Mycobacterium microti tuberculosis in its maintenance host, the field vole (Microtus agrestis): characterization of the disease and possible routes of transmission.

The field vole (Microtus agrestis) is a known maintenance host of Mycobacterium microti. Previous studies have shown that infected animals develop tuberculosis. However, the disease is also known in cats and is sporadically reported from humans and other mammalian species. We examined trapped field voles from an endemic area, using a range of diagnostic approaches. These confirmed that a combination of gross and histological examination with culture is most appropriate to identify the true prevalence of the disease, which was shown to be more than 13% at times when older animals that have previously been shown to be more likely to develop the disease dominate the population. The thorough pathological examination of diseased animals showed that voles generally develop systemic disease with most frequent involvement of spleen and liver, followed by skin, lymph nodes, and lungs. The morphology of the lesions was consistent with active disease, and their distribution suggested skin wounds or oral and/or aerogenic infection as the main portal of entry. The demonstration of mycobacteria in open skin lesions, airways, and salivary glands indicated bacterial shedding from the skin and with sputum and saliva. This suggests not only the environment but also direct contact and devouring as likely sources of infection.

Movement patterns and genetic diversity of wild and reintroduced common dormice, Muscardinus avellanarius.

Movement is an important life history trait that can have an impact on local adaptation, and other evolutionary phenomena. We used a combination of nestbox survey data and genetic techniques (genotyping at 10 microsatellite loci) to quantify patterns of movement in common dormice Muscardinus avellanarius at two distinct sites in the UK: 1) Bontuchel (a natural population) and 2) Wych (captive-bred individuals that were reintroduced to this site), over three consecutive years (2006-2008). Both methods revealed a consistent pattern of sex-biased movement (movements by adult males and females) in both populations that allowed isolation-by-distance genetic structure to develop within 1 km. The similarity of data from captive-bred and natural individuals indicated that ex situ programing has not significantly altered the natural movement behavior of common dormice; consequently, the two populations could be managed with the same conservation strategies. We also found that the reintroduced dormice in Wych maintained relatively high levels of genetic diversity. This first report of movement patterns in reintroduced and natural populations of M. avellanarius combining genetic and field-survey data highlights the role of genetic studies in the investigation of ecological behaviour and for conservation management.

Tardive dyskinesia and deficit schizophrenia.

OBJECTIVE: Despite comparable antipsychotic exposure, some patients experience involuntary movements yet others do not. Negative symptoms have been associated with tardive dyskinesia (TD), but it is not certain whether this is an association with primary negative symptoms or the effects of medications. The aim of the present study was to determine whether patients with deficit schizophrenia (who have primary negative symptoms) are more likely to experience TD than those with non-deficit schizophrenia. METHOD: In 2006, all the people with a clinical diagnosis of schizophrenia in Nithsdale, Southwest Scotland, were identified using the 'key informant' method. These patients were categorized into those with and without the deficit syndrome and assessed for the presence of TD. Patients were also assessed for akathisia and extrapyramidal side effects. RESULTS: Of the 131 people assessed, 31 were categorized as having deficit schizophrenia (23.7%) and 100 people (76.3%) as non-deficit. There was no difference between the two groups with regard to age, antipsychotic exposure, and duration of illness. There was a significant association between deficit features and TD with an odds ratio = 2.97 [95% CI 1.128-6.88, P = 0.009]. CONCLUSION: Our findings support the proposal that the pathological process underlying deficit schizophrenia can predispose to the development of TD.

The prevalence of antimicrobial-resistant Escherichia coli in sympatric wild rodents varies by season and host.

AIMS: To investigate the prevalence and temporal patterns of antimicrobial resistance in wild rodents with no apparent exposure to antimicrobials. METHODS AND RESULTS: Two sympatric populations of bank voles and wood mice were trapped and individually monitored over a 2- year period for faecal carriage of antimicrobial-resistant Escherichia coli. High prevalences of ampicillin-, chloramphenicol-, tetracycline- and trimethoprim-resistant E. coli were observed. A markedly higher prevalence of antimicrobial-resistant E. coli was found in wood mice than in bank voles, with the prevalence in both increasing over time. Superimposed on this trend was a seasonal cycle with a peak prevalence of resistant E. coli in mice in early- to mid-summer and in voles in late summer and early autumn. CONCLUSIONS: These sympatric rodent species had no obvious contact with antimicrobials, and the difference in resistance profiles between rodent species and seasons suggests that factors present in their environment are unlikely to be drivers of such resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest that rodents may represent a reservoir of antimicrobial-resistant bacteria, transmissible to livestock and man. Furthermore, such findings have implications for human and veterinary medicine regarding antimicrobial usage and subsequent selection of antimicrobial-resistant organisms.

