Emerging drugs for sickle cell anemia.

INTRODUCTION: The search for effective therapeutic interventions for sickle cell disease (SCD) has been an ongoing endeavor for over 50 years. During this period, only hydroxyurea (HU), which received US FDA approval in February 1998, was identified as an effective therapeutic agent in preventing or ameliorating the frequency of vaso-occlusive crises, acute chest syndrome and the need for blood transfusion. Approximately 25% of patients with sickle cell anemia (SCA), however, do not respond to HU and some patients experiencing serious side effects of this chemotherapeutic agent. Nevertheless, the success of HU opened the sluice gates to identify other effective drug therapies. The objective of this review is to describe the emerging drug therapies for SCA. AREAS COVERED: In this review, we describe the pathophysiology of SCD and provide an in-depth analysis of the current and new pharmacologic therapies in the field. Literature searches involved multiple databases including Medline In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus. EXPERT OPINION: SCA is a heterogeneous disease that has caused tremendous global morbidity and early mortality. More effective, individualized and inexpensive therapies are needed. New therapies targeting multiple pathways in its complex pathophysiology are under investigation

A multigrid method for the Helmholtz equation with optimized coarse grid corrections

We study the convergence of multigrid schemes for the Helmholtz equation, focusing in particular on the choice of the coarse scale operators. Let G_c denote the number of points per wavelength at the coarse level. If the coarse scale solutions are to approximate the true solutions, then the oscillatory nature of the solutions implies the requirement G_c > 2. However, in examples the requirement is more like G_c >= 10, in a trade-off involving also the amount of damping present and the number of multigrid iterations. We conjecture that this is caused by the difference in phase speeds between the coarse and fine scale operators. Standard 5-point finite differences in 2-D are our first example. A new coarse scale 9-point operator is constructed to match the fine scale phase speeds. We then compare phase speeds and multigrid performance of standard schemes with a scheme using the new operator. The required G_c is reduced from about 10 to about 3.5, with less damping present so that waves propagate over > 100 wavelengths in the new scheme. Next we consider extensions of the method to more general cases. In 3-D comparable results are obtained with standard 7-point differences and optimized 27-point coarse grid operators, leading to an order of magnitude reduction in the number of unknowns for the coarsest scale linear system. Finally we show how to include PML boundary layers, using a regular grid finite element method. Matching coarse scale operators can easily be constructed for other discretizations. The method is therefore potentially useful for a large class of discretized high-frequency Helmholtz equations.Comment: Coarse scale operators are simplified and only standard smoothers used in v3; 5 figures, 12 table

SS 433: Results of a Recent Multi-wavelength Campaign

We conducted a multi-wavelength campaign in September-October, 2002, to observe SS 433. We used 45 meter sized 30 dishes of Giant Meter Radio Telescope (GMRT) for radio observation, 1.2 meter Physical Research Laboratory Infra-red telescope at Mt Abu for IR, 1 meter Telescope at the State Observatory, Nainital for Optical photometry, 2.3 meter optical telescope at the Vainu Bappu observatory for spectrum and Rossi X-ray Timing Explorer (RXTE) Target of Opportunity (TOO) observation for X-ray observations. We find sharp variations in intensity in time-scales of a few minutes in X-rays, IR and radio wavelengths. Differential photometry at the IR observation clearly indicated significant intrinsic variations in short time scales of minutes throughout the campaign. Combining results of these wavelengths, we find a signature of delay of about two days between IR and Radio. The X-ray spectrum yielded double Fe line profiles which corresponded to red and blue components of the relativistic jet. We also present the broadband spectrum averaged over the campaign duration.Comment: 17 pages 10 figures MNRAS (submitted

Can changes in education alter future population ageing in Asia and Europe?

While population ageing is rising, the educational composition of the elderly remains rather heterogeneous. This study assesses the educational differences in future population ageing in Asia and Europe, and how future population ageing in Asia and Europe would change if the educational composition of its populations changed. A comparative population ageing measure (the Comparative Prospective Old-Age Threshold [CPOAT]) was used, which recalculates old-age thresholds after accounting for differences in life expectancy, and the likelihood of adults surviving to higher ages. Combined data from projected age- and sex-specific life-tables (from the United Nations) and projected age- and sex-specific survival ratios by different levels of education (from the Wittgenstein Centre for Demography and Global Human Capital) were used to construct projected life-tables (2015-2020, ..., 2045-2050) by educational level and sex for different regions of Asia and Europe. Based on these life-tables, future comparative prospective old-age thresholds by educational level and sex were calculated. It was found that in both Asia and Europe, and among both men and women, the projected old-age thresholds are higher for higher educated people than for less-educated people. While Europe has a larger projected share of elderly in the population than Asia, Europe's older population is better educated. In alternative future scenarios in which populations hypothetically have higher levels of education, the projected shares of elderly in the population decrease across all regions of Asia and Europe, but more so in Asia. The results highlight the effectiveness of investing in education as a policy response to the challenges associated with population ageing in Asia and Europe. Such investments are more effective in the Asian regions, where the educational infrastructure is less developed.</p

