Superinfections can induce evolutionarily stable coexistence of pathogens

Parasites reproduce and are subject to natural selection at several different, but intertwined, levels. In the recent paper, Gilchrist and Coombs (Theor. Popul. Biol. 69:145–153, 2006) relate the between-host transmission in the context of an SI model to the dynamics within a host. They demonstrate that within-host selection may lead to an outcome that differs from the outcome of selection at the host population level. In this paper we combine the two levels of reproduction by considering the possibility of superinfection and study the evolution of the pathogen’s within-host reproduction rate p. We introduce a superinfection function φ = φ(p,q), giving the probability with which pathogens with trait q, upon transmission to a host that is already infected by pathogens with trait p, “take over” the host. We consider three cases according to whether the function q → φ(p,q) (i) has a discontinuity, (ii) is continuous, but not differentiable, or (iii) is differentiable in q = p. We find that in case (i) the within-host selection dominates in the sense that the outcome of evolution at the host population level coincides with the outcome of evolution in a single infected host. In case (iii), it is the transmission to susceptible hosts that dominates the evolution to the extent that the singular strategies are the same as when the possibility of superinfections is ignored. In the biologically most relevant case (ii), both forms of reproduction contribute to the value of a singular trait. We show that when φ is derived from a branching process variant of the submodel for the within-host interaction of pathogens and target cells, the superinfection functions fall under case (ii). We furthermore demonstrate that the superinfection model allows for steady coexistence of pathogen traits at the host population level, both on the ecological, as well as on the evolutionary time scale.      

NADH diaphorase polymorphism in European fallow deer

NADH diaphorase polymorphism is reported for European fallow deer (D. d. dama) from Coto de Doñana National Park (Spain). Allele frequencies ofp=0.682 (anodic variant) andq=0.318 (cathodic variant) in 110 specimens suggest population genetic usefulness of this biallelic system in an otherwise fairly monomorphic cervid species.     

Changes in intracellular ATP‐content of CHO cells as response to hyperosmolality

A variety of approaches has been published to enhance specific productivity (q_p) of recombinant Chinese hamster ovary (CHO) cells. Changes in culture conditions, e. g. temperature shifts, sodium butyrate treatment and hyperosmolality, were shown to improve q_p. To contribute to a better understanding of the correlation between hyperosmolality and enhanced q_p, we analyzed cellular kinetics and intracellular adenine nucleotide pools during osmotic shift periods. Known phenotypes like increased formation rates for lactate and product (anti‐IL‐8 antibody; q_lactate, q_p) as well as increased cell specific uptake rate for glucose (q_glucose) were found—besides inhibition of cell growth and G1‐arrest occurred during batch cultivations with osmotic shift. The analysis of intracellular AXP pools revealed enlarged ATP amounts for cells as response to hyperosmolality while energy charges remained unchanged. Enhanced ATP‐pools coincided with severely increased ATP formation rates (q_ATP) which outweighed by far the putative requirements attributed to regulatory volume increase. Therefore elevated q_ATP mirrored an increased cellular demand for energy while experiencing hyperosmotic shift. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:1212–1216, 2015     

Obesity and Cardiovascular Disease Risk Factors in Firefighters: A Prospective Cohort Study

