate of cerebral palsy increases as intrauterine size deviates up or down from an optimum about one standard deviation heavier than population mean weight-for-gestation. AIMS: To determine whether the gender ratio or the severity of cases also varies with intrauterine size. METHODS: A total of 3454 cases of cerebral palsy among single births between 1976 and 1990 with sufficient data to assign case severity (based on intellectual impairment and walking ability) and to compare weight-for-gestation at birth to sex specific fetal growth standards, were aggregated from nine separate registers in five European countries. RESULTS: The greater the degree to which growth deviates either up or down from optimal weight-for-gestation at birth, the higher is the rate of cerebral palsy, the larger is the proportion of male cases, and the more severe is the functional disability. Compared to those with optimum growth the risk of more severe cerebral palsy in male babies is 16 times higher for those with a birth weight below the 3rd centile and four times higher when birth weight is above the 97th centile. In contrast, for mild cerebral palsy in female babies the excess risks at these growth extremes are about half these magnitudes. CONCLUSIONS: Among singleton children with cerebral palsy, abnormal intrauterine size, either small or large, is associated with more severe disability and male sex.

Birth Weight↗

The impact of bird populations on the microbiological quality of bathing waters.

To ensure optimum quality at Bathing Waters, the control of diffuse sources of bacterial contamination is receiving increasing attention. As part of an initiative to improve the quality of the EU designated bathing waters on the Fylde Coast (North West England), a project was undertaken to quantify the faecal indicator load from birds and assess the significance on water quality. High bird counts are encountered on the Fylde Coast with gulls, feral pigeons and starlings being prominent. The piers at Blackpool make an attractive roost for starlings with numbers peaking at over 30,000 in late summer. Systematic recording of bird numbers and locations was undertaken during 2001/2. Estimates were also made of the daily faecal organism production by the different species. The spatial distribution of faecal organisms from the bird population was statistically linked to synoptic water quality data. This allowed estimates to be made of the contribution from birds to the faecal pollution load at the bathing waters. The work confirmed a statistically significant link between bird populations and water quality with a marked seasonal bias.

Animals↗

Public health consequences of the J-curve hypothesis of alcohol problems.

This paper addresses some issues related to the hypothesis that the risk for premature death is a J-shaped function of alcohol intake. The first part of the paper contains a discussion of the individual level epidemiological evidence. It is argued that the evidence is not yet good enough to allow precise statements about "safe limits", nor does it allow a precise location of the "optimum" consumption level. Measurement errors and confounding variables not yet controlled for remain substantial problems. In particular, future studies need to control for social integration, as this factor may affect both health status and alcohol consumption. The second part of the paper discusses the population level relationship. It is argued that, typically, what is optimum for an individual is too much for a population. Unintended side effects of major public health importance should be expected in this area. In the last section, a plea is made for aggregate level studies as a way of addressing the public health side of the issue.

Adult↗

Population pharmacokinetics of cyclosporine in chinese cardiac transplant recipients.

STUDY OBJECTIVE: To characterize the population pharmacokinetics of cyclosporine in Chinese patients undergoing cardiac transplantation and to identify the demographic and clinical covariates affecting cyclosporine clearance. DESIGN: Population pharmacokinetic analysis using data from a retrospective chart review. SETTING: Specialty hospital in Hong Kong for treatment of cardiac and pulmonary diseases. PATIENTS: Thirty-eight Chinese adult patients (mean age 46 yrs) who had undergone routine cyclosporine therapeutic drug monitoring after cardiac transplantation between January 1, 1991, and December 31, 2003. MEASUREMENTS AND MAIN RESULTS: Data regarding dosing, demographics, clinical laboratory values, and concurrent drugs were collected retrospectively. Data were included if patients had blood cyclosporine concentrations determined for at least 12 weeks after transplantation; an average of 18 blood samples/patient were collected. Population modeling was performed using a one-compartment linear model with first-order absorption and elimination. Various demographic and clinical covariates were tested for their significant effects on the apparent oral clearance (Cl/F) of cyclosporine. The stability of the final population model was evaluated by using the bootstrap resampling method. Statistically significant associations were observed between Cl/F and each of the following covariates: body weight (BW), use of diltiazem (DIL), and hematocrit value (HCT). The final model was Cl/F=5.00*(1-DIL)+365/HCT+(0.144*BW). The interindividual variabilities of Cl/F and apparent volume of distribution were 14.5% and 40.2%, respectively. The mean parameter estimates obtained from bootstrap analyses were highly consistent with those obtained with the original data set. CONCLUSION: The estimated Cl/F values of cyclosporine in our Chinese cardiac transplant recipients appeared to be similar to those reported for Caucasian cardiac transplant recipients. Thus, our data provide support that a cyclosporine dosage regimen similar to that in Caucasian patients may be needed in Chinese cardiac transplant recipients. However, further studies are required to determine the optimum cyclosporine dosage regimen in the Chinese population.

