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

How effective is school-based deworming for the community-wide control of soil-transmitted helminths?

Background: The London Declaration on neglected tropical diseases was based in part on a new World Health Organization roadmap to “sustain, expand and extend drug access programmes to ensure the necessary supply of drugs and other interventions to help control by 2020”. Large drug donations from the pharmaceutical industry form the backbone to this aim, especially for soil-transmitted helminths (STHs) raising the question of how best to use these resources. Deworming for STHs is often targeted at school children because they are at greatest risk of morbidity and because it is remarkably cost-effective. However, the impact of school-based deworming on transmission in the wider community remains unclear. Methods: We first estimate the proportion of parasites targeted by school-based deworming using demography, school enrolment, and data from a small number of example settings where age-specific intensity of infection (either worms or eggs) has been measured for all ages. We also use transmission models to investigate the potential impact of this coverage on transmission for different mixing scenarios. Principal Findings: In the example settings <30% of the population are 5 to <15 years old. Combining this demography with the infection age-intensity profile we estimate that in one setting school children output as little as 15% of hookworm eggs, whereas in another setting they harbour up to 50% of Ascaris lumbricoides worms (the highest proportion of parasites for our examples). In addition, it is estimated that from 40–70% of these children are enrolled at school. Conclusions: These estimates suggest that, whilst school-based programmes have many important benefits, the proportion of infective stages targeted by school-based deworming may be limited, particularly where hookworm predominates. We discuss the consequences for transmission for a range of scenarios, including when infective stages deposited by children are more likely to contribute to transmission than those from adults

HIV and fertility change in rural Zimbabwe

Fertility transition and HIV epidemics are currently running parallel in some sub-Saharan African populations. Interactions between the two at the individual and population levels could accentuate or moderate the resulting demographic trends. We review a number of mechanisms through which an HIV epidemic and responses to it can affect birth rates, through the biological and behavioural proximate determinants. Uninfected as well as infected people can be affected and many of the changes could have unintended consequences for fertility at the individual level. Results from a small-scale in-depth study in two rural areas of Zimbabwe are reviewed. These indicate that the local HIV epidemic has begun to influence the proximate determinants of fertility. If observed trends persist, a modest acceleration in the recent decline in birth rates seems plausible

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

Can chemotherapy alone eliminate the transmission of soil transmitted helminths?

Background Amongst the world’s poorest populations, availability of anthelmintic treatments for the control of soil transmitted helminths (STH) by mass or targeted chemotherapy has increased dramatically in recent years. However, the design of community based treatment programmes to achieve the greatest impact on transmission is still open to debate. Questions include: who should be treated, how often should they be treated, how long should treatment be continued for? Methods Simulation and analysis of a dynamic transmission model and novel data analyses suggest refinements of the World Health Organization guidelines for the community based treatment of STH. Results This analysis shows that treatment levels and frequency must be much higher, and the breadth of coverage across age classes broader than is typically the current practice, if transmission is to be interrupted by mass chemotherapy alone. Conclusions When planning interventions to reduce transmission, rather than purely to reduce morbidity, current school-based interventions are unlikely to be enough to achieve the desired results

Mesoscopic molecular ions in Bose-Einstein condensates

We study the possible formation of large (mesoscopic) molecular ions in an ultracold degenerate bosonic gas doped with charged particles (ions). We show that the polarization potentials produced by the ionic impurities are capable of capturing hundreds of atoms into loosely bound states. We describe the spontaneous formation of these hollow molecular ions via phonon emission and suggest an optical technique for coherent stimulated transitions of free atoms into a specific bound state. These results open up new interesting possibilities for manipulating tightly confined ensembles.Comment: 4 pages (two-columns), 2 figure

Radio structures of the nuclei of nearby Seyfert galaxies and the nature of the missing diffuse emission

We present archival high spatial resolution VLA and VLBA data of the nuclei of seven of the nearest and brightest Seyfert galaxies in the Southern Hemisphere. At VLA resolution (~0.1 arcsec), the nucleus of the Seyfert galaxies is unresolved, with the exception of MCG-5-23-16 and NGC 7469 showing a core-jet structure. Three Seyfert nuclei are surrounded by diffuse radio emission related to star-forming regions. VLBA observations with parsec-scale resolution pointed out that in MRK 1239 the nucleus is clearly resolved into two components separated by ~30 pc, while the nucleus of NGC 3783 is unresolved. Further comparison between VLA and VLBA data of these two sources shows that the flux density at parsec scales is only 20% of that measured by the VLA. This suggests that the radio emission is not concentrated in a single central component, as in elliptical radio galaxies, and an additional low-surface brightness component must be present. A comparison of Seyfert nuclei with different radio spectra points out that the ``presence'' of undetected flux on milli-arcsecond scale is common in steep-spectrum objects, while in flat-spectrum objects essentially all the radio emission is recovered. In the steep-spectrum objects, the nature of this ``missing'' flux is likely due to non-thermal AGN-related radiation, perhaps from a jet that gets disrupted in Seyfert galaxies because of the denser environment of their spiral hosts.Comment: 13 pages, 9 figures; paper accepted for publication in MNRA

Hadley V. Baxendale: Still Crazy After All These Years? Panel Discussion

The following discussion about Hadley v. Baxendale took place on June 8, 2004, at the Conference on The Common Law of Contracts as a World Force in Two Ages of Revolution, held at the Oxstalls Campus of the University of Gloucestershire, in Gloucester, England. The Conference marked the 150th anniversary of Hadley. The following discussion was intended to be a free-ranging exploration of Hadley, its rule, its role in legal pedagogy, and its likely future

Should the goal for the treatment of soil transmitted Helminth (STH) infections be changed from morbidity control in children to community-wide transmission elimination?

Morbidity induced by infection with the major soil transmitted infections (STH—Ascaris lumbricoides, Trichuris trichiura, and hookworms) results in an estimated 5.19 million disability-adjusted life years (DALYs) [1]. The World Health Organization’s (WHO) policy for control centres on three groups, preschool aged children (pre-SAC), school-aged children (SAC), and women of child bearing age, on the basis that heavy infection in these groups will have a detrimental impact on anaemia, child growth, and development. The current WHO guidelines focus on school-aged children, both for monitoring infection and as a target for treatment, although treatment of pre-SAC and women of childbearing age is also recommended where sustainable delivery mechanisms exist, especially in areas of intense transmission [2,3]. The guidelines recommend treating SAC annually where any STH prevalence falls between 20% and 50% and twice a year where it exceeds 50% [3]. The London Declaration on Neglected Tropical Diseases in 2012 endorsed WHO goals to scale up mass drug administration (MDA) for STH, so that by 2020, 75% of the pre-SAC and SAC in need will be treated regularly [4]. Building on an existing roadmap, WHO announced an intention to meet the target [2,5,6]. Progress has been good in some areas, but less so in others. In 2012, global coverage of those in need was 37% for SAC and 29% for pre-SAC [5]. Data for the more recent years is as yet to be published by WHO [5], but a huge gain in coverage is not expected, despite increased drug donations from the pharmaceutical companies who manufacture the main anthelmintics. This is due in part to the logistical challenges in getting even donated drugs to these populations, who are often beyond “the end of the road.” At present, many countries with endemic STH infections are not availing themselves of the freely donated drugs to treat children. We are still a long way from the 2020 target of 75%. Even if this target is reached, will it be enough to eliminate transmission and the disease arising from heavy infections with STH? If not, how should the guidelines be changed to push towards morbidity control, and ideally, the eventual elimination of transmission