Objective: Obesity, despite being a significant determinant of fitness for duty, is reaching epidemic levels in the workplace. Firefighters’ fitness is important to their health and to public safety. Research Methods and Procedures: We examined the distribution of BMI and its association with major cardiovascular disease (CVD) risk factors in Massachusetts firefighters who underwent baseline (1996) and annual medical examinations through a statewide medical surveillance program over 5 years of follow‐up. We also evaluated firefighters’ weight change over time. Results: The mean BMI among 332 firefighters increased from 29 at baseline to 30 at the follow‐up examination (2001), and the prevalence of obesity increased from 35% to 40%, respectively (p < 0.0001). In addition, the proportion of firefighters with extreme obesity increased 4‐fold at follow‐up (from 0.6% to 2.4%, p < 0.0001). Obese firefighters were more likely to have hypertension (p = 0.03) and low high‐density lipoprotein‐cholesterol (p = 0.01) at follow‐up. Firefighters with extreme obesity had an average of 2.1 CVD risk factors (excluding obesity) in contrast to 1.5 CVD risk factors for normal‐weight firefighters (p = 0.02). Finally, on average, normal‐weight firefighters gained 1.1 pounds, whereas firefighters with BMI ≥ 35 gained 1.9 pounds per year of active duty over 5 years of follow‐up. Discussion: Obesity is a major concern among firefighters and shows worsening trends over time. Periodic medical evaluations coupled with exercise and dietary guidelines are needed to address this problem, which threatens firefighters’ health and may jeopardize public safety.     

Dynamical behavior of epidemiological models with nonlinear incidence rates

Epidemiological models with nonlinear incidence rates I ^pS^qshow a much wider range of dynamical behaviors than do those with bilinear incidence rates IS. These behaviors are determined mainly by p and , and secondarily by q. For such models, there may exist multiple attractive basins in phase space; thus whether or not the disease will eventually die out may depend not only upon the parameters, but also upon the initial conditions. In some cases, periodic solutions may appear by Hopf bifurcation at critical parameter values.     

Extinction probabilities in branching processes: A note on holgate and Lakhani's paper

Within the class of offspring distributions with given meanm>1 and probability of no offspringp _o, the probabilityq of ultimate extinction in a Galton-Watson branching process starting from one individual satisfiesp ₀<q(m,p₀)≤q<1. A short table illustrates the lower boundq(m,p ₀). Work done at the Mathematics Department, University of Washington, Seattle, U.S.A.     

CDKN2B-AS1 gene rs4977574 A/G polymorphism and coronary heart disease: A meta-analysis of 40,979 subjects

It has been implied that there is a possible relationship between cyclin-dependent protein kinase inhibitors antisense RNA 1 (CDKN2B-AS1) gene rs4977574 A/G polymorphism and coronary heart disease (CHD) susceptibility. However, as the research results are discrepant, no distinct consensus on this issue has been reached so far. In order to further elaborate the latent association of the CDKN2B-AS1 gene rs4977574 A/G polymorphism and CHD, this present meta-analysis was conducted. There were 40,979 subjects of 17 individual studies in the present meta-analysis. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to determine the association strength. Considering the significant heterogeneity among the individual studies, the random-effect models were used. In the current meta-analysis, a significant association between CDKN2B-AS1 gene rs4977574 A/G polymorphism and CHD was found under allelic (OR: 1.18, 95% CI: 1.08–1.29, p = 4.83×10⁻⁴), recessive (OR: 1.36, 95% CI: 1.11–1.67, p = 0.003), dominant (OR: 0.71, 95% CI: 0.58–0.86, p = 6.26×10⁻⁴), heterozygous (OR:1.210, 95% CI: 1.076–1.360, p = 0.001), homozygous (OR: 1.394, 95% CI: 1.163–1.671, p = 3.31×10⁻⁴) and additive (OR: 1.180, 95% CI: 1.075–1.295, p = 4.83×10⁻⁴) genetic models. A more significant association between them was found in the Asian population than that in the whole population under these genetic models (p < 0.05). However, no significant association between them was found in the Caucasian population (p > 0.05). CDKN2B-AS1 gene rs4977574 A/G polymorphism was associated with CHD susceptibility, especially in the Asian population. G allele of CDKN2B-AS1 gene rs4977574 A/G polymorphism is the risk allele for CHD.     

