Modeling of Immunosenescence and Risk of Death from Respiratory Infections: Evaluation of the Role of Antigenic Load and Population Heterogeneity

It is well known that efficacy of immune functions declines with age. It results in an increase of severity and duration of respiratory infections and also in dramatic growth of risk of death due to these diseases after age 65. The goal of this work is to describe and investigate the mechanism underlying the age pattern of the mortality rate caused by infectious diseases and to determine the cause-specific hazard rate as a function of immune system characteristics. For these purposes we develop a three-compartment model explaining observed risk-of-death. The model incorporates up-to-date knowledge about cellular mechanisms of aging, disease dynamics, population heterogeneity in resistance to infections, and intrinsic aging rate. The results of modeling show that the age-trajectory of mortality caused by respiratory infections may be explained by the value of antigenic load, frequency of infections and the rate of aging of the stem cell population (i.e. the population of T-lymphocyte progenitor cells). The deceleration of infection-induced mortality at advanced age can be explained by selection of individuals with a slower rate of stem cell aging. Parameter estimates derived from fitting mortality data indicate that infection burden was monotonically decreasing during the twentieth century, and changes in total antigenic load were gender-specific: it experienced periodic fluctuations in males and increased approximately two-fold in females

Comparison of two European paediatric emergency departments: does primary care organisation influence emergency attendance?

Backround: To compare paediatric Emergency Department (ED) attendances and admission outcomes in twoEuropean hospitals with different paediatric primary care set-up. Methods: This is a retrospective prevalence study comparing all paediatric ED attendances during calendar years 2013 in two EDs with similar catchment area: one in Italy (Trieste) where paediatric primary care is provided by office paediatricians, the other, in the UK (Cambridge), where paediatric primary care is provided by general practitioners. Data on reason for presentation, discharge diagnosis and admission rate were collected and sub-group analysis for specific age groups (<1 year, 1 \u2013 4 years, 5 \u2013 15 years) was performed. Results: Over 12 months, 20.331 children (0 \u2013 15 years old) were seen in Cambridge and 18.646 in Trieste, with a very similar age distribution in both centres, except for the youngest age group: the percentage of infants seen in comparison with the total number of children attending ED was 1/3 higher in England than in Italy (15.4% vs 11. 4%). The reasons for attendance were similar: under 1 year of age, the chief complaints were fever, breathing difficulties and gastrointestinal problems while in the older age groups trauma represented the commonest reason. Among discharge diagnoses, no differences were found between the two hospitals, except for faltering growth and \u201c well child \u201d , more frequently diagnosed in English children under 5 years. The proportion of admissions was three times higher in Cambridge (14.1% vs 4.8%) with most children being admitted for infectious diseases. Conclusions: ED attendances in infants are more common in a primary care setting provided by general practicioner and, moreover, admission rates in all age groups are 1/3 reduced by primary care based paediatricians. Due to the methodological limits of this study, it isn't possible to evaluate whether these results depend only on paediatric primary care set-up or be determined by other confounding factors. New studies are needed to confirm this preliminary evidence

Human Cytomegalovirus: detection of congenital and perinatal infection in Argentina

