The transfer of unsterilized material from Mars to Phobos: Laboratory tests, modelling and statistical evaluation.

Sample return missions to Phobos are the subject of future exploration plans. Given the proximity of Phobos to Mars, Mars' potential to have supported life, and the possibility of material transfer from Mars to Phobos, careful consideration of planetary protection is required. If life exists, or ever existed, on Mars, there is a possibility that material carrying organisms could be present on Phobos and be collected by a sample return mission such as the Japanese Martian Moons eXplorer (MMX). Here we describe laboratory experiments, theoretical modelling and statistical analysis undertaken to quantify whether the likelihood of a sample from Phobos material containing unsterilized material transferred from Mars is less than 10-6, the threshold to transition between restricted and unrestricted sample return classification for planetary protection. We have created heat, impact and radiation sterilization models based on the Phobos environment, and through statistical analyses investigated the level of sterilization expected for martian material transferred to Phobos. These analyses indicate that radiation is the major sterilization factor, sterilizing the Phobos surface over timescales of millions of years. The specific events of most relevance in the Phobos sample return context are the 'young' cratering events on Mars that result in Zunil-sized craters, which can emplace a large mass of martian material on Phobos, in a short period of time, thus inhibiting the effects of radiation sterilization. Major unknowns that cannot yet be constrained accurately enough are found to drive the results - the most critical being the determination of exact crater ages to statistical certainty, and the initial biological loading on Mars prior to transfer. We find that, when taking a conservative perspective and assuming the best-case scenario for organism survival, for a 100 g sample of the Phobos regolith to be below the planetary protection requirement for unrestricted sample return, the initial biological loading on Mars must be <8.2 × 103cfu kg-1. For the planned MMX mission, a ∼10 g sample to be obtained from a 25-30 mm diameter core as planned would require an initial martian biological loading to be <1.6 × 104cfu kg-1, in order to remain compliant with the planetary protection threshold.

Preclinical development of AMG 139, a human antibody specifically targeting IL-23.

BACKGROUND AND PURPOSE: AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. EXPERIMENTAL APPROACH: The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. KEY RESULTS: AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.). CONCLUSIONS AND IMPLICATIONS: The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.

An evaluation of the effectiveness of the Zambian Health Worker Retention Scheme (ZHWRS) for rural areas.

BACKGROUND: Zambian Health Workers Retention Scheme (ZHWRS) commenced in 2003. The schemes' original aim was to retain and recruit Zambian doctors in rural and remote districts. The aim of the ZHWRS subsequently expanded to also include other health workers, in either rural or urban areas. The scheme was formulated to address, in part, the drastic shortage of health workers. OBJECTIVES: To evaluate the effectiveness of the ZHWRS in achieving its aim. METHODS: The data on the number of health workers recruited by the ZHWRS and the spatial distribution of them was reviewed. A survey of health workers was undertaken to elicit their views of their working conditions, their job satisfaction and the effectiveness of retention schemes in retaining or increasing the numbers of and overall satisfaction of health workers. RESULTS: The ZHWRS has not been successful in recruiting sufficient numbers of health workers to reverse the shortage problem or even to meet the modest targets of the scheme itself. However, these improvements do not decrease the likelihood of Department of Health (DoH) workers leaving their rural based positions. CONCLUSIONS: The ZHWRS has not fully met either its original or revised aims. The drastic shortage of health workers in Zambia continues.

Functional characterization of ABCC2 promoter polymorphisms and allele-specific expression.

Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele-specific expression. Twelve polymorphisms in the 1.6 kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared with the reference sequence (P<0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele-specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P<0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/untranslated region variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function.

Police officer anxiety after occupational blood and body fluid exposure.

BACKGROUND: In the course of their work, police staff are at risk of exposure to blood and body fluids (BBF) and potentially at risk of acquiring a blood-borne viral infection. AIMS: To examine levels of anxiety among Scottish police staff following an occupational exposure to BBF. METHODS: Police staff who reported an incident of exposure to their occupational health (OH) provider were invited to complete a postal questionnaire about their levels of self-reported anxiety after the incident and after contact with medical services (namely, OH and accident and emergency (A&E)). RESULTS: Seventy exposed individuals (66% of those invited to take part) completed a questionnaire. Participants' self-reported anxiety after the incident varied widely. Levels of anxiety reduced over time and following contact with medical services. A&E staff were more likely to be the first point of medical contact for the most anxious individuals. Pre-incident training was not associated with post-incident anxiety. CONCLUSIONS: The findings suggest that contact with medical services helps to alleviate post-exposure anxieties among police staff.

Abstracts from the North American Rhinology & Allergy Conference, February 3, 2011, Puerto Rico.

