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1.  Lumican expression, localization and antitumor activity in prostate cancer 
Experimental cell research  2013;319(7):967-981.
The stromal reaction surrounding tumors leads to the formation of a tumor-specific microenvironment, which may play either a restrictive role or a supportive role in the growth and progression of the tumors. Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), regulates collagen fibrillogenesis. Recently, lumican has also been shown to regulate cell behavior during embryonic development, tissue repair and tumor progression. The role of lumican in cancer varies according to the type of tumor. In this study we analyze the role of lumican in the pathogenesis of prostate cancer both in vivo and in vitro. Overall lumican up-regulation was observed in the primary tumors analyzed through both real-time PCR and immunostaining. The increase in lumican expression was observed in the reactive stroma surrounding prostate primary tumors with fibrotic deposition surrounding the acinar glands. In vitro analysis demonstrated that lumican inhibited both the migration and invasion of metastatic prostate cancer cells isolated from lymph node, bone and brain. Moreover, prostate cancer cells seeded on lumican presented a decrease in the formation of cellular projections, lamellipodia detected by a decreased rearrangement in ZO-1, keratin 8/18, integrin β1 and MT1-MMP, and invadopodia detected by disruption of α-smooth muscle actin, cortactin and N-WASP. Moreover, a significant increase in prostate cancer cell invasion was observed through the peritoneum of lumican knockout mice, further demonstrating the restrictive role lumican present in the ECM has on prostate cancer invasion. In conclusion, lumican present in the reactive stroma surrounding prostate primary tumors plays a restrictive role on cancer progression, and we therefore postulate that lumican could be a valuable marker in prostate cancer staging.
doi:10.1016/j.yexcr.2013.01.023
PMCID: PMC3633477  PMID: 23399832
Lumican; desmoplasia; tumor markers; prostate cancer; cytoskeleton; cell migration
2.  A type I interferon transcriptional signature precedes autoimmunity in children genetically at-risk of type 1 diabetes 
Diabetes  2014;63(7):2538-2550.
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and anti-viral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (N=25). Using this predefined set of 225 IFN signature genes, we investigated expression of the signature in cohorts of healthy controls (N=87), T1D patients (N=64) and a large longitudinal birth cohort of children genetically predisposed to T1D (N=109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically-predisposed children prior to the development of autoantibodies (P=0.0012), but not in established T1D patients. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P=0.0064) and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P=0.007), as exemplified by IFIH1, one of the genes in our IFN signature and for which increased expression is a known disease risk factor. These findings identify transient increased expression of type I IFN genes in pre-clinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
doi:10.2337/db13-1777
PMCID: PMC4066333  PMID: 24561305
3.  SOT Symposium Highlight: Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures 
Toxicological Sciences  2013;136(2):265-273.
Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. However, this area shows great potential for improvement, with several avenues currently being pursued. This was the topic of a symposium session during the 2013 Society of Toxicology Annual Meeting in San Antonio, TX, entitled “Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures.” This symposium brought together stakeholders from academia, government, and industry to present the limitations and drawbacks of currently used indicators of injury and discussed the ongoing efforts in developing more predictive biomarkers of injury. The presentations highlighted the early challenges of using circulating inhibin B and microRNA levels, and sperm messenger RNA transcript abundance and DNA methylation profiles, as novel biomarkers of testicular toxicity.
doi:10.1093/toxsci/kft207
PMCID: PMC3858194  PMID: 24052563
biomarkers; testicular toxicity; inhibin B; microRNA; sperm.
4.  Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease 
NeuroImage : Clinical  2014;7:105-113.
The brains of patients suffering from Alzheimer's disease (AD) have three classical pathological hallmarks: amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI) and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle (AIBL) studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB) from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months.
Highlights
•The link between amyloid (Aβ) and basal forebrain degeneration in AD is unclear.•We find that basal forebrain volumes are correlated with neocortical Aβ burden.•Basal forebrain volume correlates with Aβ burden in at-risk control subjects.•Basal forebrain atrophy delineates subjects at increased risk of progressing to AD.
doi:10.1016/j.nicl.2014.11.015
PMCID: PMC4299972  PMID: 25610772
3D, 3-dimensional; Aβ, amyloid-beta; AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; AIBL, Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging; aMCI, amnestic mild cognitive impairment; CSF, cerebrospinal fluid; GM, gray matter; HC, healthy control; MCI, mild cognitive impairment; MNI, Montreal Neurological Institute; MPM, maximum probability maps; MPRAGE, magnetization prepared rapid gradient echo; MRI, magnetic resonance imaging; OR, odds ratio; PET, positron emission tomography; PiB, Pittsburgh compound B; SPSS, statistics software package for the social sciences; SUVR, standard uptake value ratio; SyN, symmetric normalization; T1W, T1-weighted; TG-ROC, two-graph receiver operating characteristic; WM, white matter; Basal forebrain; Amyloid; Alzheimer's disease; Magnetic resonance imaging; PET
5.  IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth 
Infection and Immunity  2014;82(5):1793-1800.