Adult↗

Bacteriophage latent-period evolution as a response to resource availability.

Bacteriophages (phages) modify microbial communities by lysing hosts, transferring genetic material, and effecting lysogenic conversion. To understand how natural communities are affected it is important to develop predictive models. Here we consider how variation between models--in eclipse period, latent period, adsorption constant, burst size, the handling of differences in host quantity and host quality, and in modeling strategy--can affect predictions. First we compare two published models of phage growth, which differ primarily in terms of how they model the kinetics of phage adsorption; one is a computer simulation and the other is an explicit calculation. At higher host quantities (approximately 10(8) cells/ml), both models closely predict experimentally determined phage population growth rates. At lower host quantities (10(7) cells/ml), the computer simulation continues to closely predict phage growth rates, but the explicit model does not. Next we concentrate on predictions of latent-period optima. A latent-period optimum is the latent period that maximizes the population growth of a specific phage growing in the presence of a specific quantity and quality of host cells. Both models predict similar latent-period optima at higher host densities (e.g., 17 min at 10(8) cells/ml). At lower host densities, however, the computer simulation predicts latent-period optima that are much shorter than those suggested by explicit calculations (e.g., 90 versus 1,250 min at 10(5) cells/ml). Finally, we consider the impact of host quality on phage latent-period evolution. By taking care to differentiate latent-period phenotypic plasticity from latent-period evolution, we argue that the impact of host quality on phage latent-period evolution may be relatively small.

Biological Evolution↗

Kinetics of growth inhibition in a neoplastic population after repeated cytostatic treatment.

The analysis of growth kinetics of a neoplastic population after cytostatic treatment (radiation, chemotherapy) has been modeled by means of the cell cycle transition probabilities mu and transition intensities lambda. The transition between phases of the cell cycle and quiescent G0 cells during repeated cytostatic treatment has been exposed by the probabilistic model on the basis of the experimental data. The cytostatic treatment (the most effective time, dose and therapeutic combination) can be scheduled using established size and volume of the tumor and an estimate of cell proportion in various compartments of the neoplastic population. The probabilistic model has been worked out with the object of repeated cytostatic treatments in the optimum time with respect to the reduction of resistant quiescent G0 population. By repeating treatment in these times, the G0 population may be effectively reduced, the tumor is loosing its proliferation (recovery) potential and the further tumor growth may be for a long time delayed or even ceased.

Animals↗

Selection and recombination in populations containing tandem multiplet genes.

Computer simulation for selective conditions that may apply in nature yielded three generalizations for prokaryotic organisms with recombinant mechanisms. (1) Selective forces can suffice to maintain a tandem gene family with the nearly optimum number of genes with little variance within the population. (2) Tandem genes will occur within the population unless the population is frequently cloned or unless the function due to a single copy is capable of over-providing the needs of the organism. (3) Even when there is no selective advantage or disadvantage due to extra gene copies, the population distribution becomes more skewed with time; and organisms with only single copies of the gene comprise a progressively larger fraction of the total. This may be the case with genes that function under strong cellular regulation. Evolutionary implications of these calculations are that the occurrence of unequal recombination of tandem genes would greatly slow evolution via duplication of genetic material. This difficulty and its possible resolutions are discussed.

Animals↗

Replicated evolution of integrated plastic responses during early adaptive divergence.

Colonization of a novel environment is expected to result in adaptive divergence from the ancestral population when selection favors a new phenotypic optimum. Local adaptation in the new environment occurs through the accumulation and integration of character states that positively affect fitness. The role played by plastic traits in adaptation to a novel environment has generally been ignored, except for variable environments. We propose that if conditions in a relatively stable but novel environment induce phenotypically plastic responses in many traits, and if genetic variation exists in the form of those responses, then selection may initially favor the accumulation and integration of functionally useful plastic responses. Early divergence between ancestral and colonist forms will then occur with respect to their plastic responses across the gradient bounded by ancestral and novel environmental conditions. To test this, we compared the magnitude, integration, and pattern of plastic character responses in external body form induced by shallow versus open water conditions between two sunfish ecomorphs that coexist in four postglacial lakes. The novel sunfish ecomorph is present in the deeper open water habitat, whereas the ancestral ecomorph inhabits the shallow waters along the lake margin. Plastic responses by open water ecomorphs were more correlated than those of their local shallow water ecomorph in two of the populations, whereas equal levels of correlated plastic character responses occurred between ecomorphs in the other two populations. Small but persistent differences occurred between ecomorph pairs in the pattern of their character responses, suggesting a recent divergence. Open water ecomorphs shared some similarities in the covariance among plastic responses to rearing environment. Replication in the form of correlated plastic responses among populations of open water ecomorphs suggests that plastic character states may evolve under selection. Variation between ecomorphs and among lake populations in the covariance of plastic responses suggests the presence of genetic variation in plastic character responses. In three populations, open water ecomorphs also exhibited larger plastic responses to the environmental gradient than the local shallow water ecomorph. This could account for the greater integration of plastic responses in open water ecomorphs in two of the populations. This suggests that the plastic responses of local sunfish ecomorphs can diverge through changes in the magnitude and coordination of plastic responses. Although these results require further investigation, they suggest that early adaptive evolution in a novel environment can include changes to plastic character states. The genetic assimilation of coordinated plastic responses could result in the further, and possibly rapid, divergence of such populations and could also account for the evolution of genes of major effect that contribute to suites of phenotypic differences between divergent populations.