INTRODUCTION: To establish the efficacy of bepotastine besilate ophthalmic solution (bepotastine) 1.5%, a dual acting histamine H1 receptor antagonist approved for treatment of ocular itching associated with allergic conjunctivitis, compared to placebo in relieving ocular itching and redness for subjects with active allergic rhinoconjunctivitis. METHODS: A randomized, double-masked, placebo-controlled, confirmatory natural exposure study of bepotastine 1.5% and placebo was conducted during allergy season at 12 clinical sites throughout the U.S. Following a 7-day screening period, eligible subjects ≥12 years old were assigned in a 1:1 ratio to dosing OU b.i.d. either bepotastine 1.5% (n = 123) or placebo (n = 122). Subjects recorded instantaneous grades for their ocular symptoms prior to their next dose for 14 consecutive days. Clinically significant reduction in ocular sign or symptom grades between treatment groups required p ≤ 0.05 as determined by ANCOVA analysis. RESULTS: Significant clinical effectiveness with bepotastine 1.5% was demonstrated over the 2-week treatment period in comparison to placebo in the intent-to-treat population for reducing mean instantaneous grades for both ocular itching (p = 0.007) and redness (p = 0.001). Investigator rating of efficacy over the 2-week treatment period across response categories was also superior for bepotastine 1.5% compared to placebo (p = 0.024). Only one subject discontinued participation in the study due to an adverse event. CONCLUSIONS: These data support bepotastine 1.5% as an effective treatment for allergen-induced signs and symptoms in a clinical study designed to closely resemble the conditions under which patients with allergic rhinoconjunctivitis would require treatment.

Management of blood and body fluid exposures in police service staff.

BACKGROUND: Police service staff are at risk of occupational exposure to blood and body fluids with the consequent risk of blood-borne virus (BBV) infection. AIMS: To examine the types of occupational exposure incidents experienced by Scottish police service staff and to evaluate the post-incident management provided by their occupational health (OH) services. METHODS: Data were collected on the circumstances and the post-incident management of each incident reported to OH over 12 months. An expert panel reviewed the post-incident management provided by OH. RESULTS: The panel considered that the majority of cases of occupational exposure incurred little or no risk of BBV transmission. In general, the expert panel assessed the post-incident management provided by OH units serving the police as adequate and appropriate. However, some concerns were raised in relation to a small number of incorrect risk assessments and an inconsistent approach to hepatitis C virus (HCV) follow-up blood testing. CONCLUSIONS: The study findings suggest that most Scottish police OH departments were providing adequate post-incident management. There is, however, a need for more clarity around BBV risk assessment terminology and development of a standardized HCV testing protocol.

Effects of acute hypoxia on postural and kinetic tremor.

Human physiological tremor is a complex phenomenon that is modulated by numerous mechanical, neurophysiological, and environmental conditions. Researchers investigating tremor have suggested that acute hypoxia increases tremor amplitude. Based on the results of prior studies, we hypothesized that human participants exposed to a simulated altitude of 4,500 m would display an increased tremor amplitude within the 6-12 Hz frequency range. Postural and kinetic tremors were recorded with a laser system in 23 healthy male participants before, during, and after 1 h of altitude-induced hypoxia. A large panel of tremor characteristics was used to investigate the effect of hypoxia. Acute hypoxia increased tremor frequency content between 6 and 12 Hz during both postural and kinetic tremor tasks (P < 0.05, F = 6.142, Eta(2) = 0.24 and P < 0.05, F = 3.767 Eta(2) = 0.14, respectively). Although the physiological mechanisms underlying the observed changes in tremor are not completely elucidated yet, this study confirms that acute hypoxia increases tremor frequency in the 6-12 Hz range. Furthermore, this study indicates that changes in physiological tremor can be detected at lower hypoxemic levels than previously reported (blood saturation in oxygen = 80.9%). The effects of hypoxia mainly result from a cascade of events starting with the activation of the hypothalamic-pituitary-adrenal axis causing in turn an increase in catecholamine release, leading to an augmentation of tremor amplitude in the 6- to 12-Hz interval and heart rate increase.

Ecological selection against hybrids in natural populations of sympatric threespine sticklebacks.

Experimental work has provided evidence for extrinsic post-zygotic isolation, a phenomenon unique to ecological speciation. The role that ecological components to reduced hybrid fitness play in promoting speciation and maintaining species integrity in the wild, however, is not as well understood. We addressed this problem by testing for selection against naturally occurring hybrids in two sympatric species pairs of benthic and limnetic threespine sticklebacks (Gasterosteus aculeatus). If post-zygotic isolation is a significant reproductive barrier, the relative frequency of hybrids within a population should decline significantly across the life-cycle. Such a trend in a natural population would give independent support to experimental evidence for extrinsic, rather than intrinsic, post-zygotic isolation in this system. Indeed, tracing mean individual hybridity (genetic intermediateness) across three life-history stages spanning four generations revealed just such a decline. This provides compelling evidence that extrinsic selection plays an important role in maintaining species divergence and supports a role for ecological speciation in sticklebacks.