Virulence of the intracellular pathogen Rhodococcus equi depends on a 21.3-kb pathogenicity island located on a conjugative plasmid. To date, the only nonregulatory pathogenicity island-encoded virulence factor identified is the cell envelope-associated VapA protein. Although the pathogenicity islands from porcine and equine R. equi isolates have undergone major rearrangements, the virR operon (virR-icgA-vapH-orf7-virS) is highly conserved in both, suggesting these genes play an important role in pathogenicity. VirR and VirS are transcriptional regulators controlling expression of pathogenicity island genes, including vapA. Here, we show that while vapH and orf7 are dispensable for intracellular growth of R. equi, deletion of icgA, formerly known as orf5, encoding a major facilitator superfamily transport protein, elicited an enhanced growth phenotype in macrophages and a significant reduction in macrophage viability, while extracellular growth in broth remained unaffected. Transcription of virS, located downstream of icgA, and vapA was not affected by the icgA deletion during growth in broth or in macrophages, showing that the enhanced growth phenotype caused by deletion of icgA was not mediated through abnormal transcription of these genes. Transcription of icgA increased 6-fold within 2 h following infection of macrophages and remained significantly higher 48 h postinfection compared to levels at the start of the infection. The major facilitator superfamily transport protein IcgA is the first factor identified in R. equi that negatively affects intracellular replication. Aside from VapA, it is only the second pathogenicity island-encoded structural protein shown to play a direct role in intracellular growth of this pathogenic actinomycete.
doi:10.1128/IAI.01670-13
PMCID: PMC3993432  PMID: 24549327
6.  Differences in speciation progress in feather mites (Analgoidea) inhabiting the same host: the case of Zachvatkinia and Alloptes living on arctic and long-tailed skuas 
Recent molecular phylogenetic analyses have revealed that some apparently oligoxenous feather mite species are in fact monoxenous cryptic species with little morphological differentiation. In this study we analyzed two species, Zachvatkinia isolata (Avenzoariidae) and Alloptes (Sternalloptes) stercorarii (Alloptidae) which prefer different parts of the plumage of two sister species of birds: arctic skua (Stercorarius parasiticus) and long-tailed skua (S. longicaudus) breeding on tundra in the High Arctic archipelago of Svalbard. Given that there are no reports about hybridization events between the host species, we expected that both skuas would have a species-specific acarofauna. The genetic distances among DNA-barcode sequences (COI and 28S rDNA), phylogenetic tree topologies, and haplotype networks of the COI sequences of mites suggested extensive gene flow in Z. isolata between and within populations inhabiting both skua species, whereas the Alloptes populations were host specific and sufficiently genetically separated as to warrant species-level status. The discrepancy in the genetic structure of Alloptes and Zachvatkinia populations suggests frequent but transient contacts between the two skua species in which the probability of mite exchange is much higher for Zachvatkinia, which is present in high numbers and inhabits exposed parts of primary flight feathers, than for the less abundant Alloptes that lives primarily in more protected and inaccessible parts of the plumage. We discuss the possible nature of these contacts between host species and the area(s) where they might take place. The star-like structures in the haplotype network as well as high haplotype diversity and low nucleotide diversity observed in Z. isolata are concordant with the known dispersal strategy of feather mites: vertical colonization of new host individuals followed by rapid growth of founder populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s10493-014-9856-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s10493-014-9856-1
PMCID: PMC4274374  PMID: 25342243
DNA barcoding; Haplotype network; Coalescence; Species delimitation; Spitsbergen; Ectocommensal dispersion; Stercorarius
7.  Relative Roles of GM1 Ganglioside, N-Acylneuraminic Acids, and α2β1 Integrin in Mediating Rotavirus Infection 
Journal of Virology  2014;88(8):4558-4571.