Major histocompatibility complex (MHC) heterozygote superiority to natural multi-parasite infections in the water vole (Arvicola terrestris).

The fundamental role of the major histocompatibility complex (MHC) in immune recognition has led to a general consensus that the characteristically high levels of functional polymorphism at MHC genes is maintained by balancing selection operating through host-parasite coevolution. However, the actual mechanism by which selection operates is unclear. Two hypotheses have been proposed: overdominance (or heterozygote superiority) and negative frequency-dependent selection. Evidence for these hypotheses was evaluated by examining MHC-parasite relationships in an island population of water voles (Arvicola terrestris). Generalized linear mixed models were used to examine whether individual variation at an MHC class II DRB locus explained variation in the individual burdens of five different parasites. MHC genotype explained a significant amount of variation in the burden of gamasid mites, fleas (Megabothris walkeri) and nymphs of sheep ticks (Ixodes ricinus). Additionally, MHC heterozygotes were simultaneously co-infected by fewer parasite types than homozygotes. In each case where an MHC-dependent effect on parasite burden was resolved, the heterozygote genotype was associated with fewer parasites, and the heterozygote outperformed each homozygote in two of three cases, suggesting an overall superiority against parasitism for MHC heterozygote genotypes. This is the first demonstration of MHC heterozygote superiority against multiple parasites in a natural population, a mechanism that could help maintain high levels of functional MHC genetic diversity in natural populations.

The influence of population characteristics and measurement system on barefoot plantar pressures: A systematic review and meta-regression analysis.

BACKGROUND: The measurement of plantar pressure distributions during gait can provide insights into the effects of musculoskeletal disease on foot function. A range of hardware, software, and protocols are available for the collection of this type of data, with sometimes disparate and conflicting results reported between individual studies. In this systematic review and meta-regression analysis of dynamic regional peak pressures, we aimed to test if 1) the system used to obtain the pressure measurements and 2) the characteristics of the study populations had a significant effect on the results. METHODS: A systematic review of the literature was undertaken to identify articles reporting regional peak plantar pressures during barefoot walking. A mixed-effects modeling approach was used to analyze the extracted data. Initially, the effect of the system used to collect the data was tested. Following this, the effect of participant characteristics on the results were analyzed, using moderators of cohort type (defined as the primary health characteristic of the participants), age, sex, and BMI. RESULTS: 115 participant groups were included in the analysis. Sufficient cohorts were available to test those that consisted of healthy individuals, and those with diabetes and diabetic neuropathy. Significant differences were found between results reported by studies using different pressure measurement systems in 8 of the 16 regions analyzed. The analysis of participant characteristics revealed a number of significant relationships between regional peak pressures and participant characteristics, including: BMI and midfoot plantar pressures; elevated forefoot pressures as a result of diabetic neuropathy; and sex-differences in regional loading patterns. CONCLUSIONS: At the level of the literature, we confirmed significant effects of disease status, age, BMI, and sex on regional peak plantar pressures. Researchers and clinicians should be aware that measurements of peak plantar pressure variables obtained from different collection equipment are not directly comparable.

Relative importance of Ixodes ricinus and Ixodes trianguliceps as vectors for Anaplasma phagocytophilum and Babesia microti in field vole (Microtus agrestis) populations.

The importance of Ixodes ricinus in the transmission of tick-borne pathogens is well recognized in the United Kingdom and across Europe. However, the role of coexisting Ixodes species, such as the widely distributed species Ixodes trianguliceps, as alternative vectors for these pathogens has received little attention. This study aimed to assess the relative importance of I. ricinus and I. trianguliceps in the transmission of Anaplasma phagocytophilum and Babesia microti among United Kingdom field voles (Microtus agrestis), which serve as reservoir hosts for both pathogens. While all instars of I. trianguliceps feed exclusively on small mammals, I. ricinus adults feed primarily on larger hosts such as deer. The abundance of both tick species and pathogen infection prevalence in field voles were monitored at sites surrounded with fencing that excluded deer and at sites where deer were free to roam. As expected, fencing significantly reduced the larval burden of I. ricinus on field voles and the abundance of questing nymphs, but the larval burden of I. trianguliceps was not significantly affected. The prevalence of A. phagocytophilum and B. microti infections was not significantly affected by the presence of fencing, suggesting that I. trianguliceps is their principal vector. The prevalence of nymphal and adult ticks on field voles was also unaffected, indicating that relatively few non-larval I. ricinus ticks feed upon field voles. This study provides compelling evidence for the importance of I. trianguliceps in maintaining these enzootic tick-borne infections, while highlighting the potential for such infections to escape into alternative hosts via I. ricinus.

