Measurement of single- and double-escape HPGe efficiency ratios for 60Co.

As a by-product of another measurement, ratios of the single-escape (SE) and double-escape (DE) efficiencies relative to the full-energy-peak efficiency (FE) have been measured for two HPGe detectors for 60Co. For a 2.5-cm-thick 95 cm3 crystal the results were SE/FE = 0.000 48 ± 0.000 20 and 0.003 25 ± 0.000 24 for 1173 and 1332 keV gamma-rays, respectively, and DE/FE = 0.000 90 ± 0.000 17 and 0.003 41 ± 0.000 11 for 1173 and 1332 keV, respectively. For a 3.0-cm-thick 84 cm3 crystal the results were SE/FE = 0.000 67 ± 0.000 32 and 0.003 79 ± 0.000 27 for 1173 and 1332 keV respectively, and DE/FE = 0.001 05 ± 0.000 28 and 0.004 29 ± 0.000 16 for 1173 and 1332 keV, respectively. These measurements may be of relevance in connection with Monte Carlo calculations of HPGe detector efficiencies, and may also suggest a path towards improved atomic cross-section measurements.

Evaluating drug resistance in visceral leishmaniasis: the challenges.

For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as first-line therapy in the endemic VL region in the Indian subcontinent. The application of other drugs has been limited due to adverse effects, perceived high cost, need for parenteral administration and increasing rate of treatment failures. Liposomal amphotericin B (AmB) and miltefosine (MIL) have been positioned as the effective first-line treatments; however, the number of monotherapy MIL-failures has increased after a decade of use. Since no validated molecular resistance markers are yet available, monitoring and surveillance of changes in drug sensitivity and resistance still depends on standard phenotypic in vitro promastigote or amastigote susceptibility assays. Clinical isolates displaying defined MIL- or AmB-resistance are still fairly scarce and fundamental and applied research on resistance mechanisms and dynamics remains largely dependent on laboratory-generated drug resistant strains. This review addresses the various challenges associated with drug susceptibility and -resistance monitoring in VL, with particular emphasis on the choice of strains, susceptibility model selection and standardization of procedures with specific read-out parameters and well-defined threshold criteria. The latter are essential to support surveillance systems and safeguard the limited number of currently available antileishmanial drugs.

Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine.

The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T-cell epitope-enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the safety testing of LEISHDNAVAX in naive mice and rats, complemented by the demonstration of tolerability in Leishmania-infected mice. Biodistribution and persistence were examined following single and repeated intradermal (i.d.) administration to rats. DNA vectors were distributed systemically but did not accumulate upon repeated injections. Although vector DNA was cleared from most other tissues within 60 days after the last injection, it persisted in skin at the site of injection and in draining lymph nodes. Evaluation of single-dose and repeated-dose toxicity of the vaccine candidate after i.d. administration to naive, non-infected mice did not reveal any safety concerns. LEISHDNAVAX was also well tolerated in Leishmania-infected mice. Taken together, our results substantiate a favorable safety profile of LEISHDNAVAX in both naive and infected animals and thus, support the initiation of clinical trials for both preventive and therapeutic applications of the vaccine.

Expression of transglutaminase-2 isoforms in normal human tissues and cancer cell lines: dysregulation of alternative splicing in cancer.

The multiple enzymatic activities and functions of transglutaminase type 2 (TG2) may be attributed to alternative TG2 molecules produced by differential splicing of TG2 mRNA. Different RNA transcripts of the human TG2 gene (TGM2) have been identified, but the expression of TG2 multiple transcripts has never been systematically addressed. We have confirmed and rationalized the main TG2 variants and developed a screening assay for the detection of alternative splicing of TG2, based on real-time reverse-transcription PCR. We have quantified the multiple TG2 transcripts in a wide range of normal tissues and in cancer cell lines from four different sites of origin. Our data show a significant correlation in the expression of canonical and alternative TG2 isoforms in normal human tissue, but differences in alternative splicing of TG2 in cancer cell lines, suggesting that in cancer cells the alternative splicing of TG2 is a more active process.

Preventing or controlling periodontitis reduces the occurrence of osteonecrosis of the jaw (ONJ) in rice rats (Oryzomys palustris).