ABSTRACT
N-acetyl- and N-glycolylneuraminic acids (Sia) and α2β1 integrin are frequently used by rotaviruses as cellular receptors through recognition by virion spike protein VP4. The VP4 subunit VP8*, derived from Wa rotavirus, binds the internal N-acetylneuraminic acid on ganglioside GM1. Wa infection is increased by enhanced internal Sia access following terminal Sia removal from main glycan chains with sialidase. The GM1 ligand cholera toxin B (CTB) reduces Wa infectivity. Here, we found sialidase treatment increased cellular GM1 availability and the infectivity of several other human (including RV-3) and animal rotaviruses, typically rendering them susceptible to methyl α-d-N-acetylneuraminide treatment, but did not alter α2β1 usage. CTB reduced the infectivity of these viruses. Aceramido-GM1 inhibited Wa and RV-3 infectivity in untreated and sialidase-treated cells, and GM1 supplementation increased their infectivity, demonstrating the importance of GM1 for infection. Wa recognition of α2β1 and internal Sia were at least partially independent. Rotavirus usage of GM1 was mapped to VP4 using virus reassortants, and RV-3 VP8* bound aceramido-GM1 by saturation transfer difference nuclear magnetic resonance (STD NMR). Most rotaviruses recognizing terminal Sia did not use GM1, including RRV. RRV VP8* interacted minimally with aceramido-GM1 by STD NMR. Unusually, TFR-41 rotavirus infectivity depended upon terminal Sia and GM1. Competition of CTB, Sia, and/or aceramido-GM1 with cell binding by VP8* from representative rotaviruses showed that rotavirus Sia and GM1 preferences resulted from VP8*-cell binding. Our major finding is that infection by human rotaviruses of commonly occurring VP4 serotypes involves VP8* binding to cell surface GM1 glycan, typically including the internal N-acetylneuraminic acid.
IMPORTANCE Rotaviruses, the major cause of severe infantile gastroenteritis, recognize cell surface receptors through virus spike protein VP4. Several animal rotaviruses are known to bind sialic acids at the termini of main carbohydrate chains. Conversely, only a single human rotavirus is known to bind sialic acid. Interestingly, VP4 of this rotavirus bound to sialic acid that forms a branch on the main carbohydrate chain of the GM1 ganglioside. Here, we use several techniques to demonstrate that other human rotaviruses exhibit similar GM1 usage properties. Furthermore, binding by VP4 to cell surface GM1, involving branched sialic acid recognition, is shown to facilitate infection. In contrast, most animal rotaviruses that bind terminal sialic acids did not utilize GM1 for VP4 cell binding or infection. These studies support a significant role for GM1 in mediating host cell invasion by human rotaviruses.
doi:10.1128/JVI.03431-13
PMCID: PMC3993774  PMID: 24501414
8.  Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of Mucopolysaccharidosis VII mice 
Stem cells (Dayton, Ohio)  2013;31(10):10.1002/stem.1481.
Mucopolysaccharidosis (MPS) are a family of related disorders caused by a mutation in one of the lysosomal exoglycosidases which leads to the accumulation of glycosaminoglycans (GAGs). MPS VII, caused by a mutation in β-glucuronidase, manifests hepatomegaly, skeletal dysplasia, short stature, corneal clouding and developmental delay. Current treatment regimens for MPS are not effective for treating corneal clouding and impaired mental development. We hypothesized that human umbilical mesenchymal stem cells (UMSC) transplanted into the corneal stroma could participate in the catabolism of GAGs providing a means of cell therapy for MPS. For such treatment, human UMSC were intrastromally transplanted into corneas of MPS VII mice. UMSC transplantation restored the dendritic and hexagonal morphology of host keratocytes and endothelial cells, respectively, and in vivo confocal microscopy (HRTII) revealed reduced corneal haze. Immunohistochemistry using antibodies against HS and CS chains as well as LAMP2 revealed a decrease in GAG content and both lysosomal number and size in the treated corneas. Labeling UMSC intracellular compartments prior to transplantation revealed the distribution of UMSC vesicles throughout the corneal stroma and endothelium. An in vitro co-culture assay between skin fibroblasts isolated from MPSVII mice and UMSC demonstrated that neutral vesicles released by the UMSC are taken up by the fibroblasts and proceed to fuse with the acidic lysosomes. Therefore, transplanted UMSC participate both in extracellular GAG turnover and enable host keratocytes to catabolize accumulated GAG products, suggesting that UMSC could be a novel alternative for treating corneal defects associated with MPS and other congenital metabolic disorders.