Laboratory 20-km cycle time trial reproducibility.

This study evaluated the reproducibility of laboratory based 20-km time trials in well trained versus recreational cyclists. Eighteen cyclists (age = 34 +/- 8 yrs; body mass index = 23.1 +/- 2.2 kg/m (2); VO(2max) = 4.19 +/- 0.65 L/min) completed three 20-km time trials over a month on a Velotron cycle ergometer. Average power output (PO) (W), speed, and heart rate (HR) were significantly lower in the first time trial compared to the second and third time trial. The coefficients of variation (CV) between the second and third trial of the top eight performers for average PO, time to completion, and speed were 1.2 %, 0.6 %, 0.5 %, respectively, compared to 4.8 %, 2.0 %, and 2.3 % for the bottom ten. In addition, the average HR, VO(2), and percentage of VO(2max) were similar between trials. This study demonstrated that (1) a familiarization session improves the reliability of the measurements (i.e., average PO, time to completion and speed), and (2) the CV was much smaller for the best performers.

Widespread gene flow and high genetic variability in populations of water voles Arvicola terrestris in patchy habitats.

Theory predicts that the impact of gene flow on the genetic structure of populations in patchy habitats depends on its scale and the demographic attributes of demes (e.g. local colony sizes and timing of reproduction), but empirical evidence is scarce. We inferred the impact of gene flow on genetic structure among populations of water voles Arvicola terrestris that differed in average colony sizes, population turnover and degree of patchiness. Colonies typically consisted of few reproducing adults and several juveniles. Twelve polymorphic microsatellite DNA loci were examined. Levels of individual genetic variability in all areas were high (H(O) = 0.69-0.78). Assignments of juveniles to parents revealed frequent dispersal over long distances. The populations showed negative F(IS) values among juveniles, F(IS) values around zero among adults, high F(ST) values among colonies for juveniles, and moderate, often insignificant, F(ST) values for parents. We inferred that excess heterozygosity within colonies reflected the few individuals dispersing from a large area to form discrete breeding colonies. Thus pre-breeding dispersal followed by rapid reproduction results in a seasonal increase in differentiation due to local family groups. Genetic variation was as high in low-density populations in patchy habitats as in populations in continuous habitats used for comparison. In contrast to most theoretical predictions, we found that populations living in patchy habitats can maintain high levels of genetic variability when only a few adults contribute to breeding in each colony, when the variance of reproductive success among colonies is likely to be low, and when dispersal between colonies exceeds nearest-neighbour distances.

Speciation in reverse: morphological and genetic evidence of the collapse of a three-spined stickleback (Gasterosteus aculeatus) species pair.

Historically, six small lakes in southwestern British Columbia each contained a sympatric species pair of three-spined sticklebacks (Gasterosteus aculeatus). These pairs consisted of a 'benthic' and 'limnetic' species that had arisen postglacially and, in four of the lakes, independently. Sympatric sticklebacks are considered biological species because they are morphologically, ecologically and genetically distinct and because they are strongly reproductively isolated from one another. The restricted range of the species pairs places them at risk of extinction, and one of the pairs has gone extinct after the introduction of an exotic catfish. In another lake, Enos Lake, southeastern Vancouver Island, an earlier report suggested that its species pair is at risk from elevated levels of hybridization. We conducted a detailed morphological analysis, as well as genetic analysis of variation at five microsatellite loci for samples spanning a time frame of 1977 to 2002 to test the hypothesis that the pair in Enos Lake is collapsing into a hybrid swarm. Our morphological analysis showed a clear breakdown between benthics and limnetics. Bayesian model-based clustering indicated that two morphological clusters were evident in 1977 and 1988, which were replaced by 1997 by a single highly variable cluster. The most recent 2000 and 2002 samples confirm the breakdown. Microsatellite analysis corroborated the morphological results. Bayesian analyses of population structure in a sample collected in 1994 indicated two genetically distinct populations in Enos Lake, but only a single genetic population was evident in 1997, 2000, and 2002. In addition, genetic analyses of samples collected in 1997, 2000, and 2002 showed strong signals of 'hybrids'; they were genetically intermediate to parental genotypes. Our results support the idea that the Enos Lake species pair is collapsing into a hybrid swarm. Although the precise mechanism(s) responsible for elevated hybridization in the lake is unknown, the demise of the Enos Lake species pair follows the appearance of an exotic crayfish, Pascifasticus lenisculus, in the early 1990s.