INTRODUCTION: Osteonecrosis of the jaw (ONJ) is an adverse event that requires association of both systemic risk factors, such as powerful anti-resorptives (pARs; e.g. zoledronic acid [ZOL]), and local oral risk factors (e.g. tooth extraction, periodontitis). Whereas optimal oral health prior to initiate pARs is recognized as critically important for minimizing ONJ risk, the efficacy of preventive/maintenance measures in patients who are taking pARs is understudied. Rice rats fed a standard diet (STD), rich in insoluble fiber, develop localized periodontitis. STD-rats with localized periodontitis treated with ZOL for 18-24 wk develop ONJ. Hence, we hypothesized that controlling/preventing localized periodontitis in the ZOL-treated rats, reduces ONJ occurrence. METHODS: We used two approaches to attempt reducing periodontitis prevalence: 1) periodontal cleaning (PC); and 2) replacing the STD-diet with a nutritionally-equivalent diet high in soluble fiber (SF). 75 four-week-old male rats were weight-randomized into five groups (n = 15) in a 24-week experiment. Three groups ate the STD-diet and two the high SF-diet. STD-diet groups received intravenous (IV) vehicle (VEH) q4wks (STD + VEH), 80 µg/kg ZOL q4wks IV (STD + ZOL), or ZOL plus PC q2wks (STD + ZOL + PC). The SF-diet groups received VEH (SF + VEH) or ZOL (SF + ZOL). Jaws were processed for histopathology and evaluated for ONJ prevalence and tissue-level periodontitis. RESULTS: 1) 40% of STD + VEH rats developed maxillary localized periodontitis with no ONJ; 2) 50% of STD + ZOL rats developed ONJ; 3) 7% of STD + ZOL + PC rats developed ONJ (p < 0.01 vs. STD + ZOL); and 4) one SF + ZOL rat developed localized periodontitis, and no SF + VEH or SF + ZOL rats developed ONJ (p < 0.001 vs. STD + ZOL). CONCLUSIONS: 1) Periodontal cleaning in ZOL-treated rats decreases localized periodontitis severity and reduces ONJ prevalence; and 2) feeding a SF-diet to ZOL-treated rats reduces both incidence of localized periodontitis and ONJ. Our data indicates strong oral microbial community shifts according to oral health condition and trends in the shifts associated with diet.

Binding of C-reactive protein to antigen-induced but not mitogen-induced T lymphoblasts.

The C-reactive protein (CRP), an acute phase reactant which binds selectively to T (thymus-derived) lymphocytes, was found to bind to lymphoblasts formed upon stimulation with antigens but not with mitogens. Binding of CRP thus serves as a marker for antigen-reactive (-reacted) as opposed to mitogen-reative (-reacted) T cells, suggesting that these represent separate subpopulations, and supports the developing concept that CRP play an important role in the regulation of responses critical to inflammation, host defense, and tissue repair.

The impact cratering record on triton.

Impact craters on Triton are scarce owing to the relatively recent resurfacing by icy melts. The most heavily cratered surface has a crater density about the same as the lunar maria. The transition diameter from simple to complex craters occurs at a diameter of about 11 kilometers, and the depth-diameter relationship is similar to that of other icy satellites when gravity is taken into account. The crater size-frequency distribution has a differential -3 slope (cumulative -2 slope) and is the same as that for the fresh crater population on Miranda. The most heavily cratered region is on the leading hemisphere in Triton's orbit. Triton may have a leading-trailing asymmetry in its crater population. Based primarily on the similarity of size distributions on Triton and Miranda and the relatively young surface on Triton, the source of Triton's craters is probably comets. The very peculiar size distribution of sharp craters on the "cantaloupe" terrain and other evidence suggests they are volcanic explosion craters.

Voyager 2 in the uranian system: imaging science results.

Voyager 2 images of the southern hemisphere of Uranus indicate that submicrometersize haze particles and particles of a methane condensation cloud produce faint patterns in the atmosphere. The alignment of the cloud bands is similar to that of bands on Jupiter and Saturn, but the zonal winds are nearly opposite. At mid-latitudes (-70 degrees to -27 degrees ), where winds were measured, the atmosphere rotates faster than the magnetic field; however, the rotation rate of the atmosphere decreases toward the equator, so that the two probably corotate at about -20 degrees . Voyager images confirm the extremely low albedo of the ring particles. High phase angle images reveal on the order of 10(2) new ringlike features of very low optical depth and relatively high dust abundance interspersed within the main rings, as well as a broad, diffuse, low optical depth ring just inside the main rings system. Nine of the newly discovered small satellites (40 to 165 kilometers in diameter) orbit between the rings and Miranda; the tenth is within the ring system. Two of these small objects may gravitationally confine the e ring. Oberon and Umbriel have heavily cratered surfaces resembling the ancient cratered highlands of Earth's moon, although Umbriel is almost completely covered with uniform dark material, which perhaps indicates some ongoing process. Titania and Ariel show crater populations different from those on Oberon and Umbriel; these were probably generated by collisions with debris confined to their orbits. Titania and Ariel also show many extensional fault systems; Ariel shows strong evidence for the presence of extrusive material. About halfof Miranda's surface is relatively bland, old, cratered terrain. The remainder comprises three large regions of younger terrain, each rectangular to ovoid in plan, that display complex sets of parallel and intersecting scarps and ridges as well as numerous outcrops of bright and dark materials, perhaps suggesting some exotic composition.