doi:10.1002/stem.1481
PMCID: PMC3812352  PMID: 23897660
Mucopolysaccharidosis; umbilical cord mesenchymal stem cells; cornea; glycosaminoglycans; exosomes
9.  Exploring the effects of immunity and life history on the dynamics of an endogenous retrovirus 
Mammalian DNA is littered with the signatures of past retroviral infections. For example, at least 8% of the human genome can be attributed to endogenous retroviruses (ERVs). We take a single-locus approach to develop a simple susceptible–infected–recovered model to investigate the circumstances under which a disease-causing retrovirus can become incorporated into the host genome and spread through the host population if it were to confer an immunological advantage. In the absence of any fitness benefit provided by the long terminal repeat (LTR), we conclude that signatures of ERVs are likely to go to fixation within a population when the probability of evolving cellular/humoral immunity to a related exogenous version of the virus is extremely small. We extend this model to examine whether changing the speed of the host life history influences the likelihood that an exogenous retrovirus will incorporate and spread to fixation. Our results reveal the parameter space under which incorporation of exogenous retroviruses into a host genome may be beneficial to the host. In our final model, we find that the likelihood of an LTR reaching fixation in a host population is not strongly affected by host life history.
doi:10.1098/rstb.2012.0505
PMCID: PMC3758189  PMID: 23938754
endogenous retrovirus; endogenous viral element derived immunity; immunity; susceptible–infected–recovered model; life history
10.  Melatonin Signaling Modulates Clock Genes Expression in the Mouse Retina 
PLoS ONE  2014;9(9):e106819.
Previous studies have shown that retinal melatonin plays an important role in the regulation of retinal daily and circadian rhythms. Melatonin exerts its influence by binding to G-protein coupled receptors named melatonin receptor type 1 and type 2 and both receptors are present in the mouse retina. Earlier studies have shown that clock genes are rhythmically expressed in the mouse retina and melatonin signaling may be implicated in the modulation of clock gene expression in this tissue. In this study we determined the daily and circadian expression patterns of Per1, Per2, Bmal1, Dbp, Nampt and c-fos in the retina and in the photoreceptor layer (using laser capture microdissection) in C3H-f+/+ and in melatonin receptors of knockout (MT1 and MT2) of the same genetic background using real-time quantitative RT-PCR. Our data indicated that clock and clock-controlled genes are rhythmically expressed in the retina and in the photoreceptor layer. Removal of melatonin signaling significantly affected the pattern of expression in the retina whereas in the photoreceptor layer only the Bmal1 circadian pattern of expression was affected by melatonin signaling removal. In conclusion, our data further support the notion that melatonin signaling may be important for the regulation of clock gene expression in the inner or ganglion cells layer, but not in photoreceptors.
doi:10.1371/journal.pone.0106819
PMCID: PMC4159264  PMID: 25203735
11.  The Overarching Influence of the Gut Microbiome on End-Organ Function: The Role of Live Probiotic Cultures 
Pharmaceuticals  2014;7(9):954-989.
At the time of birth, humans experience an induced pro-inflammatory beneficial event. The mediators of this encouraged activity, is a fleet of bacteria that assault all mucosal surfaces as well as the skin. Thus initiating effects that eventually provide the infant with immune tissue maturation. These effects occur beneath an emergent immune system surveillance and antigenic tolerance capability radar. Over time, continuous and regulated interactions with environmental as well as commensal microbial, viral, and other antigens lead to an adapted and maintained symbiotic state of tolerance, especially in the gastrointestinal tract (GIT) the organ site of the largest microbial biomass. However, the perplexing and much debated surprise has been that all microbes need not be targeted for destruction. The advent of sophisticated genomic techniques has led to microbiome studies that have begun to clarify the critical and important biochemical activities that commensal bacteria provide to ensure continued GIT homeostasis. Until recently, the GIT and its associated micro-biometabolome was a neglected factor in chronic disease development and end organ function. A systematic underestimation has been to undervalue the contribution of a persistent GIT dysbiotic (a gut barrier associated abnormality) state. Dysbiosis provides a plausible clue as to the origin of systemic metabolic disorders encountered in clinical practice that may explain the epidemic of chronic diseases. Here we further build a hypothesis that posits the role that subtle adverse responses by the GIT microbiome may have in chronic diseases. Environmentally/nutritionally/and gut derived triggers can maintain microbiome perturbations that drive an abnormal overload of dysbiosis. Live probiotic cultures with specific metabolic properties may assist the GIT microbiota and reduce the local metabolic dysfunctions. As such the effect may translate to a useful clinical treatment approach for patients diagnosed with a metabolic disease for end organs such as the kidney and liver. A profile emerges that shows that bacteria are diverse, abundant, and ubiquitous and have significantly influenced the evolution of the eukaryotic cell.