Parasite interactions in natural populations: insights from longitudinal data.

The physiological and immunological state of an animal can be influenced by current infections and infection history. Consequently, both ongoing and previous infections can affect host susceptibility to another parasite, the biology of the subsequent infection (e.g. infection length) and the impact of infection on host morbidity (pathology). In natural populations, most animals will be infected by a succession of different parasites throughout the course of their lives, with probably frequent concomitant infections. The relative timing of different infections experienced by a host (i.e. the sequence of infection events), and the effects on factors such as host susceptibility and host survival, can only be derived from longitudinal data on individual hosts. Here we review some of the evidence for the impact of co-infection on host susceptibility, infection biology and pathology focusing on insights obtained from both longitudinal studies in humans and experiments that explicitly consider the sequence of infection. We then consider the challenges posed by longitudinal infection data collected from natural populations of animals. We illustrate their usefulness using our data of microparasite infections associated with field vole (Microtus agrestis) populations to examine impacts on susceptibility and infection length. Our primary aim is to describe an analytical approach that can be used on such data to identify interactions among the parasites. The preliminary analyses presented here indicate both synergistic and antagonistic interactions between microparasites within this community and emphasise that such interactions could have significant impacts on host-parasite fitness and dynamics.

Tuberculosis (Mycobacterium microti) in wild field vole populations.

Vole tuberculosis (TB; Mycobacterium microti) is an understudied endemic infection. Despite progressing slowly, it causes severe clinical pathology and overt symptoms in its rodent host. TB was monitored for 2 years in wild field voles in Kielder Forest, UK. The prevalence of characteristic cutaneous TB lesions was monitored longitudinally at 4 sites, with individuals live-trapped and repeatedly monitored. A prevalence of 5.2% of individuals with lesions was recorded (n=2791). In a cross-sectional study, 27 sites were monitored bi-annually, with TB assessed by post-mortem examination for macroscopic lesions, and by culture and histopathology. Seventy-nine voles (10.78%; n=733) were positive for mycobacteria, with the highest prevalence in spring (13.15%; n=327). TB prevalence varied, with between 0% and 50% of voles infected per site. Prevalence increased with age (mass), and apparent seasonality was due to a higher proportion of older animals in spring. Survival analysis supported this result, with cutaneous lesions only manifesting in the advanced stages of infection, and therefore only being found on older voles. The body condition of individuals with lesions declined at the time when the lesion was first recorded, when compared to individuals without lesions, suggesting there may be an acute phase of infection during its advanced stage. Although predicted survival following the appearance of a cutaneous lesion was lower than for uninfected individuals, this was not significant.

Virtually optimized insoles for offloading the diabetic foot: A randomized crossover study.

Integration of objective biomechanical measures of foot function into the design process for insoles has been shown to provide enhanced plantar tissue protection for individuals at-risk of plantar ulceration. The use of virtual simulations utilizing numerical modeling techniques offers a potential approach to further optimize these devices. In a patient population at-risk of foot ulceration, we aimed to compare the pressure offloading performance of insoles that were optimized via numerical simulation techniques against shape-based devices. Twenty participants with diabetes and at-risk feet were enrolled in this study. Three pairs of personalized insoles: one based on shape data and subsequently manufactured via direct milling; and two were based on a design derived from shape, pressure, and ultrasound data which underwent a finite element analysis-based virtual optimization procedure. For the latter set of insole designs, one pair was manufactured via direct milling, and a second pair was manufactured through 3D printing. The offloading performance of the insoles was analyzed for forefoot regions identified as having elevated plantar pressures. In 88% of the regions of interest, the use of virtually optimized insoles resulted in lower peak plantar pressures compared to the shape-based devices. Overall, the virtually optimized insoles significantly reduced peak pressures by a mean of 41.3kPa (p<0.001, 95% CI [31.1, 51.5]) for milled and 40.5kPa (p<0.001, 95% CI [26.4, 54.5]) for printed devices compared to shape-based insoles. The integration of virtual optimization into the insole design process resulted in improved offloading performance compared to standard, shape-based devices. CLINICAL TRIAL REGISTRATION: ISRCTN19805071, www.ISRCTN.org.