Acclimatization↗

German constitutional doctrine in the 1920s and 1930s and pitfalls of the contemporary conception of normality in biology and medicine.

From the end of the First World War, a broad discussion took place within the framework of the revived German constitutional teaching on the question of the physical normality of man. The founder of the so-called statistical concept of normality, which preceded the still widespread normal (reference) interval concept, is H. Rautmann, who gave it the character of a tool for discriminating between health and disease. Among some of his successors (Bauer, Borchardt, Günther), however, it was considered more a means of establishing a type, without supposing any precise relation between the frequency of a character in the population and the probability of the occurrence of disease. The concept of a statistical norm as a certain region of the variation range of a character determined by the parameters of Gaussian distribution was criticized both by the supporters of the ideal norm (Hildebrandt) and those who were in favour of a 'personal' norm (Grote). The underlying motifs of these three conceptions of normality influenced German constitutional doctrine until after the end of the Second World War, but without a satisfactory solution to the diagnosis of physical normality being found. Since the 1950s, world medicine has moved more and more in the direction of prevention, with the emphasis on a study of individual dispositions to disease and its precursors. In this connection a new view of health has gained importance whereby it is considered a smoothly gradated condition, not sharply distinguished from disease ('continual' model of health and disease as opposed to the previous 'alternative' model). The purpose of diagnostic characters is no longer merely to place patients in clearly defined categories as healthy or affected by one disease or another, but has taken on the function of indices of the disposition to disease among those who exhibit 'gross normality'. Discrimination between the alternative and continuous models allows a clarification to be made of the sources of the confusion in which the pre-war concept of statistical normality had found itself. Today many exceptions are known to the rule that the functional optimum lies in the region of the population mean, both for the population as a whole and for individuals; and immense variability has been found in the manner in which individuals in the population attain health.(ABSTRACT TRUNCATED AT 400 WORDS)

Anthropometry↗

Single daily dosing of aminoglycosides.

To evaluate the rationale behind dosing aminoglycosides as a single daily dose versus traditional dosing approaches, we conducted a MEDLINE search to identify all pertinent articles, and also reviewed the references of all articles. Single daily dosing of aminoglycosides is not a new concept, having been examined since 1974. The advantages of this regimen include optimum concentration-dependent bactericidal activity, longer dosing intervals due to the postantibiotic effect (PAE), and prevention of bacterial adaptive resistance. Because of longer dosing intervals, toxicity may also be delayed or reduced. Costs may be reduced due to decreased monitoring and administration. Clinically, the regimen has been implemented in various patient populations with reported success. Questions remain, however, about optimum dose, peak and trough serum concentrations, and dose adjustment in patients with renal impairment or neutropenia. More clinical experience with this method in large numbers of patients has to be published. Pharmacists can be instrumental in monitoring patients receiving once-daily therapy and by educating health care professionals as to the rationale behind the therapy.

Aminoglycosides↗

Intracellular nuclease activities of buffalo rumen bacterial population.

Nuclease activities of the predominantly bacterial population obtained from buffalo rumen were investigated. Optimum temperature for hydrolysis of both DNA and RNA was 50 degrees C whereas DNAase activity was observed to be stable up to 50 degrees C, a decrease in RNAase activity was observed even after 40 degrees C. Two pH optima, one at 5.5 and the other at 7.5, were recorded for hydrolysis of DNA. RNAase activity was maximum between pH 6.0 to 7.0. Whereas DNAase activity was stable near its optimum pH, RNAase activity was stable between pH 7.0 to 8.5. Mn2+ ions stimulated DNAase activity. It was strongly inhibited by Hg2+, Zn2+, Pb2+ and Ag+. RNAase activity was stimulated by Mg2+ ions and was strongly inhibited by Hg2+, Cu2+, Zn2+ and Ag+. Cysteine hydrochloride and 2-mercaptoethanol stimulated DNAase activity. The activity was strongly inhibited by N-ethylmaleimide, 4-chloromercuribenzoate, 8-quinolinol, iodoacetic acid and 1,10-phenanthroline. RNAase activity was stimulated by cysteine hydrochloride, reduced glutathione and 2-mercaptoethanol and was strongly inhibited by 4-chloromercuribenzoate, 8-quinolinol and 2,2'bipyridyl.