doi:10.3390/ph7090954
PMCID: PMC4190499  PMID: 25244509
probiotics; Lactobacillus; Bifidobacteria; gastrointestinal tract; commensal bacteria; brain; kidneys; skeletal muscle; adipose tissue; heart
12.  A new way to integrate selection when both demography and selection gradients vary over time 
When both selection and demography vary over time, how can the long-run expected strength of selection on quantitative traits be measured? There are two basic steps in the proposed new analysis: one relates trait values to fitness components and the other relates fitness components to total fitness. We used one population projection matrix for each state of the environment together with a model of environmental dynamics, defining total fitness as the stochastic growth rate. We multiplied environment-specific, stage-specific mean-standardized selection gradients by environment-specific, stage-specific elasticities of the stochastic growth rate, summing over all relevant life history and environmental paths. Our two example traits were floral tube length in a rainforest herb and the timing of birth in Red Deer. For each species, we constructed two models of environmental dynamics, including one based on historical climate records. We found that total integrated selection, as well as the relative contributions of life-history pathways and environments, varied with environmental dynamics. Temporal patterning in the environment has selective consequences. Linking models of environmental change to relevant short term data on demography and selection may permit estimation of the force of selection over the long-term in variable environments.
doi:10.1086/657141
PMCID: PMC4115803  PMID: 25089083
variable selection gradients; environment-specific elasticity; structured populations; integrated elasticity; climate and demography
13.  Mechatronic Feasibility of Minimally Invasive, Atraumatic Cochleostomy 
BioMed Research International  2014;2014:181624.
Robotic assistance in the context of lateral skull base surgery, particularly during cochlear implantation procedures, has been the subject of considerable research over the last decade. The use of robotics during these procedures has the potential to provide significant benefits to the patient by reducing invasiveness when gaining access to the cochlea, as well as reducing intracochlear trauma when performing a cochleostomy. Presented herein is preliminary work on the combination of two robotic systems for reducing invasiveness and trauma in cochlear implantation procedures. A robotic system for minimally invasive inner ear access was combined with a smart drilling tool for robust and safe cochleostomy; evaluation was completed on a single human cadaver specimen. Access to the middle ear was successfully achieved through the facial recess without damage to surrounding anatomical structures; cochleostomy was completed at the planned position with the endosteum remaining intact after drilling as confirmed by microscope evaluation.
doi:10.1155/2014/181624
PMCID: PMC4109217  PMID: 25110661
14.  Feasibility Study of a Hand Guided Robotic Drill for Cochleostomy 
BioMed Research International  2014;2014:656325.
The concept of a hand guided robotic drill has been inspired by an automated, arm supported robotic drill recently applied in clinical practice to produce cochleostomies without penetrating the endosteum ready for inserting cochlear electrodes. The smart tactile sensing scheme within the drill enables precise control of the state of interaction between tissues and tools in real-time. This paper reports development studies of the hand guided robotic drill where the same consistent outcomes, augmentation of surgeon control and skill, and similar reduction of induced disturbances on the hearing organ are achieved. The device operates with differing presentation of tissues resulting from variation in anatomy and demonstrates the ability to control or avoid penetration of tissue layers as required and to respond to intended rather than involuntary motion of the surgeon operator. The advantage of hand guided over an arm supported system is that it offers flexibility in adjusting the drilling trajectory. This can be important to initiate cutting on a hard convex tissue surface without slipping and then to proceed on the desired trajectory after cutting has commenced. The results for trials on phantoms show that drill unit compliance is an important factor in the design.
doi:10.1155/2014/656325
PMCID: PMC4109386  PMID: 25110684
15.  Objectively Assessed Physical Activity and Subsequent Health Service Use of UK Adults Aged 70 and Over: A Four to Five Year Follow Up Study 
PLoS ONE  2014;9(5):e97676.
Objectives
To examine the associations between volume and intensity of older peoples' physical activity, with their subsequent health service usage over the following four to five years.
Study Design
A prospective cohort design using baseline participant characteristics, objectively assessed physical activity and lower limb function provided by Project OPAL (Older People and Active Living). OPAL-PLUS provided data on numbers of primary care consultations, prescriptions, unplanned hospital admissions, and secondary care referrals, extracted from medical records for up to five years following the baseline OPAL data collection.
Participants and Data Collection
OPAL participants were a diverse sample of 240 older adults with a mean age of 78 years. They were recruited from 12 General Practitioner surgeries from low, middle, and high areas of deprivation in a city in the West of England. Primary care consultations, secondary care referrals, unplanned hospital admissions, number of prescriptions and new disease diagnoses were assessed for 213 (104 females) of the original 240 OPAL participants who had either consented to participate in OPAL-PLUS or already died during the follow-up period.