BACKGROUND: Human cytomegalovirus (CMV) is one of the most commonly found agents of congenital infections. Primary maternal infection is associated with risk of symptomatic congenital diseases, and high morbidity is frequently associated with very low birth weight. Neonates with asymptomatic infection develop various sequelae during infancy. This is the first Argentine study performed in neonates with congenital and postnatal HCMV infection. The purpose of this study was to evaluate the performance of the polymerase chain reaction (PCR) technique with different pairs of primers, to detect cytomegalovirus isolated in tissue cultures and directly in urine and dried blood spot (DBS) specimens. Results were compared with IgM detection. METHODS: The study was performed between 1999 and 2001 on routine samples in the Laboratory. A total of 61 urine and 56 serum samples were selected from 61 newborns/infants, 33 patients whose samples were analyzed during the first two to three weeks of life were considered congenital infections; the remaining 28 patients whose samples were taken later than the third week were grouped as perinatal infections, although only in 4 the perinatal transmission of infection was determined unequivocally Cytomegalovirus diagnosis was made by isolating the virus from urine samples in human foreskin fibroblast cells. Three different primer pairs directed to IE, LA and gB genes were used for the HCMV PCR assay in viral isolates. Subsequently, PCR and nested PCR (nPCR) assays with gB primers were performed directly in urine and in 11 samples of dried blood spot (DBS) on Guthrie Card, these results were then compared with serology. RESULTS: The main clinical manifestations of the 33 patients with congenital infection were purpura, jaundice, hepatomegaly and anaemia. Three patients presented low birth weight as single symptom, 10, intracranial calcifications, and 2, kidney failure. In the 28 patients grouped as with perinatal infection, anaemia, hepatosplenomegaly and enzymatic alteration were predominant, and 4 patients were HIV positive. The primers used to amplify the gB region had a PCR positivity rate of 100%, whereas those that amplified IE and LA regions had a PCR positivity rate of 54% and 61% respectively, in CMV isolates. Amplification by PCR of urine samples (with no previous DNA extraction), using primers for the gB region, detected 34/61 positive samples. Out of the 33 samples from patients with congenital infection, 24 (73%) were positive. When nPCR was used in these samples, all were positive, whereas in the remaining 28 patients, two negative cases were found. Cytomegalovirus DNA detection in 11 samples was also carried out in DBS: 7 DBS samples were positive and 4 were negative. CONCLUSIONS: Primers directed to the gB fragment region were the best choice for the detection of CMV DNA in positive isolates. In congenital infections, direct PCR in urine was positive in a high percentage (73%) of samples; however, in patients grouped as with perinatal infection only 36% of the cases were positive. With n-PCR, total sample positivity reached 97%. PCR technique performed in DBS allowed identifying congenital infection in four patients and to be confirmed in 3. These results show the value of nPCR for the detection of all cases of CMV infection. The assay offers the advantage that it may be performed within the normal working day and provides reliable results in a much shorter time frame than that required for either traditional tissue culture or the shell-viral assay

Soliton ratchets induced by ac forces with harmonic mixing

The ratchet dynamics of a kink (topological soliton) of a dissipative sine-Gordon equation in the presence of ac forces with harmonic mixing (at least bi-harmonic) of zero mean is studied. The dependence of the kink mean velocity on system parameters is investigated numerically and the results are compared with a perturbation analysis based on a point particle representation of the soliton. We find that first order perturbative calculations lead to incomplete descriptions, due to the important role played by the soliton-phonon interaction in establishing the phenomenon. The role played by the temporal symmetry of the system in establishing soliton ratchets is also emphasized. In particular, we show the existence of an asymmetric internal mode on the kink profile which couples to the kink translational mode through the damping in the system. Effective soliton transport is achieved when the internal mode and the external force get phase locked. We find that for kinks driven by bi-harmonic drivers consisting of the superposition of a fundamental driver with its first odd harmonic, the transport arises only due to this {\it internal mode} mechanism, while for bi-harmonic drivers with even harmonic superposition, also a point-particle contribution to the drift velocity is present. The phenomenon is robust enough to survive the presence of thermal noise in the system and can lead to several interesting physical applications.Comment: 9 pages, 13 figure

Soliton ratchets

The mechanism underlying the soliton ratchet, both in absence and in presence of noise, is investigated. We show the existence of an asymmetric internal mode on the soliton profile which couples, trough the damping in the system, to the soliton translational mode. Effective soliton transport is achieved when the internal mode and the external force are phase locked. We use as working model a generalized double sine-Gordon equation. The phenomenon is expected to be valid for generic soliton systems.Comment: 4 pages, 4 figure

Bubbles, clusters and denaturation in genomic DNA: modeling, parametrization, efficient computation

The paper uses mesoscopic, non-linear lattice dynamics based (Peyrard-Bishop-Dauxois, PBD) modeling to describe thermal properties of DNA below and near the denaturation temperature. Computationally efficient notation is introduced for the relevant statistical mechanics. Computed melting profiles of long and short heterogeneous sequences are presented, using a recently introduced reparametrization of the PBD model, and critically discussed. The statistics of extended open bubbles and bound clusters is formulated and results are presented for selected examples.Comment: to appear in a special issue of the Journal of Nonlinear Mathematical Physics (ed. G. Gaeta