Animals↗

Epidemiology and disease-control under gene-for-gene plant-pathogen interaction.

An introduction of disease-resistant variety of a crop plant often leads to the development of a virulent race in pathogen species that restores the pathogenicity to the resistant crop. This often makes disease control of crop plants extremely difficult. In this paper, we theoretically explore the optimal 'multiline' control, which makes use of several different resistant varieties, that minimizes the expected degree of crop damages caused by epidemic outbreaks of the pathogen. We examine both single-locus and two-locus gene-for-gene (GFG) systems for the compatibility relationship between host genotypes and pathogen genotypes, in which host haplotype has either susceptible or resistant allele in each resistance locus, and the pathogen haplotype has either avirulent or virulent allele in the corresponding virulence locus. We then study the optimal planting strategy of host resistant genotypes based on standard epidemiological dynamics with pathogen spore stages. The most striking result of our single-locus GFG model is that there exists an intermediate optimum mixing ratio for the susceptible and resistant crops that maximizes the final yield, in spite of the fact that the susceptible crop has no use to fight against either avirulent or virulent race of the pathogen. The intermediate mixture is optimum except when the initial pathogen spore population in the season consists exclusively of the virulent race. The optimal proportion of resistant crops is approximately 1/R(0), where R(0) is the basic reproductive ratio of pathogen--the rest (the vast majority if R(0) is large) of crops should be the susceptible genotype. By mixing susceptible and resistant crops, we can force the pathogen races to compete with each other for their available hosts. This competition between avirulent and virulent races prevents the fatal outbreak of the virulent race (the super-race) that can infect all the host genotypes. In the two-locus GFG control, there again exists the optimal mixing ratio for the fraction of universally susceptible genotype and the total fraction of various resistant genotypes, with the ratio close to 1/R(0).

Crops, Agricultural↗

Whole blood selenium content in healthy adults in the Czech Republic.

Over a 5-year period, from 1996 to 2001, blood selenium levels were recorded in a set of 2414 healthy blood donors (1781 men and 633 women; 880 smokers and 1534 nonsmokers) living in four selected areas of the Czech Republic. About 100 blood samples per year and region were analyzed using the HGA method. The internal and external quality controls of this method were performed throughout the duration of the study. In general, blood selenium concentrations (81.9 and 106.7 microg/l for median and 90th percentile, respectively) did not reach optimum values; in approximately 10% of the population sample, values lower than 60 microg/l were detected. Nonetheless, the values obtained increased significantly, with median concentrations of 73.2 microg/l in 1996 and 91.5 microg/l in 2001. The percentage of subjects with a whole blood selenium level of less than 60 microg/l also decreased from nearly 20% in 1996 to 0.2% in 2001. No substantial regional or gender-related differences were observed, but significantly lower blood selenium levels were found in smokers as opposed to nonsmokers. Although mild selenium deficiency continues to be observed, the data presented do not indicate extremely low selenium levels in the population sample.

Adult↗

Reducing postnatal pain from perineal tears by using lignocaine gel: a double-blind randomized trial.

BACKGROUND: Perineal pain is one of the most common causes of maternal morbidity in the early puerperium. Several randomized trials have shown that topical application of local anesthetics is effective in reducing postepisiotomy pain, but no randomized study has assessed the efficacy of local anesthetics for other perineal trauma. This study investigated if topically applied 2 percent lignocaine gel was an effective treatment for this group of women. METHODS: A double-blind placebo controlled trial was conducted in a regional teaching hospital in the northwest of England. One hundred and forty-nine women who had sustained a first- or second-degree tear were allocated by sealed envelopes to the lignocaine gel or placebo group. The primary outcome was self-reported pain at 24 hours postdelivery as measured on a numerical rating scale (pain score). Secondary outcomes included pain scores at 48 hours, the need for oral analgesia, and maternal satisfaction. Based on a pilot study, we calculated that 128 women were required to detect a 25 percent difference in pain scores between the two groups with 80 percent power (alpha = 0.05). The pain scores of women in each trial arm were compared using the unpaired t test and 95 percent confidence intervals. RESULTS: Women using lignocaine gel had lower average pain scores, although this only reached statistical significance at 48 hours after delivery (p = 0.023). In general, women liked using the study gel. No difference was found in consumption of oral analgesia. CONCLUSIONS: This study suggested that lignocaine gel may be effective on the second postnatal day. Further research is required to assess the optimum timing of this intervention and the population that would most benefit from its use.

Administration, Topical↗