The Association of IL-6, TNFα and CRP Gene Polymorphisms with Coronary Artery Disease in a Tunisian Population: A Case–Control study

Coronary artery disease is an inflammatory disease. Systemic markers of inflammation such as Interleukin-6, Tumor Necrosis Factor alpha and C-reactive protein have previously been shown to be associated with increased risk of cardiovascular events. The aim of the present study is to assess the role of variants in the IL-6 (??174 G/C), TNFα (??308 A/G) and CRP (+?1059G/C) genes as susceptibility markers for CAD in a Tunisian population. The investigation was conducted as a case–control study involving 204 patients and 400 age-gender matched controls. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism analysis. There are significant differences between CAD patients and the control group with regard to BMI (p?<?10^–3) and family history of CAD (p?<?10^–3). The CAD patients are more likely to have a history of smoking (p?<?10^–3), have a higher value of TC (p?=?0.003), LDLc (p?=?0.016), hs-CRP (p?=?0.01), IL6 (p?<?10^–3) and TNFα (p?=?0.038). Our analysis showed significant differences between cases and controls in genotypic distribution of IL6-174CC (p?=?0.003; OR?=?7.71 CI (1.58–37.56)), TNFα ??308 AA (p?=?0.004; OR?=?2.95 (1.57–5.51)) and CRP?+?1059 CC (p?<?10^–3; OR?=?5.40 (2.30–12.68)). However, we failed to find an association between the different genotypes and the inflammatory markers levels. Our results suggest that the presence of IL-6 (??174 G/C), TNFα (-308 A/G) and CRP (+?1059G/C) polymorphisms, may be considered to be a risk factor for CAD in Tunisian population.

     

Analysis of an SEIRS epidemic model with two delays

 A disease transmission model of SEIRS type with exponential demographic structure is formulated. All newborns are assumed susceptible, there is a natural death rate constant, and an excess death rate constant for infective individuals. Latent and immune periods are assumed to be constants, and the force of infection is assumed to be of the standard form, namely proportional to I(t)/N(t) where N(t) is the total (variable) population size and I(t) is the size of the infective population. The model consists of a set of integro-differential equations. Stability of the disease free proportion equilibrium, and existence, uniqueness, and stability of an endemic proportion equilibrium, are investigated. The stability results are stated in terms of a key threshold parameter. More detailed analyses are given for two cases, the SEIS model (with no immune period), and the SIRS model (with no latent period). Several threshold parameters quantify the two ways that the disease can be controlled, by forcing the number or the proportion of infectives to zero. Received 8 May 1995; received in revised form 7 November 1995     

Sample Size Requirements in Studies of the Etiologic Fraction

This paper outlines methods of determining sample size for epidemiologic research in studies of the etiologic fraction. The basic model with a dichotomous disease and a single dichotomous exposure factor is considered. To determine sample size, the researcher must specify: the magnitude of the etiologic fraction ε to be detected as statistically significant, the level of significance α, the power 1 - β of the test, p the proportion of the population exposed to the risk factor and R the proportion of the population with the disease. Sample size formulas and tables are presented for the case-control, cohort and cross-sectional designs. Optimal allocation considerations are examined to minimize cost for a specified power. Extensive use is made of Walter's results concerning the asymptotic variance of the maximum likelihood estimator of the etiologic fraction for the three epidemiologic study designs.     

Dietary Patterns and the Metabolic Syndrome in Obese and Non‐obese Framingham Women**