Voyager 2 at neptune: imaging science results.

Voyager 2 images of Neptune reveal a windy planet characterized by bright clouds of methane ice suspended in an exceptionally clear atmosphere above a lower deck of hydrogen sulfide or ammonia ices. Neptune's atmosphere is dominated by a large anticyclonic storm system that has been named the Great Dark Spot (GDS). About the same size as Earth in extent, the GDS bears both many similarities and some differences to the Great Red Spot of Jupiter. Neptune's zonal wind profile is remarkably similar to that of Uranus. Neptune has three major rings at radii of 42,000, 53,000, and 63,000 kilometers. The outer ring contains three higher density arc-like segments that were apparently responsible for most of the ground-based occultation events observed during the current decade. Like the rings of Uranus, the Neptune rings are composed of very dark material; unlike that of Uranus, the Neptune system is very dusty. Six new regular satellites were found, with dark surfaces and radii ranging from 200 to 25 kilometers. All lie inside the orbit of Triton and the inner four are located within the ring system. Triton is seen to be a differentiated body, with a radius of 1350 kilometers and a density of 2.1 grams per cubic centimeter; it exhibits clear evidence of early episodes of surface melting. A now rigid crust of what is probably water ice is overlain with a brilliant coating of nitrogen frost, slightly darkened and reddened with organic polymer material. Streaks of organic polymer suggest seasonal winds strong enough to move particles of micrometer size or larger, once they become airborne. At least two active plumes were seen, carrying dark material 8 kilometers above the surface before being transported downstream by high level winds. The plumes may be driven by solar heating and the subsequent violent vaporization of subsurface nitrogen.

Characterizing laser-plasma ion accelerators driving an intense neutron beam via nuclear signatures.

Compact, bright neutron sources are opening up several emerging applications including detection of nuclear materials for national security applications. At Los Alamos National Laboratory, we have used a short-pulse laser to accelerate deuterons in the relativistic transparency regime. These deuterons impinge on a beryllium converter to generate neutrons. During the initial experiments where these neutrons were used for active interrogation of uranium and plutonium, we observed ß-delayed neutron production from decay of 9Li, formed by the high-energy deuteron bombardment of the beryllium converter. Analysis of the delayed neutrons provides novel evidence of the divergence of the highest energy portion of the deuterons (i.e., above 10 MeV/nucleon) from the laser axis, a documented feature of the breakout afterburner laser-plasma ion acceleration mechanism. These delayed neutrons form the basis of non-intrusive diagnostics for determining the features of deuteron acceleration as well as monitoring neutron production for the next generation of laser-driven neutron sources.

Kinetoplastida: new therapeutic strategies.

New formulations and therapeutic switching of the established drugs, amphotericin B and paromomycin, together with the discovery of miltefosine, have significantly improved the opportunities for treatment of visceral leishmaniasis (VL) chemotherapy. However, for human African trypanosomiasis (HAT), Chagas disease and cutaneous leishmaniases there has been limited progress. For HAT, a novel diamidine, parfuramidine, is in phase III clinical trial for early-stage disease, but for the treatment of late-stage disease there are no new drugs and combinations of eflornithine with melarsoprol or nifurtimox have been the focus of clinical studies. For Chagas disease, different classes of compounds that have validated biochemical targets, sterol biosynthesis methylases and cysteine proteases, are in various stages of development. The genome sequences that are now available for the pathogens that cause the leishmaniases and trypanosomiases, and new methods for rapid validation of targets, are part of the solution to discover new drugs. The integration of medicinal chemistry, pharmacokinetics, project planning and interaction with the pharma/biotech sector are essential if progress is to be made. Although there are financial constraints, the appearance of new funding sources and not-for-profit product development partnerships offers hope for drug development.

Dendro-dendritic cholinergic excitation controls dendritic spike initiation in retinal ganglion cells.

