Experimental human hookworm infection: a narrative historical review

In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy

High eccentricity planets from the Anglo-Australian Planet Search

We report Doppler measurements of the stars HD187085 and HD20782 which indicate two high eccentricity low-mass companions to the stars. We find HD187085 has a Jupiter-mass companion with a ~1000d orbit. Our formal `best fit' solution suggests an eccentricity of 0.47, however, it does not sample the periastron passage of the companion and we find that orbital solutions with eccentricities between 0.1 and 0.8 give only slightly poorer fits (based on RMS and chi^2) and are thus plausible. Observations made during periastron passage in 2007 June should allow for the reliable determination of the orbital eccentricity for the companion to HD187085. Our dataset for HD20782 does sample periastron and so the orbit for its companion can be more reliably determined. We find the companion to HD20782 has M sin i=1.77+/-0.22M_JUP, an orbital period of 595.86+/-0.03d and an orbit with an eccentricity of 0.92+/-0.03. The detection of such high-eccentricity (and relatively low velocity amplitude) exoplanets appears to be facilitated by the long-term precision of the Anglo-Australian Planet Search. Looking at exoplanet detections as a whole, we find that those with higher eccentricity seem to have relatively higher velocity amplitudes indicating higher mass planets and/or an observational bias against the detection of high eccentricity systems.Comment: to appear in MNRA

Oscillation frequencies and mode lifetimes in alpha Centauri A

We analyse our recently-published velocity measurements of alpha Cen A (Butler et al. 2004). After adjusting the weights on a night-by-night basis in order to optimize the window function to minimize sidelobes, we extract 42 oscillation frequencies with l=0 to 3 and measure the large and small frequency separations. We give fitted relations to these frequencies that can be compared with theoretical models and conclude that the observed scatter about these fits is due to the finite lifetimes of the oscillation modes. We estimate the mode lifetimes to be 1-2 d, substantially shorter than in the Sun.Comment: Accepted by Ap

The production of Necator americanus larvae for use in experimental human infection

Background: Although there is unprecedented interest in experimental human hookworm infection, details of hookworm manufacture and characterisation have been sparsely reported. In this report, we detail the production and characterisation of Necator americanus larvae for use in a recently published clinical trial. Methods: Faeces was obtained from an experimentally infected donor. Faecal hookworm DNA was determined by quantitative PCR. Paired samples were incubated in either sterile water or sterile water mixed with antimicrobials (amphotericin and gentamicin). Coproculture was performed by modified Harada-Mori method. The harvested larvae were then processed in either sterile water or antiseptic solution. Larval yield was then calculated (larvae per gram), larval viability was determined by thermally induced motility assay and microbial burden was determined at the day of harvest, at 48 h and at 7 days. Results: Twenty-eight faecal cultures were performed over 16 months. The faecal hookworm DNA content was variable over this time. There was no association of larval yield with faecal hookworm DNA content. Pre-treatment of faeces with antimicrobials did not influence larval yield. Larval motility was 85.3% (95% CI 79.3–91.3%). Incubation of larvae in antiseptics did not reduce viability at 14 days with a marginal mean of 68.6% (95% CI 59.1–78.1%) washed in water vs. 63.3% (95% CI 53.8 – 72.9%) when incubated in betadine (p = 0.38). Larvae washed in sterile water did not meet microbial bioburden criteria. Incubation in antiseptic resulted in acceptable microbial bioburden at 48 h but not at 7 days. Although the addition of gentamicin did reduce the microbial bio-burden acceptable levels, it was found to significantly lower larval motility at 7 days compared to incubation in sterile water and motility at 7 days 37.8% (95% CI 4.7–70.9%) vs. 67.3% (95% CI 35.2–99.3%, p < 0.001), respectively. Conclusions: Despite standardised culture methodologies and the use of a single donor, larval yield varied considerably between batches and had no association with faecal hookworm DNA. Larval viability decreases over time and the age of larvae at time of use are likely to be important. Microbial bioburden maybe temporarily reduced by incubation in antiseptics and has little effect on viability. Incubation of larvae in gentamicin is effective at reducing microbial bioburden but is deleterious to larval viability

