Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia.

BACKGROUND: Severe malarial anemia (SMA) remains a major cause of pediatric illness and mortality in Sub-Saharan Africa. Here we test the hypothesis that prenatal exposures, reflected by soluble inflammatory mediators in cord blood, can condition an individual's susceptibility to SMA. METHODS: In a Tanzanian birth cohort (n = 743), we measured cord blood concentrations of tumor necrosis factor (TNF), TNF receptors I and II (TNF-RI and TNF-RII), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFN-γ). After adjusting for conventional covariates, we calculated the hazard ratios (HR) for time to first SMA event with log(e) cytokine concentrations dichotomized at the median, by quartile, and per standard deviation (SD) increase. RESULTS: Low levels of TNF, TNF-RI, IL-1β, and IL-5 and high levels of TNF-RII were associated statistically significantly and respectively with approximately 3-fold, 2-fold, 8-fold, 4-fold, and 3-fold increased risks of SMA (Hb < 50 g/L). TNF, TNF-RI, and IL-1β concentrations were inversely and log-linearly associated with SMA risk; the HR (95% confidence interval [CI]) per 1-SD increase were respectively 0.81 (.65, 1.02), 0.76 (.62, .92), and 0.50 (.40, .62). CONCLUSIONS: These data suggest that proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins

Parasite Burden and Severity of Malaria in Tanzanian Children

BACKGROUND: Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. METHODS: We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. RESULTS: Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman’s second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. CONCLUSIONS: Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.

Residues and World-Sheet Instantons

We reconsider the question of which Calabi-Yau compactifications of the heterotic string are stable under world-sheet instanton corrections to the effective space-time superpotential. For instance, compactifications described by (0,2) linear sigma models are believed to be stable, suggesting a remarkable cancellation among the instanton effects in these theories. Here, we show that this cancellation follows directly from a residue theorem, whose proof relies only upon the right-moving world-sheet supersymmetries and suitable compactness properties of the (0,2) linear sigma model. Our residue theorem also extends to a new class of "half-linear" sigma models. Using these half-linear models, we show that heterotic compactifications on the quintic hypersurface in CP^4 for which the gauge bundle pulls back from a bundle on CP^4 are stable. Finally, we apply similar ideas to compute the superpotential contributions from families of membrane instantons in M-theory compactifications on manifolds of G_2 holonomy.Comment: 47 page

Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study.

Hepcidin, the master regulator of bioavailable iron, is a key mediator of anemia and also plays a central role in host defense against infection. We hypothesized that measuring hepcidin levels in cord blood could provide an early indication of interindividual differences in iron regulation with quantifiable implications for anemia, malaria, and mortality-related risk. Hepcidin concentrations were measured in cord plasma from a birth cohort (N = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002-2006). At the time of delivery, cord hepcidin levels were correlated with inflammatory mediators, iron markers, and maternal health conditions. Hepcidin levels were 30% (95% confidence interval [CI]: 12%, 44%) lower in children born to anemic mothers and 48% (95% CI: 11%, 97%) higher in placental malaria-exposed children. Relative to children in the lowest third, children in the highest third of cord hepcidin had on average 2.5 g/L (95% CI: 0.1, 4.8) lower hemoglobin levels over the duration of follow-up, increased risk of anemia and severe anemia (adjusted hazard ratio [HR] [95% CI]: 1.18 [1.03, 1.36] and 1.34 [1.08, 1.66], respectively), and decreased risk of malaria and all-cause mortality (adjusted HR [95% CI]: 0.78 [0.67, 0.91] and 0.34 [0.14, 0.84], respectively). Although longitudinal measurements of hepcidin and iron stores are required to strengthen causal inference, these results suggest that hepcidin may have utility as a biomarker indicating children's susceptibility to anemia and infection in early life

Mapping the Galactic Halo I. The `Spaghetti' Survey

We describe a major survey of the Milky Way halo designed to test for kinematic substructure caused by destruction of accreted satellites. We use the Washington photometric system to identify halo stars efficiently for spectroscopic followup. Tracers include halo giants (detectable out to more than 100 kpc), blue horizontal branch stars, halo stars near the main sequence turnoff, and the ``blue metal-poor stars'' of Preston et al (1994). We demonstrate the success of our survey by showing spectra of stars we have identified in all these categories, including giants as distant as 75 kpc. We discuss the problem of identifying the most distant halo giants. In particular, extremely metal-poor halo K dwarfs are present in approximately equal numbers to the distant giants for V fainter than 18, and we show that our method will distinguish reliably between these two groups of metal-poor stars. We plan to survey 100 square degrees at high galactic latitude, and expect to increase the numbers of known halo giants, BHB stars and turnoff stars by more than an order of magnitude. In addition to the strong test that this large sample will provide for the question `was the Milky Way halo accreted from satellite galaxies?', we will improve the accuracy of mass measurements of the Milky Way beyond 50 kpc via the kinematics of the many distant giants and BHB stars we will find. We show that one of our first datasets constrains the halo density law over galactocentric radii of 5-20 kpc and z heights of 2-15 kpc. The data support a flattened power-law halo with b/a of 0.6 and exponent -3.0. More complex models with a varying axial ratio may be needed with a larger dataset.Comment: 55 pages, 22 figures, to appear in the Astronomical Journa