A role for vector-independent transmission in rodent trypanosome infection?

Within host-pathogen systems where vector-borne transmission is the primary route of infection, little or no attention has been paid to the relative importance of secondary or alternative routes of transmission. Here, by contrast, we report the results from a controlled longitudinal field-scale experiment in which the prevalence of fleas (Siphonaptera) was manipulated and the occurrence and distribution of a flea-borne protozoan (Trypanosoma (Herpetosoma) microti) in a natural field vole (Microtus agrestis) population was monitored over a 2-year period. A non-systemic insecticide was applied to individual voles within two treatment grids and the prevalences of fleas and of T. microti were monitored on these and on two control grids. Blood samples were taken from all voles and PCR-based methods used to determine infection status. Insecticidal treatment was highly effective at reducing overall flea prevalence and recaptured animals (treated ca. 4 weeks previously) were very rarely infested (ca. 3%, compared with 50-70+% normally). On the other hand, the probability of trypanosome infection was reduced in treated animals on experimental grids to only around one-third of that normally observed. This suggests that direct, as opposed to flea-borne, transmission may not only occur, it may also be of epidemiological importance. The possibility that the importance of such transmission routes may have been underestimated in 'vector-borne' infections more generally is discussed.

Sympatric Ixodes trianguliceps and Ixodes ricinus ticks feeding on field voles (Microtus agrestis): potential for increased risk of Anaplasma phagocytophilum in the United Kingdom?

The importance of wild rodents as reservoirs of zoonotic tick-borne pathogens is considered low in the United Kingdom because, in studies to date, those parasitized by exophilic Ixodes ricinus ticks carry almost exclusively larvae and thus have a minor role in transmission cycles. In a cross-sectional study, 11 (6.7%) of 163 field voles (Microtus agrestis) captured at field sites in Northern England were PCR-positive for Anaplasma phagocytophilum. The voles were found to act as hosts for both larval and nymphal I. ricinus and all stages of the nidicolous tick I. trianguliceps, and eight individuals were infested with ticks of both species at the same time. Two of 158 larval and one of 13 nymphal I. ricinus, as well as one of 14 larval and one of 15 nymphal I. trianguliceps collected from the rodents were PCR-positive. These findings suggest that habitats where field voles are abundant in the United Kingdom may pose a risk of A. phagocytophilum infection because (i) field voles, the most abundant terrestrial mammal in the United Kingdom, may be a competent reservoir; (ii) the field voles are hosts for both nymphal and larval ixodid ticks so they could support endemic cycles of A. phagocytophilum; and (iii) they are hosts for nidicolous I. trianguliceps, which may alone maintain endemic cycles, and exophilic I. ricinus ticks, which could act as a bridge vector and transmit infections to humans and domesticated animals.

Induction of zinc deficiency in sheep and its correction with a soluble glass bolus containing zinc.

Balance studies were carried out on four Suffolk-cross lambs which were fed a diet containing only 1.2 mg zinc/kg dry matter; zinc deficiency was induced within three weeks. After a period during which the deficiency was relieved by a pica, the zinc deficient state was re-established. Each sheep was then treated with a soluble glass bolus containing zinc, cobalt and selenium. The plasma zinc concentration of the sheep rapidly increased and was maintained for between six and 10 weeks. The bolus was able to supply the daily requirement of the sheep for zinc, with no detrimental effect on their copper status.

Acute abdominal pain in children.

This preliminary communication describes the initial results of a further special study investigating the disease spectrum and clinical presentation in a total of 1080 children admitted to hospital with acute abdominal pain (677 from the Children's Hospital, Sheffield, England, and the remaining 403 from hospitals in Paris, Oslo, Copenhagen, and Deventer). The disease spectrum in children differs radically from that in adults, well over 90% of cases being due to either acute appendicitis or non-specific abdominal pain (NSAP). The clinical presentation of both appendicitis and NSAP was found to differ from that in older age groups. These findings imply clearly that the use of the existing OMGE database for computer-aided diagnosis--using data drawn from cases of all ages--may not be optimal in children. A fresh database (using only children's data) was therefore created and tested. Its sensitivity for appendicitis was equivalent to that of inexperienced clinicians (79.6% versus 77.3%). The computer's specificity (over 70%) was higher than that of clinicians (52.7%). The findings also re-emphasise the value of disciplined data collection, and the implications for teaching are discussed.