Objectives: To examine the relationship between habitual dietary patterns and the metabolic syndrome (MetS) in women and to identify foci for preventive nutrition interventions. Research Methods and Procedures: Dietary patterns, nutrient intake, cardiovascular disease (CVD), and MetS risk factors were characterized in 1615 Framingham Offspring‐Spouse Study (FOS) women. Dietary pattern subgroups were compared for MetS prevalence and CVD risk factor status using logistic regression and analysis of covariance. Analyses were performed overall in women and stratified on obesity status; multivariate models controlled for age, apolipoprotein E (APOE) genotypes, and CVD risk factors. Results: Food and nutrient profiles and overall nutritional risk of five non‐overlapping habitual dietary patterns of women were identified including Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calories. Rates of hypertension and low high‐density lipoprotein levels were high in non‐obese women, but individual MetS risk factor levels were substantially increased in obese women. Overall MetS risk varied by dietary pattern and obesity status, independently of APOE and CVD risk factors. Compared with obese or non‐obese women and women overall with other dietary patterns, MetS was highest in those with the Empty Calorie pattern (contrast p value: p < 0.05). Discussion: This research shows the independent relationship between habitual dietary patterns and MetS risk in FOS women and the influence of obesity status. High overall MetS risk and the varying prevalence of individual MetS risk factors in female subgroups emphasize the importance of preventive nutrition interventions and suggest potential benefits of targeted behavior change in both obese and non‐obese women by dietary pattern.     

'Photoinhibition' of Heliconia under natural tropical conditions: the importance of leaf orientation for light interception and leaf temperature

The influence of irradiance on photosynthesis under natural conditions was studied in aseasonal Singapore using three Heliconia taxa: H. rostrata, H. psittacorum × H. spathocircinata cv. Golden Torch and H. psittacorum cv. Tay. When grown under full sunlight, all three heliconias exhibited reduced phatosynthetic capacities and lowered chlorophyll content per leaf area as compared with those grown under intermediate and deep shade. A marked decrease in the chlorophyll fluorescence F_v/Fm ratio and an increase in photochemical quenching (1- q_p) and non-photochemical quenching (q_N) were observed in upper leaves of plants grown under full sunlight. Increases in q_N suggest that ‘photoinhibition’ (decreases in F_v/F_m) in Heliconia grown under natural tropical conditions are probably due to photoprotective energy dissipation processes. The quantum yield, the maximum photosynthetic rate, F_v/F_m and the chlorophyll content of upper leaves were lower than those of lower leaves on the same plants grown under full sunlight. Similarly, lower values were obtained for the tip (sun) portion than for the base (shaded) portion of the leaves. The changes in F_v/F_m and in the levels of (1 –q_p) in leaves grown under intermediate and deep shade were negligible in plants during the course of day. However, there was a steep decrease in F_v/F_m and an increase in the levels of (1 –q_p), along with an increase in incident light in the sun leaves. The lowest F_v/F_m and the highest level of (1 –q_p) indicated minimum PSII efficiency at midday in full sun. These results indicate that, in Heliconia, the top leaves (particularly leaf tips) experienced sustained decreases in PSII efficiency upon exposure to full sunlight. Although all three taxa exhibited sustained decreases in photosynthetic capacity in full sunlight, the sun leaves of ‘Tay’ showed higher photosynthetic capacity than those of the other two taxa. This could be due, at least in part, to the vertical leaf angle and smaller lamina area. When the upright leaves of ‘Tay’ were constrained to a horizontal angle, they exhibited lower PSII efficiency (F_vIF_m ratio), while horizontal leaves of ‘Rostrata’ and ‘Golden Torch’ inclined lo near-vertical angles showed increased efficiency. Thus, an increase in leaf angle helps to achieve a reduction in the sustained decrease in PSII efficiency by decreasing the levels of incident sunlight and subsequently the leaf temperature.     

Estimation and Prediction of Generalized Growth Curve with Grouping Variances in AR(q) Dependence Structure

In this paper we consider maximum likelihood analysis of generalized growth curve model with the Box‐Cox transformation when the covariance matrix has AR(q) dependence structure with grouping variances. The covariance matrix under consideration is Σ = D _σ CD _σ where C is the correlation matrix with stationary autoregression process of order q, q < p and D _σ is a diagonal matrix with p elements divided into g(≤ p) groups, i.e., D _σ is a function of {σ₁, …, σ_g} and – 1 < ρ < 1 and σ_l, l = 1, …, g, are unknown. We consider both parameter estimation and prediction of future values. Results are illustrated with real and simulated data.     

