African trypanosomiasis in travelers returning to the United Kingdom.

Two returning safari tourists with African trypanosomiasis were admitted to the Hospital for Tropical Diseases, London, in a 3-day period, compared with six cases in the previous 14 years. We describe the clinical features, diagnosis, and problems encountered in accessing appropriate therapy, and discuss the potential for emergence of this disease in increasingly adventurous international travelers

Polarimetry of the Type Ia Supernova SN 1996X

We present broad-band and spectropolarimetry of the Type Ia SN 1996X obtained on April 14, 1996 (UT), and broad-band polarimetry of SN 1996X on May 22,1996, when the supernova was about a week before and 4 weeks after optical maximum, respectively. The Stokes parameters derived from the broad-band polarimetry are consistent with zero polarization. The spectropolarimetry, however, shows broad spectral features which are due intrinsically to an asymmetric SN atmosphere. The spectral features in the flux spectrum and the polarization spectrum show correlations in the wavelength range from 4900 AA up to 5500 AA. The degree of this intrinsic component is low (<0.3 %). Theoretical polarization spectra have been calculated. It is shown that the polarization spectra are governed by line blending. Consequently, for similar geometrical distortions, the residual polarization is smaller by about a factor of 2 to 3 compared to the less blended Type II atmosphere, making it intrinsically harder to detect asphericities in SNIa. Comparison with theoretical model polarization spectra shows a resemblance to the observations. Taken literally, this implies an asphericity of about 11 % in the chemical distribution in the region of partial burning. This may not imperil the use of Type Ia supernovae as standard candles for distance determination, but nontheless poses a source of uncertainty. SN 1996X is the first Type Ia supernova for which spectropolarimetry revealed a polarized component intrinsic to the supernova and the first Type Ia with spectropolarimetry well prior to optical maximum.Comment: 7 pages, 5 figures, macros 'aas2pp4.sty,psfig.tex'. LaTeX Style. Astrophysical Journal Letters, submitted September 199

Functional Enhancement of Electrofusion-derived BRIN-BD11 Insulin-secreting Cells After Implantation into Diabetic Mice

Electrofusion-derived BRIN-BD11 cells are glucosesensitive insulin-secreting cells which provide an archetypal bioengineered surrogate β-cell for insulin replacement therapy in diabetes mellitus, 5x106 BRIN-BD11 cells were implanted intraperitoneally into severely hyperglycaemic (>24mmol/l) streptozotocin-induced insulin-treated diabetic athymic nude (nu/nu) mice. The implants reduced hyperglycaemia such that insulin injections were discontinued by 5–16 days (<17mmol/l) and normoglycaemia (<9mmol/l) was achieved by 7–20 days. Implanted cells were removed after 28 days and re-established in culture. After re-culture for 20 days, glucose-stimulated (16.7mmol/l) insulin release was enhanced by 121% (p<0.001) compared to non-implanted cells. Insulin responses to glucagon-like peptide-1 (10−9mol/l), cholecystokinin-8 (10−8 mol/l) and L-alanine (10 mmol/l) were increased by 32%, 31% and 68% respectively (p<0.05–0.01). Insulin content of the cells was 148% greater at 20 days after re-culture than before implantation (p<0.001), but basal insulin release (at 5.6 mmol/l glucose) was not changed. After re-culture for 40 days, insulin content declined to 68% of the content before implantation (p<0.01), although basal insulin release was unchanged. However, the insulin secretory responses to glucose, glucagonlike peptide-1, cholecystokinin-8 and L-alanine were decreased after 40 days of re-culture to 65%, 72%, 73% and 42% respectively of the values before implantation (p<0.05–0.01). The functional enhancement of electrofusion-derived surrogate β-cells that were re-cultured for 20 days after implantation and restoration of normoglycaemia indicates that the in vivo environment could greatly assist β-cell engineering approaches to therapy for diabetes

