How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements

Universality classes in anisotropic non-equilibrium growth models

We study the effect of generic spatial anisotropies on the scaling behavior in the Kardar-Parisi-Zhang equation. In contrast to its "conserved" variants, anisotropic perturbations are found to be relevant in d > 2 dimensions, leading to rich phenomena that include novel universality classes and the possibility of first-order phase transitions and multicritical behavior. These results question the presumed scaling universality in the strong-coupling rough phase, and shed further light on the connection with generalized driven diffusive systems.Comment: 4 pages, revtex, 2 figures (eps files enclosed

Significant differences in incubation times in sheep infected with bovine spongiform encephalopathy result from variation at codon 141 in the PRNP gene

The susceptibility of sheep to prion infection is linked to variation in the PRNP gene, which encodes the prion protein. Common polymorphisms occur at codons 136, 154 and 171. Sheep which are homozygous for the A<sub>136</sub>R<sub>154</sub>Q<sub>171</sub> allele are the most susceptible to bovine spongiform encephalopathy (BSE). The effect of other polymorphisms on BSE susceptibility is unknown. We orally infected ARQ/ARQ Cheviot sheep with equal amounts of BSE brain homogenate and a range of incubation periods was observed. When we segregated sheep according to the amino acid (L or F) encoded at codon 141 of the PRNP gene, the shortest incubation period was observed in LL141 sheep, whilst incubation periods in FF<sub>141</sub> and LF<sub>141</sub> sheep were significantly longer. No statistically significant differences existed in the expression of total prion protein or the disease-associated isoform in BSE-infected sheep within each genotype subgroup. This suggested that the amino acid encoded at codon 141 probably affects incubation times through direct effects on protein misfolding rates

Antigen-driven T-cell turnover.

A mathematical model is developed to characterize the distribution of cell turnover rates within a population of T lymphocytes. Previous models of T-cell dynamics have assumed a constant uniform turnover rate; here we consider turnover in a cell pool subject to clonal proliferation in response to diverse and repeated antigenic stimulation. A basic framework is defined for T-cell proliferation in response to antigen, which explicitly describes the cell cycle during antigenic stimulation and subsequent cell division. The distribution of T-cell turnover rates is then calculated based on the history of random exposures to antigens. This distribution is found to be bimodal, with peaks in cell frequencies in the slow turnover (quiescent) and rapid turnover (activated) states. This distribution can be used to calculate the overall turnover for the cell pool, as well as individual contributions to turnover from quiescent and activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T-cell infection by HIV is explored. We show that our model can resolve the paradox of high levels of viral replication occurring while only a small fraction of cells are infected

High-resolution thermal expansion measurements under Helium-gas pressure

We report on the realization of a capacitive dilatometer, designed for high-resolution measurements of length changes of a material for temperatures 1.4 K $\leq T \leq$ 300 K and hydrostatic pressure $P \leq$ 250 MPa. Helium ($^4$He) is used as a pressure-transmitting medium, ensuring hydrostatic-pressure conditions. Special emphasis has been given to guarantee, to a good approximation, constant-pressure conditions during temperature sweeps. The performance of the dilatometer is demonstrated by measurements of the coefficient of thermal expansion at pressures $P \simeq$ 0.1 MPa (ambient pressure) and 104 MPa on a single crystal of azurite, Cu$_3$(CO$_3$)$_2$(OH)$_2$, a quasi-one-dimensional spin S = 1/2 Heisenberg antiferromagnet. The results indicate a strong effect of pressure on the magnetic interactions in this system.Comment: 8 pages, 7 figures, published in Rev. Sci. Instrum with minor change

The evolution of faint AGN between z~1 and z~5 from the COMBO-17 survey

We present a determination of the optical/UV AGN luminosity function and its evolution, based on a large sample of faint (R<24) QSOs identified in the COMBO-17 survey. Using multi-band photometry in 17 filters within 350nm < lambda_obs < 930nm, we could simultaneously determine photometric redshifts with an accuracy of sigma_z<0.03 and obtain spectral energy distributions. The redshift range covered by the sample is 1.2<z<4.8, which implies that even at z~3, the sample reaches below luminosities corresponding to M_B = -23, conventionally employed to distinguish between Seyfert galaxies and quasars. We clearly detect a broad plateau-like maximum of quasar activity around z~2 and map out the smooth turnover between z~1 and z~4. The shape of the LF is characterised by some mild curvature, but no sharp `break' is present within the range of luminosities covered. Using only the COMBO-17 data, the evolving LF can be adequately described by either a pure density evolution (PDE) or a pure luminosity evolution (PLE) model. However, the absence of a strong L*-like feature in the shape of the LF inhibits a robust distinction between these modes. We present a robust estimate for the integrated UV luminosity generation by AGN as a function of redshift. We find that the LF continues to rise even at the lowest luminosities probed by our survey, but that the slope is sufficiently shallow that the contribution of low-luminosity AGN to the UV luminosity density is negligible. Although our sample reaches much fainter flux levels than previous data sets, our results on space densities and LF slopes are completely consistent with extrapolations from recent major surveys such as SDSS and 2QZ.Comment: 17 pages, 14 figures, Astronomy & Astrophysics, in print, revised versio

A close look into the carbon disk at the core of the planetary nebula CPD-568032

We present high spatial resolution observations of the dusty core of the Planetary Nebula with Wolf-Rayet central star CPD-568032. These observations were taken with the mid-infrared interferometer VLTI/MIDI in imaging mode providing a typical 300 mas resolution and in interferometric mode using UT2-UT3 47m baseline providing a typical spatial resolution of 20 mas. The visible HST images exhibit a complex multilobal geometry dominated by faint lobes. The farthest structures are located at 7" from the star. The mid-IR environment of CPD-568032 is dominated by a compact source, barely resolved by a single UT telescope in a 8.7 micron filter. The infrared core is almost fully resolved with the three 40-45m projected baselines ranging from -5 to 51 degree but smooth oscillating fringes at low level have been detected in spectrally dispersed visibilities. This clear signal is interpreted in terms of a ring structure which would define the bright inner rim of the equatorial disk. Geometric models allowed us to derive the main geometrical parameters of the disk. For instance, a reasonably good fit is reached with an achromatic and elliptical truncated Gaussian with a radius of 97+/-11 AU, an inclination of 28+/-7 degree and a PA for the major axis at 345+/-7 degree. Furthermore, we performed some radiative transfer modeling aimed at further constraining the geometry and mass content of the disk, by taking into account the MIDI dispersed visibilities, spectra, and the large aperture SED of the source. These models show that the disk is mostly optically thin in the N band and highly flared.Comment: Paper accepted in A&

Mortality in patients with successful initial response to highly active antiretroviral therapy is still higher than in non-HIV-infected individuals.

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level or = 100,000 copies/mL) measured at 24 weeks and infection via intravenous drug use (IDU) (HR = 0.16, 95% CI: 0.10 to 0.26, non-IDU vs. IDU) were significantly associated with progression to death. For non-IDU patients with 600 x 10 CD4 cells/L and an HIV RNA level <100,000 copies/mL at 24 weeks, mortality was predicted to be 5.3 (95% CI: 3.5 to 8.4) and 10.4 (95% CI: 6.4 to 17.4) times higher than in the general population for 25-year-old men and women, respectively, and 1.15 (95% CI: 1.08 to 1.25) and 1.29 (95% CI: 1.16 to 1.50) times higher for 65-year-old men and women, respectively. Hence, mortality in HIV-infected patients with a good initial response to HAART is still higher than in the general population