Breeding system and demography shape population genetic structure across ecological and climatic zones in the African freshwater snail, Bulinus forskalii (Gastropoda, Pulmonata), intermediate host for schistosomes.

The role of breeding system and population bottlenecks in shaping the distribution of neutral genetic variation among populations inhabiting patchily distributed, ephemeral water bodies was examined for the hermaphroditic freshwater snail Bulinus forskalii, intermediate host for the medically important trematode Schistosoma guineensis. Levels of genetic variation at 11 microsatellite loci were assessed for 600 individuals sampled from 19 populations that span three ecological and climatic zones (ecozones) in Cameroon, West Africa. Significant heterozygote deficiencies and linkage disequilibria indicated very high selfing rates in these populations. Despite this and the large genetic differentiation detected between populations, high levels of genetic variation were harboured within these populations. The high level of gene flow inferred from assignment tests may be responsible for this pattern. Indeed, metapopulation dynamics, including high levels of gene flow as well as extinction/contraction and recolonization events, are invoked to account for the observed population structuring, which was not a consequence of isolation-by-distance. Because B. forskalii populations inhabiting the northern, Sahelian area are subject to more pronounced annual cycles of drought and flood than the southern equatorial ones, they were expected to be subject to population bottlenecks of increased frequency and severity and, therefore, show reduced genetic variability and elevated population differentiation. Contrary to predictions, the populations inhabiting the most northerly ecozone exhibited higher genetic diversity and lower genetic differentiation than those in the most southerly one, suggesting that elevated gene flow in this region is counteracting genetic drift.

Development and testing of an active area neutron dosemeter.

This paper describes the design, development and testing of an active area neutron dosemeter (AAND). The classic moderator and central detector is retained but in AAND this arrangement is augmented by small thermal neutron detectors positioned within the moderating body. The outputs from these detectors are combined using an appropriately weighted linear superposition to fit both the ambient dose equivalent and the radiation weighting factor. Experimental verifications of both the modelled detector energy reponses and the overall AAND response are given. In the relatively soft D2O moderated 252Cf spectra, the AAND determined both the H*(10) and mean radiation weighting factor to better than +10%.

Parentage assignment detects frequent and large-scale dispersal in water voles.

Estimating the rate and scale of dispersal is essential for predicting the dynamics of fragmented populations, yet empirical estimates are typically imprecise and often negatively biased. We maximized detection of dispersal events between small, subdivided populations of water voles (Arvicola terrestris) using a novel method that combined direct capture-mark-recapture with microsatellite genotyping to identify parents and offspring in different populations and hence infer dispersal. We validated the method using individuals known from trapping data to have dispersed between populations. Local populations were linked by high rates of juvenile dispersal but much lower levels of adult dispersal. In the spring breeding population, 19% of females and 33% of males had left their natal population of the previous year. The average interpopulation dispersal distance was 1.8 km (range 0.3-5.2 km). Overall, patterns of dispersal fitted a negative exponential function. Information from genotyping increased the estimated rate and scale of dispersal by three- and twofold, respectively, and hence represents a powerful tool to provide more realistic estimates of dispersal parameters.

Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome.

Fatigue is a common symptom of neurological diseases that affect basal ganglia function. We used proton magnetic resonance spectroscopy ((1)H MRS) to study the metabolic functions of the basal ganglia in chronic fatigue syndrome (CFS) to test the hypothesis that fatigue in CFS may have a neurogenic component. (1)H MRS of left basal ganglia was carried out in eight non-psychiatric patients with CFS and their results were compared to age- and sex-matched healthy asymptomatic healthy controls. A highly significant increase in the spectra from choline-containing compounds was seen in the CFS patient group (p < 0.001). In the absence of regional structural or inflammatory pathology, increased choline resonance in CFS may be an indicator of higher cell membrane turnover due to gliosis or altered intramembrane signalling.

HIV/AIDS policies, practices and conditions in South African prisons: Criticisms and alternatives. Towards a research agenda.

The level of HIV infection in South African prisoners is unknown. However, given that 4.2 million citizens or 20% of the adult population are infected by HIV then the problem of infection within the prison system would seem to be a large and a significant management issue. Policies to treat HIV+ prisoners and prevent HIV transmission have been developed. However, the efficacy of those programmes implemented to prevent HIV transmission is questionable. The reasons for this situation include lack of resources like condoms, lubricant, disinfectants and availability of testing. Prison conditions also militate against success especially overcrowding, poor health care and nutrition. Little research has been undertaken into HIV within the prison system and the lack of transparency in management of the system is a major hindrance in achieving better public policy outcomes. The issues of importance to policy research on HIV/AIDS in prison, which should receive early attention, include: 1) Prevalence rate determination; 2) Treatment of HIV+ prisoners; 3) Education programmes; and 4) Early release policy and practices.