Prescription-induced jump distributions in multiplicative Poisson processes

Generalized Langevin equations (GLE) with multiplicative white Poisson noise pose the usual prescription dilemma leading to different evolution equations (master equations) for the probability distribution. Contrary to the case of multiplicative gaussian white noise, the Stratonovich prescription does not correspond to the well known mid-point (or any other intermediate) prescription. By introducing an inertial term in the GLE we show that the Ito and Stratonovich prescriptions naturally arise depending on two time scales, the one induced by the inertial term and the other determined by the jump event. We also show that when the multiplicative noise is linear in the random variable one prescription can be made equivalent to the other by a suitable transformation in the jump probability distribution. We apply these results to a recently proposed stochastic model describing the dynamics of primary soil salinization, in which the salt mass balance within the soil root zone requires the analysis of different prescriptions arising from the resulting stochastic differential equation forced by multiplicative white Poisson noise whose features are tailored to the characters of the daily precipitation. A method is finally suggested to infer the most appropriate prescription from the data

Lorentz-breaking effects in scalar-tensor theories of gravity

In this work, we study the effects of breaking Lorentz symmetry in scalar-tensor theories of gravity taking torsion into account. We show that a space-time with torsion interacting with a Maxwell field by means of a Chern-Simons-like term is able to explain the optical activity in syncrotron radiation emitted by cosmological distant radio sources. Without specifying the source of the dilaton-gravity, we study the dilaton-solution. We analyse the physical implications of this result in the Jordan-Fierz frame. We also analyse the effects of the Lorentz breaking in the cosmic string formation process. We obtain the solution corresponding to a cosmic string in the presence of torsion by keeping track of the effects of the Chern-Simons coupling and calculate the charge induced on this cosmic string in this framework. We also show that the resulting charged cosmic string gives us important effects concerning the background radiation.The optical activity in this case is also worked out and discussed.Comment: 10 pages, no figures, ReVTex forma

Live-virus exposure of vaccine-protected macaques alters the anti-HIV-1 antibody repertoire in the absence of viremia

Background: We addressed the question whether live-virus challenges could alter vaccine-induced antibody (Ab) responses in vaccinated rhesus macaques (RMs) that completely resisted repeated exposures to R5-tropic simian-human immunodeficiency viruses encoding heterologous HIV clade C envelopes (SHIV-Cs). Results: We examined the Ab responses in aviremic RMs that had been immunized with a multi-component protein vaccine (multimeric HIV-1 gp160, HIV-1 Tat and SIV Gag-Pol particles) and compared anti-Env plasma Ab titers before and after repeated live-virus exposures. Although no viremia was ever detected in these animals, they showed significant increases in anti-gp140 Ab titers after they had encountered live SHIVs. When we investigated the dynamics of anti-Env Ab titers during the immunization and challenge phases further, we detected the expected, vaccine-induced increases of Ab responses about two weeks after the last protein immunization. Remarkably, these titers kept rising during the repeated virus challenges, although no viremia resulted. In contrast, in vaccinated RMs that were not exposed to virus, anti-gp140 Ab titers declined after the peak seen two weeks after the last immunization. These data suggest boosting of pre-existing, vaccine-induced Ab responses as a consequence of repeated live-virus exposures. Next, we screened polyclonal plasma samples from two of the completely protected vaccinees by peptide phage display and designed a strategy that selects for recombinant phages recognized only by Abs present after – but not before – any SHIV challenge. With this “subtractive biopanning” approach, we isolated V3 mimotopes that were only recognized after the animals had been exposed to live virus. By detailed epitope mapping of such anti-V3 Ab responses, we showed that the challenges not only boosted pre-existing binding and neutralizing Ab titers, but also induced Abs targeting neo-antigens presented by the heterologous challenge virus. Conclusions: Anti-Env Ab responses induced by recombinant protein vaccination were altered by the multiple, live SHIV challenges in vaccinees that had no detectable viral loads. These data may have implications for the interpretation of “vaccine only” responses in clinical vaccine trials