The retina processes visual images to compute features such as the direction of image motion. Starburst amacrine cells (SACs), axonless feed-forward interneurons, are essential components of the retinal direction-selective circuitry. Recent work has highlighted that SAC-mediated dendro-dendritic inhibition controls the action potential output of direction-selective ganglion cells (DSGCs) by vetoing dendritic spike initiation. However, SACs co-release GABA and the excitatory neurotransmitter acetylcholine at dendritic sites. Here we use direct dendritic recordings to show that preferred direction light stimuli evoke SAC-mediated acetylcholine release, which powerfully controls the stimulus sensitivity, receptive field size and action potential output of ON-DSGCs by acting as an excitatory drive for the initiation of dendritic spikes. Consistent with this, paired recordings reveal that the activation of single ON-SACs drove dendritic spike generation, because of predominate cholinergic excitation received on the preferred side of ON-DSGCs. Thus, dendro-dendritic release of neurotransmitters from SACs bi-directionally gate dendritic spike initiation to control the directionally selective action potential output of retinal ganglion cells.

Miltefosine: issues to be addressed in the future.

Future issues that need to be addressed for miltefosine are efficacy against non-Indian visceral leishmaniasis, efficacy in HIV-coinfected patients, efficacy against the many forms of cutaneous and mucosal disease, effectiveness under clinical practice conditions, generation of drug resistance and the need to provide a second antileishmanial agent to protect against this disastrous event, and the ability to maintain reproductive contraceptive practices under routine clinical conditions.

Are today's junior doctors confident in managing patients with minor injury?

OBJECTIVES: To assess the confidence of junior doctors in managing minor injuries, compared with other common acute conditions. METHOD: A questionnaire designed to elicit areas of confidence and subjective competence was distributed to junior doctors working in the emergency department in December 2004. RESULTS: Junior doctors felt most competent and confident working with medical trolley patients and least competent working with patients with minor injury. A lack of teaching and experience in handling minor injuries (which are seen by nurse practitioners in a separate unit during the day) was highlighted. CONCLUSIONS: Nurse-led minor injury units may have an effect on junior doctors' experience and confidence in minor injury care. Further effort needs to be made to increase the training of junior doctors in minor injury care.

An unusual rugby injury.

We describe an unusual sports injury in a young man, a combination of obturator hip dislocation with an ipsilateral anterior cruciate ligament injury. Traumatic non-prosthetic hip dislocations, particularly obturator hip dislocations, are extremely rare sports injuries and have not previously been reported in conjunction with a knee ligament injury. The severe pain and obvious deformity from the hip injury can distract from other injuries, particularly to the ipsilateral knee. This case reinforces the need for a thorough assessment of the knee joint, before hip reduction if possible and certainly after reduction of the dislocation.

Uncertainty quantification for radiation measurements: Bottom-up error variance estimation using calibration information.

One example of top-down uncertainty quantification (UQ) involves comparing two or more measurements on each of multiple items. One example of bottom-up UQ expresses a measurement result as a function of one or more input variables that have associated errors, such as a measured count rate, which individually (or collectively) can be evaluated for impact on the uncertainty in the resulting measured value. In practice, it is often found that top-down UQ exhibits larger error variances than bottom-up UQ, because some error sources are present in the fielded assay methods used in top-down UQ that are not present (or not recognized) in the assay studies used in bottom-up UQ. One would like better consistency between the two approaches in order to claim understanding of the measurement process. The purpose of this paper is to refine bottom-up uncertainty estimation by using calibration information so that if there are no unknown error sources, the refined bottom-up uncertainty estimate will agree with the top-down uncertainty estimate to within a specified tolerance. Then, in practice, if the top-down uncertainty estimate is larger than the refined bottom-up uncertainty estimate by more than the specified tolerance, there must be omitted sources of error beyond those predicted from calibration uncertainty. The paper develops a refined bottom-up uncertainty approach for four cases of simple linear calibration: (1) inverse regression with negligible error in predictors, (2) inverse regression with non-negligible error in predictors, (3) classical regression followed by inversion with negligible error in predictors, and (4) classical regression followed by inversion with non-negligible errors in predictors. Our illustrations are of general interest, but are drawn from our experience with nuclear material assay by non-destructive assay. The main example we use is gamma spectroscopy that applies the enrichment meter principle. Previous papers that ignore error in predictors have shown a tendency for inverse regression to have lower error variance than classical regression followed by inversion. This paper supports that tendency both with and without error in predictors. Also, the paper shows that calibration parameter estimates using error in predictor methods perform worse than without using error in predictor methods in the case of inverse regression, but perform better than without using error in predictor methods in the case of classical regression followed by inversion. Both inverse and classical regression involve the ratio of dependent random variables; therefore, the assumed error distribution(s) will matter in parameter estimation and in uncertainty calculations. Mainly for that reason, calibration using a single predictor is distinct from simple regression, and it has not been thoroughly treated in the literature, nor in the ISO Guide to the Expression of Uncertainty in Measurements (GUM). Our refined approach is based on simulation, because we illustrate that analytical approximations are not adequate when there are, for example, 10 or fewer calibration measurements, which is common in calibration applications, each consisting of measured responses from known quantities.