Results
In regression modelling, adjusted for socio-economic variables, existing disease, weight status, minutes of moderate-to-vigorous physical activity (MVPA) per day predicted subsequent numbers of prescriptions. Steps taken per day and MVPA also predicted unplanned hospital admissions, although the strength of the effect was reduced when further adjustment was made for lower limb function.
Conclusions
Community-based programs are needed which are successful in engaging older adults in their late 70s and 80s in more walking, MVPA and activity that helps them avoid loss of physical function. There is a potential for cost savings to health services through reduced reliance on prescriptions and fewer unplanned hospital admissions.
doi:10.1371/journal.pone.0097676
PMCID: PMC4035293  PMID: 24866573
16.  Experimental manipulation reveals few subclinical impacts of a parasite community in juvenile kangaroos 
Graphical abstract
Highlights
•We examine differences between parasitised and non-parasitised juvenile kangaroos.•Kangaroo helminths affect host albumin levels.•Kangaroo helminths have surprisingly few effects on host growth and body condition.•Haematological parameters are more sensitive to parasitism than growth parameters.•Juvenile kangaroos can possibly compensate for the costs of parasites.
Large mammalian herbivores are commonly infected with gastrointestinal helminths. In many host species, these helminths cause clinical disease and may trigger conspicuous mortality events. However, they may also have subclinical impacts, reducing fitness as well as causing complex changes to host growth patterns and body condition. Theoretically, juveniles should experience significantly greater costs from parasites, being immunologically naive and undergoing a significant growth phase. The aims of our study were to quantify the subclinical effects of helminths in juvenile eastern grey kangaroos (Macropus giganteus), which commonly harbour large burdens of gastrointestinal nematodes and are susceptible to associated mass mortality during cold, wet conditions. We conducted a field experiment on a population of free-ranging kangaroos, removing nematodes from one group of juveniles using an anthelmintic treatment. We then compared growth parameters (body condition and growth rates) and haematological parameters of this group with an age-matched, parasitised (untreated) control group. Treated juvenile kangaroos had significantly higher levels of plasma protein (albumin) but, contrary to our predictions, showed negligible changes in all the other parameters measured. Our results suggest that juvenile kangaroos are largely unaffected by their gastrointestinal helminth burdens, and may be able to compensate for the costs of parasites.
doi:10.1016/j.ijppaw.2014.03.005
PMCID: PMC4142266  PMID: 25161906
Costs; Helminths; Haematology; Juveniles; Macropus giganteus; Parasites
17.  Lifestyle medicine for depression 
BMC Psychiatry  2014;14:107.
The prevalence of depression appears to have increased over the past three decades. While this may be an artefact of diagnostic practices, it is likely that there are factors about modernity that are contributing to this rise. There is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can potentially be modified, yet they receive little consideration in the contemporary treatment of depression, where medication and psychological intervention remain the first line treatments. “Lifestyle Medicine” provides a nexus between public health promotion and clinical treatments, involving the application of environmental, behavioural, and psychological principles to enhance physical and mental wellbeing. This may also provide opportunities for general health promotion and potential prevention of depression. In this paper we provide a narrative discussion of the major components of Lifestyle Medicine, consisting of the evidence-based adoption of physical activity or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. We also discuss other potential lifestyle factors that have a more nascent evidence base, such as environmental issues (e.g. urbanisation, and exposure to air, water, noise, and chemical pollution), and the increasing human interface with technology. Clinical considerations are also outlined. While data supports that some of these individual elements are modifiers of overall mental health, and in many cases depression, rigorous research needs to address the long-term application of Lifestyle Medicine for depression prevention and management. Critically, studies exploring lifestyle modification involving multiple lifestyle elements are needed. While the judicious use of medication and psychological techniques are still advocated, due to the complexity of human illness/wellbeing, the emerging evidence encourages a more integrative approach for depression, and an acknowledgment that lifestyle modification should be a routine part of treatment and preventative efforts.
doi:10.1186/1471-244X-14-107
PMCID: PMC3998225  PMID: 24721040
Lifestyle; Depression; Exercise; Diet; Smoking; Alcohol; Prevention; Treatment
18.  Mismatch Between Birth Date and Vegetation Phenology Slows the Demography of Roe Deer 
PLoS Biology  2014;12(4):e1001828.
This study of a French deer population reveals the demographic costs associated with the failure of a herbivore to modify its life cycle timing to respond to a warming world.