Functional MRI Assessment of Renal Fibrosis in Rat Models

poster abstractIntroduction Renal fibrosis is a common consequence of chronic kidney diseases which affects a large population. Therefore, it is important to establish imaging based noninvasive biomarkers to monitor the progression or regression of renal fibrosis instead of biopsy. Magnetic resonance imaging (MRI) could provide both high spatial resolution and excellent tissue contrast for visualization of kidney morphology. Moreover, MRI is capable of assessing pseudo perfusion (Df) and perfusion fraction (Pf) with intra-voxel incoherent motion (IVIM) imaging (1), tissue oxygenation with T2* mapping (2), macromolecular composition with T1rho imaging (3) and kidney function (eGFR) with dynamic contrast enhanced (DCE) imaging (4). This study is aimed to evaluate the sensitivity of these MRI techniques to the renal fibrotic changes in a rat model. Methods A total of 4 rats were scanned at early (2-5 days) and late (25-35 days) time points after surgical intervention (unilateral ureteral obstruction to induce renal fibrosis) on a Siemens Tim Trio 3T scanner using an 80mm inner diameter 8-channel rat body coil (RAPID, USA) under a stable anesthetized condition. Axial images of 80mm FOV, 2mm slice thick and sub-millimeter in-place resolution were acquired for different functional MRI techniques with following parameters, respectively: IVIM with10 b-values of 0 - 750 s/mm2. T2*: with 10 TEs of 8 - 66 ms; T1rho: with 9 TSL times of 5 - 80 ms; DCE: with150 dynamic measurements at a temporal resolution of 1.01 s. before and after a 15s injection of 1.1 ml GD-DTPA through rat tail with a power injector. Functional data were processed and analyzed using custom MATLAB programs or analysis tools installed in the MRI console workstation. Results Figure 1 shows an anatomical image of the obstructed (R) and healthy (L) rat kidneys. Figures 2-4 show example T1rho map, IVIM Df map, and T2* map, respectively. Quantitative results based on ROI measurements are summarized in table 1. Changes consistent with the expected progression of fibrosis were observed in the obstructed kidney (R) while the healthy kidney (L) and muscle region remained stable. Figure 5 shows the DCE-MRI images at baseline as well as 45s, 95s and 240s after contrast infusion. The timing and intensity of signal changes are clearly different between two kidneys. Quantitative results of DCE-MRI data and comparison with PET study is reported in a separate abstract. Discussion High quality anatomical and functional images of rat kidney can be obtained on a clinical 3.0T MR scanner with dedicated small animal coils and optimized imaging techniques. The findings suggest that IVIM, T2*, T1rho and DCE can be used to assess and monitor different aspects of physiological changes in kidney fibrosis