China-Africa and China-Asia Collaboration on Schistosomiasis Control: A SWOT Analysis.

Schistosomiasis, a disease caused by a trematode, parasitic worm, is a worldwide public health problem. In spite of great progress with regard to morbidity control, even elimination of this infection in recent decades, there are still challenges to overcome in sub-Saharan Africa and endemic areas in Southeast Asia. Regarded as one of the most successful countries with respect to schistosomiasis control, The People's Republic of China has accumulated considerable experience and learnt important lessons in various local settings that could benefit schistosomiasis control in other endemic countries. Based on an analysis of conceived strengths, weaknesses, opportunities and threats (SWOT) of potential collaborative activities with regard to schistosomiasis in Africa and Asia, this article addresses the importance of collaborative efforts and explores the priorities that would be expected to facilitate the transfer of Chinese experience to low- and middle-income countries in Africa and Asia.

Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction.

BACKGROUND: Glycoprotein (GP) VI plays a crucial role in platelet activation and aggregation. We investigated whether polymorphic variation at the GP VI locus confers an increased risk of myocardial infarction (MI). METHODS AND RESULTS: Coding and 5' and 3' non-coding regions of the GP VI gene were analyzed by polymerase chain reaction and conformation sensitive gel electrophoresis in 21 healthy subjects. Ten dimorphisms, 5 of which predicted amino acid substitutions (T13254C, A19871G, A21908G, A22630T, C22644A), were identified. Two core haplotypes involving 7 dimorphisms (C10781A and G10873A and all those predicting amino acid substitutions) were apparent. The contribution of the T13254C dimorphism, which predicted the substitution of serine 219 by proline, to risk of MI was assessed in 525 patients with acute MI and 474 controls, all aged <75 years. The allelic odds ratio (OR) for MI associated with the 13254C allele was 1.16 (95% CI, 0.91 to 1.46; P=0.23). Compared with corresponding control subgroups, the 13254CC genotype was more common among cases who were female (OR, 4.52; 95% CI, 1.23 to 16.64; P=0.029), nonsmokers (OR, 2.50; 95% CI, 0.98 to 6.38; P=0.048), aged >/=60 years (OR, 6.48; 95% CI, 1.47 to 28.45; P=0.009) or carried the beta-fibrinogen -148T allele associated with increased fibrinogen levels (OR, 10.49; 95% CI, 1.32 to 83.42; P=0.02). In logistic regression analysis that took other cardiovascular risk factors into account, the interactions of GP VI genotype with age (P=0.005) and beta-fibrinogen genotype (P=0.035) remained significant. CONCLUSIONS: The GP VI 13254CC genotype increases the risk of MI, particularly in older individuals, and the interaction of the GP VI 13254C allele with other candidate risk alleles may accentuate this risk.

The on-line characterization of a radium slurry by gamma-ray spectrometry.

We have developed an in-line monitor to directly measure the (226)Ra concentration in a nuclear waste stream using quantitative gamma-ray spectrometry applied to the 186keV emission. The waste stream is in the form of a slurry composed of the solid waste material mixed with water. The concentration measurement includes a self-attenuation correction factor determined from a transmission measurement using the 122keV gamma from (57)Co. Presented here is the model for the measurement system and results from some initial tests.

Uncertainty in rate loss corrections based on counting a periodic pulser.

Tomographic gamma scanning of waste produces three-dimensional transmission and emission images. These are used to derive item-specific attenuation correction factors that improve the accuracy of non-destructive waste assay. For each vertical layer, data grabs of short duration are acquired as the waste item is rotated and translated. The image reconstruction demands accurate rate loss corrections to minimize assay bias. For this application a pulser was used to perform the necessary rate loss corrections. In this work, we summarize the benefits of the pulser approach and review the basic principles on which the method is based. We extend the treatment to include a derivation of the expression for the uncertainty in the net pulser peak area in the presence of an underlying continuum. We report experimental results, taken using a Canberra model WM2900 Tomographic Gamma Scanner, over a broad range of count-rates and peak-to-continuum ratios. Repeat counts under controlled conditions allowed the correction factor and its variance to be determined and compared against expectations. These results confirm the validity of the correction factor formula and the corresponding expression for its uncertainty. The rate loss analysis has been built into a Monte Carlo Replicate engine to allow the uncertainty to be propagated into the total measurement uncertainty of the final assay.