Marked impacts of climate change on biodiversity have frequently been demonstrated, including temperature-related shifts in phenology and life-history traits. One potential major impact of climate change is the modification of synchronization between the phenology of different trophic levels. High phenotypic plasticity in laying date has allowed many bird species to track the increasingly early springs resulting from recent environmental change, but although changes in the timing of reproduction have been well studied in birds, these questions have only recently been addressed in mammals. To track peak resource availability, large herbivores like roe deer, with a widespread distribution across Europe, should also modify their life-history schedule in response to changes in vegetation phenology over time. In this study, we analysed the influence of climate change on the timing of roe deer births and the consequences for population demography and individual fitness. Our study provides a rare quantification of the demographic costs associated with the failure of a species to modify its phenology in response to a changing world. Given these fitness costs, the lack of response of roe deer birth dates to match the increasingly earlier onset of spring is in stark contrast with the marked phenotypic responses to climate change reported in many other mammals. We suggest that the lack of phenotypic plasticity in birth timing in roe deer is linked to its inability to track environmental cues of variation in resource availability for the timing of parturition.
Author Summary
Climate change can alter the synchronization of life cycles between organisms at different points in the food chain. If species do not respond to climate change, the timing of peak resource availability may fail to match the timing of peak energy expenditure. Many bird species have been able to advance their laying date to match a change in the timing of caterpillar abundance. Herbivores are similarly expected to track changes in the timing of vegetation growth. In this study, we combine statistical analysis with demographic modeling to analyze the influence of a climate-driven shift in the timing of the spring vegetation flush on the birth date and demography of roe deer. In recent years, climate change has generated a marked increase in local temperatures and a progressively earlier vegetation flush. Despite these changes, we observed no shift in timing of the birth date of roe deer over the 27-year study period. This failure to track environmental change resulted in a mismatch between vegetation flush and birth date, which in turn caused a decrease in survival of the young, and hence a reduction in roe deer fitness. Birth date was under strong directional selection, but was not strongly heritable, suggesting that any evolutionary response of birth date to climate change might be limited. We suggest that a plastic response in birth date did not occur because reproduction is triggered by day length rather than resource availability in roe deer.
doi:10.1371/journal.pbio.1001828
PMCID: PMC3972086  PMID: 24690936
19.  Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells 
PLoS Pathogens  2014;10(3):e1003998.
It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon contributes to the lymphocyte activation observed following RRV infection of NOD mice, and may play a role in diabetes acceleration by rotavirus.
Author Summary
Understanding how viruses contribute to type 1 diabetes development is vital for disease prevention. Infection of children at-risk of diabetes with the gastrointestinal pathogen rotavirus is associated with increased immune responses to pancreatic islets, leading to the proposal that rotavirus infection may accelerate progression to diabetes. In a mouse model, we showed previously that rotavirus accelerates diabetes onset, in conjunction with virus spread to the lymph nodes, draining the intestine and pancreas. At these sites, rotavirus associates with antigen-presenting cells of the immune system, including dendritic cells, leading to their maturation, and induces the activation of B and T cells. Here we use this mouse model to define the contribution of rotavirus-exposed antigen-presenting cells to the activation of neighboring B and T cells. We found that rotavirus-exposed dendritic cells induce B and T cell activation through secretion of type I interferon. Activation of these dendritic cells depends on recognition of viral RNA by Toll-like receptor 7. Our studies suggest that this mechanism of B and T cell activation may occur in RRV-infected mice and contribute to their accelerated diabetes development. A similar mechanism may be involved in the enhanced islet autoantibody responses of children following rotavirus infection.
doi:10.1371/journal.ppat.1003998
PMCID: PMC3968122  PMID: 24676425
20.  Frontiers in Pulmonary Hypertension in Infants and Children With Bronchopulmonary Dysplasia 
Pediatric pulmonology  2012;47(11):1042-1053.
Summary
Pulmonary hypertension (PH) is an increasingly recognized complication of premature birth and bronchopulmonary dysplasia (BPD), and is associated with increased morbidity and mortality. Extreme phenotypic variability exists among preterm infants of similar gestational ages, making it difficult to predict which infants are at increased risk for developing PH. Intrauterine growth retardation or drug exposures, postnatal therapy with prolonged positive pressure ventilation, cardiovascular shunts, poor postnatal lung and somatic growth, and genetic or epigenetic factors may all contribute to the development of PH in preterm infants with BPD. In addition to the variability of severity of PH, there is also qualitative variability seen in PH, such as the variable responses to vasoactive medications. To reduce the morbidity and mortality associated with PH, a multi-pronged approach is needed. First, improved screening for and increased recognition of PH may allow for earlier treatment and better clinical outcomes. Second, identification of both prenatal and postnatal risk factors for the development of PH may allow targeting of therapy and resources for those at highest risk. Third, understanding the pathophysiology of the preterm pulmonary vascular bed may help improve outcomes through recognizing pathways that are dysregulated in PH, identifying novel biomarkers, and testing novel treatments. Finally, the recognition of conditions and exposures that may exacerbate or lead to recurrent PH is needed to help with developing treatment guidelines and preventative strategies that can be used to reduce the burden of disease.