Very Red and Extremely Red Galaxies in the Fields of z ~ 1.5 Radio-Loud Quasars

We previously identified an excess of mostly red galaxies around 31 RLQs at z=1-2. These fields have an ERO (extremely red object, R-K>6) density 2.7 times higher than the field. Assuming the EROs are passively evolved galaxies at the quasar redshifts, they have characteristic luminosities of only ~L^*. We also present new observations of four z~1.54 RLQ fields: (1) Wide-field J & Ks data confirm an Abell richness ~2 excess within 140" of Q0835+580 but an excess only within 50" of Q1126+101. (2) In 3 fields we present deep narrow-band redshifted H-alpha observations. We detect five candidate galaxies at the quasar redshifts, a surface density 2.5x higher than the field. (3) SCUBA sub-mm observations of 3 fields detect 2 quasars and 2 galaxies with SEDs best fit as highly reddened galaxies at the quasar z. (4) H-band adaptive optics (AO) imaging is used to estimate redshifts for 2 red, bulge-dominated galaxies using the Kormendy relation. Both have structural redshifts foreground to the quasar, but these are not confirmed by photometric redshifts, possibly because their optical photometry is corrupted by scattered light from the AO guidestar. (5) We use quantitative SED fits to constrain the photometric redshifts z_ph for some galaxies. Most galaxies near Q0835+580 are consistent with being at its redshift, including a candidate very old passively evolving galaxy. Many very & extremely red objects have z_ph z_q, and dust reddening is required to fit most of them, including many objects whose fits also require relatively old stellar populations. Large reddenings of E(B-V)~0.6 are required to fit four J-K selected EROs, though all but one of them have best-fit z_ph>z_q. These objects may represent a population of dusty high-z galaxies underrepresented in optically selected samples. (Abridged)Comment: Missing object 1126.424 added to Table 4; title changed to save people the apparent trouble of reading the abstract. 38 pages, 16 figures, 2 in color; all-PostScript figure version available from http://astro.princeton.edu/~pathall/tp3.ps.g

Five Planets Orbiting 55 Cancri

We report 18 years of Doppler shift measurements of a nearby star, 55 Cancri, that exhibit strong evidence for five orbiting planets. The four previously reported planets are strongly confirmed here. A fifth planet is presented, with an apparent orbital period of 260 days, placing it 0.78 AU from the star in the large empty zone between two other planets. The velocity wobble amplitude of 4.9 \ms implies a minimum planet mass \msini = 45.7 \mearthe. The orbital eccentricity is consistent with a circular orbit, but modest eccentricity solutions give similar \chisq fits. All five planets reside in low eccentricity orbits, four having eccentricities under 0.1. The outermost planet orbits 5.8 AU from the star and has a minimum mass, \msini = 3.8 \mjupe, making it more massive than the inner four planets combined. Its orbital distance is the largest for an exoplanet with a well defined orbit. The innermost planet has a semi-major axis of only 0.038 AU and has a minimum mass, \msinie, of only 10.8 \mearthe, one of the lowest mass exoplanets known. The five known planets within 6 AU define a {\em minimum mass protoplanetary nebula} to compare with the classical minimum mass solar nebula. Numerical N-body simulations show this system of five planets to be dynamically stable and show that the planets with periods of 14.65 and 44.3 d are not in a mean-motion resonance. Millimagnitude photometry during 11 years reveals no brightness variations at any of the radial velocity periods, providing support for their interpretation as planetary.Comment: accepted to Ap

Evaluation of 11C-Acetate and 18 F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2−/− mice in order to facilitate therapeutic translational studies from bench to bedside. Methods 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2−/− mice (n = 3/tracer) with HCC and 12 m MDR2−/+ control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2−/− (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list. Results Hepatic18F-FDG metabolism was not significantly increased in MDR2−/− mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2−/− mice when compared to MDR2−/+ controls. Serum AFP and LPA levels increased in MDR2−/− mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative. Conclusions Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2−/− mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study 1) HCC emergence/progression in patients and 2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC

On the Double Planet System Around HD 83443

The Geneva group has reported two Saturn-mass planets orbiting HD 83443 (K0V) with periods of 2.98 and 29.8 d. The two planets have raised interest in their dynamics because of the possible 10:1 orbital resonance and the strong gravitational interactions. We report precise Doppler measurements of HD 83443 obtained with the Keck/HIRES and the AAT/UCLES spectrometers. These measurements strongly confirm the inner planet with period of 2.985 d, with orbital parameters in very good agreement with those of the Geneva group. However these Doppler measurements show no evidence of the outer planet, at thresholds of 1/4 (3 m/s) of the reported velocity amplitude of 13.8 m/s. Thus, the existence of the outer planet is in question. Indeed, the current Doppler measurements reveal no evidence of any second planet with periods less than a year.Comment: 26 pages incl. 3 tables and 8 figures; uses AASTE