Weight Change and Risk of Developing Type 2 Diabetes

Objective: To examine the association between weight change and risk of type 2 diabetes and whether initial weight modifies the association. Research Methods and Procedures: This is a prospective cohort study of 20, 187 alumni from Harvard University and the University of Pennsylvania. At baseline in 1962 or 1966, men (mean age, 45.9 years) reported their weight, height, and other risk factors. They also had had their weight and height measured at university entry (mean age, 18.5 years). Participants were followed from baseline to 1998 for type 2 diabetes. Results: During follow‐up, 1223 men developed type 2 diabetes. Weight gain significantly increased the risk of this disease. The multivariate relative risks associated with BMI change from university entry to baseline of <?0.5, ±0.5, >0.5 to 1.0, >1.0 to 1.5, >1.5 to 2.0, >2.0 to 3.0, and >3.0 kg/m² per decade were 0.88, 1.00 (referent), 1.29, 2.09, 2.69, 4.67, and 7.02, respectively (p for trend < 0.0001). Even among men with a low initial BMI < 21 kg/m², weight gain significantly increased risk; the corresponding relative risks were (no cases), 1.00 (referent), 1.00, 1.93, 2.47, 4.82, and 7.68, respectively (p for trend < 0.0001). Discussion: A low initial BMI does not ameliorate the increase in risk of type 2 diabetes with weight gain. Avoidance of weight gain, even among lean individuals, is important to reduce the risk of this disease.     

E‐Selectin Genotypes and Risk of Type 2 Diabetes in Women

Endothelial dysfunction increases risk for type 2 diabetes. We examined whether variation in the gene for E‐selectin (SELE), a biomarker of endothelial dysfunction, was associated with levels of E‐selectin or diabetes quantitative traits (including fasting levels of insulin and hemoglobin A_1c) in 719 nondiabetic participants of the Nurses’ Health Study or with risk of diabetes in 602 incident (over 10 years of follow‐up) cases and 655 control women matched for age, race, and fasting status. Variation in three single nucleotide polymorphisms previously associated with cardiovascular disease risk and having effects on E‐selectin function, S128R, G98T, and L554F, was not significantly (p > 0.05) associated with levels of E‐selectin or diabetes quantitative traits, or with risk of incident diabetes in the primary analysis. Among women with low levels of subclinical inflammation (C‐reactive protein levels below the population median), S128R R allele carriers had a diabetes risk factor‐adjusted relative risk of incident diabetes of 1.71 (95% confidence interval, 1.04 to 2.81) relative to those with the SS genotype. Apart from an association in this subgroup, we conclude that the E‐selectin variants we examined are not important genetic risk factors for type 2 diabetes in women.     

Increased effect of the ApoE gene on survival at advanced age in healthy and long‐lived Danes: two nationwide cohort studies

Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a ‘frail’ or ‘risky’ genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE ε4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE ε4 allele on survival in a sample of the healthiest and long‐lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE ε4 allele were followed from 1998 until death or end of follow‐up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE ε4 status in 1998, 1546 had died at the end of the 10‐year follow‐up. Carriers of the ApoE ε4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92–103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE ε4 allele on mortality with age do not support previous findings of decreased influence ApoE ε4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age.     

Relative contribution of caries and periodontal disease in adult tooth loss among patients reporting to the Institute of Dental Sciences,Belgaum, India