A Simple Model for the DNA Denaturation Transition

We study pairs of interacting self-avoiding walks on the 3d simple cubic lattice. They have a common origin and are allowed to overlap only at the same monomer position along the chain. The latter overlaps are indeed favored by an energetic gain. This is inspired by a model introduced long ago by Poland and Sheraga [J. Chem. Phys. {\bf 45}, 1464 (1966)] for the denaturation transition in DNA where, however, self avoidance was not fully taken into account. For both models, there exists a temperature T_m above which the entropic advantage to open up overcomes the energy gained by forming tightly bound two-stranded structures. Numerical simulations of our model indicate that the transition is of first order (the energy density is discontinuous), but the analog of the surface tension vanishes and the scaling laws near the transition point are exactly those of a second order transition with crossover exponent \phi=1. Numerical and exact analytic results show that the transition is second order in modified models where the self-avoidance is partially or completely neglected.Comment: 29 pages, LaTeX, 20 postscript figure

Statistical Mechanics of Torque Induced Denaturation of DNA

A unifying theory of the denaturation transition of DNA, driven by temperature T or induced by an external mechanical torque Gamma is presented. Our model couples the hydrogen-bond opening and the untwisting of the helicoidal molecular structure. We show that denaturation corresponds to a first-order phase transition from B-DNA to d-DNA phases and that the coexistence region is naturally parametrized by the degree of supercoiling sigma. The denaturation free energy, the temperature dependence of the twist angle, the phase diagram in the T,Gamma plane and isotherms in the sigma, Gamma plane are calculated and show a good agreement with experimental data.Comment: 5 pages, 3 figures, model improve

Effect of Trends on Detrended Fluctuation Analysis

Detrended fluctuation analysis (DFA) is a scaling analysis method used to estimate long-range power-law correlation exponents in noisy signals. Many noisy signals in real systems display trends, so that the scaling results obtained from the DFA method become difficult to analyze. We systematically study the effects of three types of trends -- linear, periodic, and power-law trends, and offer examples where these trends are likely to occur in real data. We compare the difference between the scaling results for artificially generated correlated noise and correlated noise with a trend, and study how trends lead to the appearance of crossovers in the scaling behavior. We find that crossovers result from the competition between the scaling of the noise and the ``apparent'' scaling of the trend. We study how the characteristics of these crossovers depend on (i) the slope of the linear trend; (ii) the amplitude and period of the periodic trend; (iii) the amplitude and power of the power-law trend and (iv) the length as well as the correlation properties of the noise. Surprisingly, we find that the crossovers in the scaling of noisy signals with trends also follow scaling laws -- i.e. long-range power-law dependence of the position of the crossover on the parameters of the trends. We show that the DFA result of noise with a trend can be exactly determined by the superposition of the separate results of the DFA on the noise and on the trend, assuming that the noise and the trend are not correlated. If this superposition rule is not followed, this is an indication that the noise and the superimposed trend are not independent, so that removing the trend could lead to changes in the correlation properties of the noise.Comment: 20 pages, 16 figure

Effect of nonstationarities on detrended fluctuation analysis

Detrended fluctuation analysis (DFA) is a scaling analysis method used to quantify long-range power-law correlations in signals. Many physical and biological signals are ``noisy'', heterogeneous and exhibit different types of nonstationarities, which can affect the correlation properties of these signals. We systematically study the effects of three types of nonstationarities often encountered in real data. Specifically, we consider nonstationary sequences formed in three ways: (i) stitching together segments of data obtained from discontinuous experimental recordings, or removing some noisy and unreliable parts from continuous recordings and stitching together the remaining parts -- a ``cutting'' procedure commonly used in preparing data prior to signal analysis; (ii) adding to a signal with known correlations a tunable concentration of random outliers or spikes with different amplitude, and (iii) generating a signal comprised of segments with different properties -- e.g. different standard deviations or different correlation exponents. We compare the difference between the scaling results obtained for stationary correlated signals and correlated signals with these three types of nonstationarities.Comment: 17 pages, 10 figures, corrected some typos, added one referenc