Activation of Penile Proadipogenic Peroxisome Proliferator-Activated Receptor γ with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development

Exposure to the estrogen receptor alpha (ERα) ligand diethylstilbesterol (DES) between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ERα and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Transcripts for PPARs α, β, and γ and γ1a splice variant were detected in Sprague-Dawley normal rat penis with PPARγ predominating. In addition, PPARγ1b and PPARγ2 were newly induced by DES. The PPARγ transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPARγ protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ERα and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPARγ expression. These results suggest a biological overlap between PPARγ and ERα and highlight a mechanism for endocrine disruption

At-wavelength optical metrology development at the ALS

Nano-focusing and brightness preservation for ever brighter synchrotron radiation and free electron laser beamlines require surface slope tolerances of x-ray optics on the order of 100 nrad. While the accuracy of fabrication and ex situ metrology of x-ray mirrors has improved over time, beamline in situ performance of the optics is often limited by application specific factors such as x-ray beam heat loading, temperature drift, alignment, vibration, etc. In the present work, we discuss the recent results from the Advanced Light Source developing high accuracy, in situ, at-wavelength wavefront measurement techniques to surpass 100-nrad accuracy surface slope measurements with reflecting x-ray optics. The techniques will ultimately allow closed-loop feedback systems to be implemented for x-ray nano-focusing. In addition, we present a dedicated metrology beamline endstation, applicable to a wide range of in situ metrology and test experiments. The design and performance of a bendable Kirkpatrick-Baez (KB) mirror with active temperature stabilization will also be presented. The mirror is currently used to study, refine, and optimize in situ mirror alignment, bending and metrology methods essential for nano-focusing application

High Prevalence of Multidrug-Tolerant Bacteria and Associated Antimicrobial Resistance Genes Isolated from Ornamental Fish and Their Carriage Water

Background: Antimicrobials are used to directly control bacterial infections in pet (ornamental) fish and are routinely added to the water these fish are shipped in to suppress the growth of potential pathogens during transport. Methodology/Principal Findings: To assess the potential effects of this sustained selection pressure, 127 Aeromonas spp. isolated from warm and cold water ornamental fish species were screened for tolerance to 34 antimicrobials. Representative isolates were also examined for the presence of 54 resistance genes by a combination of miniaturized microarray and conventional PCR. Forty-seven of 94 Aeromonas spp. isolates recovered from tropical ornamental fish and their carriage water were tolerant to >= 15 antibiotics, representing seven or more different classes of antimicrobial. The quinolone and fluoroquinolone resistance gene, qnrS2, was detected at high frequency (37% tested recent isolates were positive by PCR). Class 1 integrons, IncA/C broad host range plasmids and a range of other antibiotic resistance genes, including floR, blaTEM21, tet(A), tet(D), tet(E), qacE2, sul1, and a number of different dihydrofolate reductase and aminoglycoside transferase coding genes were also detected in carriage water samples and bacterial isolates. Conclusions: These data suggest that ornamental fish and their carriage water act as a reservoir for both multi-resistant bacteria and resistance genes

An AzTEC 1.1 mm survey of the GOODS-N field – I. Maps, catalogue and source statistics

This article has been accepted for publication in Monthly Notices Of The Royal Astronomical Society ©: 2008 T. A. Perera et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We have conducted a deep and uniform 1.1 mm survey of the Great Observatories Origins Deep Survey-North (GOODS-N) field with AzTEC on the James Clerk Maxwell Telescope. Here, we present the first results from this survey including maps, the source catalogue and 1.1 mm number counts. The results presented here were obtained from a 245 arcmin2 region with a near uniform coverage to a depth of 0.96–1.16 mJy beam−1. Our robust catalogue contains 28 source candidates detected with S/N ≥ 3.75, only ∼1– 2 of which are expected to be spurious detections. Of these source candidates, eight are also detected by Submillimetre Common-User Bolometer Array (SCUBA) at 850 μm in regions where there is a good overlap between the two surveys. The major advantage of our survey over that with SCUBA is the uniformity of coverage. We calculate number counts using two different techniques: the first using a frequentist parameter estimation and the second using a Bayesian method. The two sets of results are in good agreement. We find that the 1.1 mm differential number counts are well described in the 2–6 mJy range by the functional form dN/dS=N′(S′/S) exp(−S/S′) with fitted parameters S′= 1.25 ± 0.38 mJy and dN/dS= 300 ± 90 mJy−1deg−2 at 3 mJy