doi:10.1002/ppul.22609
PMCID: PMC3963167  PMID: 22777709
pulmonary hypertension; bronchopulmonary dysplasia; prematurity; chronic lung disease
23.  Exploring the effects of spatial autocorrelation when identifying key drivers of wildlife crop-raiding 
Ecology and Evolution  2014;4(5):582-593.
Few universal trends in spatial patterns of wildlife crop-raiding have been found. Variations in wildlife ecology and movements, and human spatial use have been identified as causes of this apparent unpredictability. However, varying spatial patterns of spatial autocorrelation (SA) in human–wildlife conflict (HWC) data could also contribute. We explicitly explore the effects of SA on wildlife crop-raiding data in order to facilitate the design of future HWC studies. We conducted a comparative survey of raided and nonraided fields to determine key drivers of crop-raiding. Data were subsampled at different spatial scales to select independent raiding data points. The model derived from all data was fitted to subsample data sets. Model parameters from these models were compared to determine the effect of SA. Most methods used to account for SA in data attempt to correct for the change in P-values; yet, by subsampling data at broader spatial scales, we identified changes in regression estimates. We consequently advocate reporting both model parameters across a range of spatial scales to help biological interpretation. Patterns of SA vary spatially in our crop-raiding data. Spatial distribution of fields should therefore be considered when choosing the spatial scale for analyses of HWC studies. Robust key drivers of elephant crop-raiding included raiding history of a field and distance of field to a main elephant pathway. Understanding spatial patterns and determining reliable socio-ecological drivers of wildlife crop-raiding is paramount for designing mitigation and land-use planning strategies to reduce HWC. Spatial patterns of HWC are complex, determined by multiple factors acting at more than one scale; therefore, studies need to be designed with an understanding of the effects of SA. Our methods are accessible to a variety of practitioners to assess the effects of SA, thereby improving the reliability of conservation management actions.
doi:10.1002/ece3.837
PMCID: PMC4098139  PMID: 25035800
Elephant; Generalized Linear Model; Human–wildlife conflict; Okavango Delta; spatial scale
24.  Parturition date for a given female is highly repeatable within five roe deer populations 
Biology Letters  2013;9(1):20120841.
Births are highly synchronized among females in many mammal populations in temperate areas. Although laying date for a given female is also repeatable within populations of birds, limited evidence suggests low repeatability of parturition date for individual females in mammals, and between-population variability in repeatability has never, to our knowledge, been assessed. We quantified the repeatability of parturition date for individual females in five populations of roe deer, which we found to vary between 0.54 and 0.93. Each year, some females gave birth consistently earlier in the year, whereas others gave birth consistently later. In addition, all females followed the same lifetime trajectory for parturition date, giving birth progressively earlier as they aged. Giving birth early should allow mothers to increase offspring survival, although few females managed to do so. The marked repeatability of parturition date in roe deer females is the highest ever reported for a mammal, suggesting low phenotypic plasticity in this trait.
doi:10.1098/rsbl.2012.0841
PMCID: PMC3565495  PMID: 23234861
repeatability; Capreolus capreolus; trajectory; birth date
25.  Effects of Resveratrol and Nebivolol on Isolated Vascular and Cardiac Tissues from Young Rats 
The mechanisms by which resveratrol and nebivolol induce vasodilation are not clearly understood. It has been postulated that both agents stimulate the production of nitric oxide; however, this remains to be conclusively established. The major aim of this study was to examine the vasodilatory and antiarrhythmic effects of both resveratrol and nebivolol and to provide further insight into possible mechanisms of action. Cardiac and vascular tissues were isolated from healthy male rodents. Results indicate that resveratrol and nebivolol decrease the action potential duration and induce mild vasorelaxation in aortic and mesenteric segments. Relaxation induced by resveratrol was prevented by the addition of verapamil, Nω-nitro-L-arginine-methyl ester, and 4-aminopyridine. This suggests that nebivolol and resveratrol act as putative antiarrhythmic and vasodilatory agents in vitro through possible indirect nitric oxide mechanisms.
doi:10.1155/2014/720386
PMCID: PMC3950595  PMID: 24696678

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