Improving the LSST dithering pattern and cadence for dark energy studies

The Large Synoptic Survey Telescope (LSST) will explore the entire southern sky over 10 years starting in 2022 with unprecedented depth and time sampling in six filters, $ugrizy$. Artificial power on the scale of the 3.5 deg LSST field-of-view will contaminate measurements of baryonic acoustic oscillations (BAO), which fall at the same angular scale at redshift $z \sim 1$. Using the HEALPix framework, we demonstrate the impact of an "un-dithered" survey, in which $17\%$ of each LSST field-of-view is overlapped by neighboring observations, generating a honeycomb pattern of strongly varying survey depth and significant artificial power on BAO angular scales. We find that adopting large dithers (i.e., telescope pointing offsets) of amplitude close to the LSST field-of-view radius reduces artificial structure in the galaxy distribution by a factor of $\sim$10. We propose an observing strategy utilizing large dithers within the main survey and minimal dithers for the LSST Deep Drilling Fields. We show that applying various magnitude cutoffs can further increase survey uniformity. We find that a magnitude cut of $r < 27.3$ removes significant spurious power from the angular power spectrum with a minimal reduction in the total number of observed galaxies over the ten-year LSST run. We also determine the effectiveness of the observing strategy for Type Ia SNe and predict that the main survey will contribute $\sim$100,000 Type Ia SNe. We propose a concentrated survey where LSST observes one-third of its main survey area each year, increasing the number of main survey Type Ia SNe by a factor of $\sim$1.5, while still enabling the successful pursuit of other science drivers.Comment: 9 pages, 6 figures, published in SPIE proceedings; corrected typo in equation

Different opinion on the reported role of Poldip2 and ACSM1 in a mammalian lipoic acid salvage pathway controlling HIF-1 activation.

Paredes et al recently described Poldip2 as a novel regulator of mitochondrial lipoylation through stabilisation of ACSM1 (1). We have several concerns with their proposed model based on the following reasons.Wellcome 102770/Z/13/Z and 205252/Z/16/Z Lister Institute RG8795

Change of direction in the biomechanics of atherosclerosis

The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear stress (WSS) on endothelial cells (EC). This theory is challenged by the changes in lesion location that occur with age in human and rabbit aortas. Furthermore, a number of point-wise comparisons of lesion prevalence and WSS have failed to support it. Here we investigate the hypothesis that multidirectional flow-characterized as the average magnitude of WSS components acting transversely to the mean vector (transWSS)-plays a key role. Maps of lesion prevalence around aortic branch ostia in immature and mature rabbits were compared with equivalent maps of time average WSS, the OSI (an index characterizing oscillatory flow) and transWSS, obtained from computational simulations; Spearman's rank correlation coefficients were calculated for aggregated data and 95% confidence intervals were obtained by bootstrapping methods. Lesion prevalence correlated positively, strongly and significantly with transWSS at both ages. Correlations of lesion prevalence with the other shear metrics were not significant or were significantly lower than those obtained for transWSS. No correlation supported the low, oscillatory WSS theory. The data are consistent with the view that multidirectional near-wall flow is highly pro-atherogenic. Effects of multidirectional flow on EC, and methods for investigating them, are reviewed. The finding that oscillatory flow has pro-inflammatory effects when acting perpendicularly to the long axis of EC but anti-inflammatory effects when acting parallel to it may explain the stronger correlation of lesion prevalence with transWSS than with the OSI

Estimating arterial cyclic strain from the spacing of endothelial nuclei

Background: The non-uniform distribution of atherosclerosis within the arterial system is widely attributed to variation in haemodynamic wall shear stress. It may also depend on variation in pressure-induced stresses and strains within the arterial wall; these have been less widely investigated, at least in part because of a lack of suitable techniques. Objectives: Here we show that local arterial strain can be determined from impressions left by endothelial cells on the surface of vascular corrosion casts made at different pressures, even though only one pressure can be examined in each vessel. The pattern of pits in the cast caused by protruding endothelial nuclei was subject to “retro-deformation” to identify the pattern that would have occurred in the absence of applied stresses. Methods: Retaining the nearest-neighbour pairs found under this condition, changes in nearest-neighbour vectors were calculated for the pattern seen in the cast, and the ratio of mean changes at different pressures determined. This approach removes errors in simple nearest-neighbour analyses caused by the nearest neighbour changing as deformation occurs. Results: The accuracy, precision and robustness of the approach were validated using simulations. The method was implemented using confocal microscopy of casts of the rabbit aorta made at systolic and diastolic pressures; results agreed well with the ratio of the macroscopic dimensions of the casts. Conclusions: Applying the new technique to areas around arterial branches could support or refute the hypothesis that the development of atherosclerosis is influenced by mural strain, and the method may be applicable to other tissues

BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer

Background: Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms. Methods: Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through nextgeneration sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour. Results: Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells. Conclusions: To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitorbased therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer

Reproductive Ecology of the Azooxanthellate Coral Tubastraea coccinea in the Equatorial Eastern Pacific: Part V. Dendrophylliidae

The reproductive ecology of Tubastraea coccinea Lesson, an azooxanthellate tropical scleractinian coral, was studied over various periods from 1985 to 2006 at four principal eastern Pacific locations in Costa Rica, Panamá, and the Galápagos Islands (Ecuador). This small (polyp diameter 0.8–1.0 cm), relatively cryptic species produced ova and planulae year round, including colonies with as few as 2–10 polyps. Of 424 colonies examined histologically, 13.7% contained both ova and sperm. Mature ova varied in diameter from ~300 to 800 µm and the time from spawning and fertilization of oocytes to release of brooded planulae was about 6 weeks. Planulae were 0.5–1.5 mm long and they settled and metamorphosed on a variety of substrates after 1–3 days. Spermaries, though more difficult to distinguish in histological sections, were present throughout the year. Spent spermaries were never observed in sections, but several colonies in Panamá and the Galápagos Islands released sperm from night one to night five after full moon, indicating the potential for cross-fertilization among colonies. Planula release was observed at Uva Island (Panamá) in March, May, June, and July, and in general planula presence was higher at warm ocean temperatures at all sites, whether or not the sites were inXuenced by seasonal upwelling. Annual fecundity estimates for T. coccinea are comparable with other high fecundity brooding species, including the zooxanthellate Porites panamensis, with which it co-occurs in Panamá. Tubastraea coccinea is widely distributed in the tropical Indo-Pacific and has colonized substrates in the western Atlantic. In addition to the reproductive characteristics described in the present study, other features of the biology of T. coccinea, such as an ability to withstand conditions that produce bleaching and mortality in zooxanthellate species, may account for its widespread, low-latitude distribution in multiple oceans

Measuring the efficacy of anti-malarial drugs in vivo: quantitative PCR measurement of parasite clearance

BACKGROUND: Artemisinin-based combination therapy, currently considered the therapy of choice for uncomplicated Plasmodium falciparum malaria in endemic countries, may be under threat from newly emerging parasite resistance to the artemisinin family of drugs. Studies in Southeast Asia suggest some patients exhibit an extended parasite clearance time in the three days immediately following treatment with artesunate monotherapy. This phenotype is likely to become a more important trial endpoint in studies of anti-malarial drug efficacy, but currently requires frequent, closely spaced blood sampling in hospitalized study participants, followed by quantitation of parasite density by microscopy. METHODS: A simple duplex quantitative PCR method was developed in which distinct fluorescent signals are generated from the human and parasite DNA components in each blood sample. The human amplification target in this assay is the β tubulin gene, and the parasite target is the unique methionine tRNA gene (pgmet), which exhibits perfect sequence identity in all six Plasmodium species that naturally infect humans. In a small series of malaria cases treated as hospital in-patients, the abundance of pgmet DNA was estimated relative to the human DNA target in daily peripheral blood samples, and parasite clearance times calculated. RESULTS: The qPCR assay was reproducibly able to replicate parasite density estimates derived from microscopy, but provided additional data by quantification of parasite density 24 hours after the last positive blood film. Robust estimates of parasite clearance times were produced for a series of patients with clinical malaria. CONCLUSIONS: Large studies, particularly in Africa where children represent a major proportion of treated cases, will require a simpler blood sample collection regime, and a method capable of high throughput. The duplex qPCR method tested may fulfil these criteria, and should now be evaluated in such field studies