Objectives: To examine the reasons for tooth loss in an adult population. Methods: Patients who reported to the department of prosthodontics in Institute of Dental Sciences, Belgaum, located in the north‐western part of the state of Karnataka, in the southern region of India over a period of 2 months, with at least one missing tooth (excluding third molars) constituted the sample size. There were a total of 365 patients (185 females and 180 males) within the age group of 16–84 years (mean age 51.06 ± 16.47 years) who fulfilled this criterion. Socio‐demographic profile was recorded along with a clinical examination for assessing the number and pattern of tooth loss. The reasons for tooth loss were recorded according to the history reported by the patient. Results: In the present study of 365 patients, 58.9% of the patients were completely edentulous, 41% were partially dentate, of which 20.8% had lost their teeth from caries, 11% from periodontal disease and 9.3% from a combination of reasons. More females had lost their teeth because of dental caries whereas more males had lost their teeth because of periodontal disease, this being statistically significant. (χ² = 16.53, p = 0.001). Highly significant results were obtained for age and reasons for tooth loss. (χ² = 150.39, p < 0.001). Irrespective of the socio‐economic status, dental caries was the most common cause for tooth loss in partially dentate patients though it was not statistically significant (χ² = 13.62, p = 0.325). Mandibular first molars were the teeth most frequently lost due to dental caries. The maxillary left central incisor was most frequently lost due to periodontal disease, followed by the maxillary right central incisor. Conclusions: Since both dental caries and periodontal disease contributed to tooth loss at different ages, risk indicators need to be identified.     

Excess Weight and the Risk of Incident Coronary Heart Disease Among Men and Women

Overweight and obesity have been prospectively associated with the risk of coronary heart disease (CHD). Less clear is the relation of excess weight to risk of CHD among men and women with comorbid conditions, and the proportion of CHD risk attributable to excess weight in the US population. To assess the risk of CHD associated with excess weight among men and women with and without associated comorbid conditions, and determine the population attributable risk of CHD associated with excess weight. The study population consisted of two prospective cohorts, the Health Professionals Follow‐up Study (HPFS) (N = 42,351 men; age range at baseline, 39–75 years) and the Nurses' Health Study (NHS) (N = 76,703 women; age range at baseline, 39–65 years). A total of 2,771 incident cases of CHD among the men and 2,359 among the women were documented over the 16 years of follow‐up. Overall, the relative risk (RR) of CHD associated with BMI ≥30 kg/m² compared with BMI 18.5–22.9 kg/m² was 2.13 (95% confidence interval (CI), 1.82–2.48) among the men and 2.48 (95% CI, 2.20–2.80) among the women. The risk of CHD increased with BMI, both with and without the presence of comorbid conditions. Our estimates suggest that more than a third of all incident CHD in US men and women may be attributed to excess weight. Excess weight is associated with increased risk of CHD among men and women, both alone and in combination with comorbid conditions, though the results require careful interpretation. A substantial proportion of incident CHD may be attributed to excess weight.     

Numerical Simulation of Unsteady Blood Flow through Capillary Networks

A numerical method is implemented for computing unsteady blood flow through a branching capillary network. The evolution of the discharge hematocrit along each capillary segment is computed by integrating in time a one-dimensional convection equation using a finite-difference method. The convection velocity is determined by the local and instantaneous effective capillary blood viscosity, while the tube to discharge hematocrit ratio is deduced from available correlations. Boundary conditions for the discharge hematocrit at divergent bifurcations arise from the partitioning law proposed by Klitzman and Johnson involving a dimensionless exponent, q≥1. When q=1, the cells are partitioned in proportion to the flow rate; as q tends to infinity, the cells are channeled into the branch with the highest flow rate. Simulations are performed for a tree-like, perfectly symmetric or randomly perturbed capillary network with m generations. When the tree involves more than a few generations, a supercritical Hopf bifurcation occurs at a critical value of q, yielding spontaneous self-sustained oscillations in the absence of external forcing. A phase diagram in the m–q plane is presented to establish conditions for unsteady flow, and the effect of various geometrical and physical parameters is examined. For a given network tree order, m, oscillations can be induced for a sufficiently high value of q by increasing the apparent intrinsic viscosity, decreasing the ratio of the vessel diameter from one generation to the next, or by decreasing the diameter of the terminal vessels. With other parameters fixed, oscillations are inhibited by increasing m. The results of the continuum model are in excellent agreement with the predictions of a discrete model where the motion of individual cells is followed from inlet to outlet.