Acute abdominal pain in patients over 50 years of age.

This study aimed to discover whether the disease spectrum in elderly patients (50 years and over) differed from that in other ages, and to compare patient presentation, progress and outcome between different age groups. In all, a total of 2406 patients from the OMGE series who were aged 50 and over were studied. Cholecystitis was the commonest disease category, commoner even than NSAP and appendicitis. Obstruction was more than three times as common in the elderly patients. One in four obstruction cases eventually proved to be due to an undiagnosed hernia. Cancer rates rose to 24% in patients over 70; whilst vascular causes accounted for 2.3% of patients over 50. As regards outcome, the risk to life rose steeply after the age of 50, possibly reflecting low rates of diagnostic accuracy. The clinical presentation of appendicitis was quite different in those over 50. Patients over 50 years with acute abdominal pain should be viewed differently from other younger patients, with special care being taken to look for hernia, cancer, and vascular disease. Educational material should also be reviewed to reflect the different features of the elderly patient. It is clear that further data on elderly patients are urgently required.

Molecular excitons in a copper azadipyrrin complex.

Exciton coupling is investigated in a copper azadipyrrin complex, Cu(L-aza)2. Exciton coupling in Cu(L-aza)2 assuming a single π-π* state on the L-aza ligand fails to account for the electronic structure of Cu(L-aza)2, which displays two almost equal intensity transitions at 15 600 cm(-1) and 17 690 cm(-1). TD-UB3LYP/6-31G(d) calculations suggest multiple π-π* transitions for the L-aza ligands and simple vector addition of the transition dipoles predicts two nearly orthogonal co-planar excitonic transitions that correctly reproduce the absorption band profile. Empirical modelling of absolute resonance Raman intensities using wavepacket dynamics confirms Cu(L-aza)2 has two equal intensity orthogonal exciton transitions. The phenyl substituents at the α- and γ-positions of the pyrrole rings play a central role in determining the orientation of the transition dipoles. Consequently the π-π* transitions for the L-aza ligands are oriented towards the substituent groups and are not in the plane of the pyrrole rings. Mode displacements in the Franck-Condon (FC) region obtained from the wavepacket model suggest that pyrrole ring and phenyl modes control the exciton FC dynamics. Our results suggest that Cu(L-aza)2 is an ideal model for theoretical, computational and experimental investigations of molecular excitons in molecular systems.

A novel device for improving marker placement accuracy.

BACKGROUND: Repeatability of marker placement has been acknowledged as a major factor affecting the reliability of multi-segment foot models. A novel device is proposed that is intended to reduce marker placement error and its effect on the reliability of inter-segmental foot kinematic data is investigated. METHOD: The novel device was tested on eight healthy subjects. Landmarks were identified and indicated on the subject's foot at the start of testing using pen, and these points were used to guide placement. Markers were twice attached by a podiatrist using a standard approach, and twice by a researcher who used the novel device. Replacement accuracy and the kinematic reliability of the foot model data for both techniques were analysed. RESULTS: The mean marker placement variability using the novel device placement device was 1.1mm (SD 0.28) compared to 1.4mm (SD 0.23) when using standard placement techniques. Results suggest that these reductions in placement error tended to improve the overall reliability of the multi-segment data from the foot model. DISCUSSION: The novel device is a simple and inexpensive tool for improving the placement consistency of skin-mounted markers.

Susceptibility to Yersinia pestis experimental infection in wild Rattus rattus, reservoir of plague in Madagascar.

In Madagascar, the black rat, Rattus rattus, is the main reservoir of plague (Yersinia pestis infection), a disease still responsible for hundreds of cases each year in this country. This study used experimental plague challenge to assess susceptibility in wild-caught rats to better understand how R. rattus can act as a plague reservoir. An important difference in plague resistance between rat populations from the plague focus (central highlands) and those from the plague-free zone (low altitude area) was confirmed to be a widespread phenomenon. In rats from the plague focus, we observed that sex influenced plague susceptibility, with males slightly more resistant than females. Other individual factors investigated (weight and habitat of sampling) did not affect plague resistance. When infected at high bacterial dose (more than 105 bacteria injected), rats from the plague focus died mainly within 3-5 days and produced specific antibodies, whereas after low-dose infection (< 5,000 bacteria), delayed mortality was observed and surviving seronegative rats were not uncommon. These results concerning plague resistance level and the course of infection in the black rat would contribute to a better understanding of plague circulation in Madagascar.