Acute Neuronal Injury and Blood Genomic Profiles in a Nonhuman Primate Model for Ischemic Stroke

The goal of this study was to characterize acute neuronal injury in a novel nonhuman primate (NHP) ischemic stroke model by using multiple outcome measures. Silk sutures were inserted into the M1 segment of the middle cerebral artery of rhesus macaques to achieve permanent occlusion of the vessel. The sutures were introduced via the femoral artery by using endovascular microcatheterization techniques. Within hours after middle cerebral artery occlusion (MCAO), infarction was detectable by using diffusion-weighted MRI imaging. The infarcts expanded by 24 h after MCAO and then were detectable on T2-weighted images. The infarcts seen by MRI were consistent with neuronal injury demonstrated histologically. Neurobehavioral function after MCAO was determined by using 2 neurologic testing scales. Neurologic assessments indicated that impairment after ischemia was limited to motor function in the contralateral arm; other neurologic and behavioral parameters were largely unaffected. We also used microarrays to examine gene expression profiles in peripheral blood mononuclear cells after MCAO-induced ischemia. Several genes were altered in a time-dependent manner after MCAO, suggesting that this ischemia model may be suitable for identifying blood biomarkers associated with the presence and severity of ischemia. This NHP stroke model likely will facilitate the elucidation of mechanisms associated with acute neuronal injury after ischemia. In addition, the ability to identify candidate blood biomarkers in NHP after ischemia may prompt the development of new strategies for the diagnosis and treatment of ischemic stroke in humans.Abbreviations: MCAO, middle cerebral artery occlusion; NHP, nonhuman primate; PBMC, peripheral blood mononuclear cellsStroke is a debilitating neurologic condition, and little progress has been made in the development of neuroprotective treatments for acute stroke. The Stroke Therapy Academic Industry Roundtable (STAIR) report suggested that preclinical candidates for stroke therapy should be validated by testing in large animals with similarities to humans, such as nonhuman primates (NHP).²⁶ NHP stroke models have been developed in several species, including rhesus monkeys, marmosets, and baboons, by using a variety of techniques for middle cerebral artery occlusion (MCAO).^{4,10,12,13,14,25,32} The rhesus macaque is ideal for stroke studies because of its structural similarities to human brain. The rhesus brain is gyrencephalic, which makes it preferable to those of lissencephalic primates (for example, marmosets) and is functionally similar to human brain.⁶ In addition, the immunologic profile of rhesus macaques is similar to that of humans; therefore these animals are the preferred model for the study of immune responses to infectious diseases such as HIV/SIV, Dengue virus, and others.^17,23,30In addition to their use for neuroprotection assessment, NHP stroke models can facilitate efforts to develop diagnostic tools for identifying and treating stroke symptoms. The use of genomics in peripheral blood cells has been shown to be an excellent method to identify candidate biomarkers and cellular mechanisms associated with stroke.^28,29 Blood biomarkers can be used to rapidly determine the occurrence, timing, subtype, and severity of stroke.^11,15 One possible reason for the lack of viable stroke biomarkers may be the research models used to search for these markers. Although rodent stroke models have yielded a wealth of information on the mechanisms associated with brain ischemia, the findings have not translated well to human clinical trials.²⁶ Recent studies in human patients showed promising results when genomic tools have been used to screen for novel stroke biomarkers.^3,16,27 However, validation of human studies is limited by the need for large data sets in light of heterogeneity in stroke onset, subtype, comorbidities, and other factors. In addition, it is also impossible to know the exact time of stroke onset in most patients.Here we characterized acute neuronal injury in a novel, minimally invasive permanent ischemic stroke model involving rhesus macaques. Using endovascular catheterization techniques, we introduced silk sutures into the M1 segment of the middle cerebral artery and permanently occluded it. This procedure reliably produced infarcts that could be measured by MRI of the macaque brains during the acute phase period. The procedure resulted in discrete and limited neurobehavioral deficits, indicating the potential of this stroke model for chronic neuroprotection studies in the future. In addition, we used microarrays to identify blood genomic profiles that were altered in a time-dependent manner after ischemia. These studies characterize a preclinical model that is suitable for elucidating the mechanisms associated with cerebral ischemia and that may aid in identifying strategies for the diagnosis and treatment of stroke in humans.     

Lack of Evidence for the Prior Residence Effect in the Allegheny Mountain Dusky Salamander (Desmognathus ochrophaeus)

Territorial disputes are frequently settled by an advantage afforded to one of the contestants by asymmetries such as size difference, strength and motivation. Allegheny Mountain Dusky Salamanders (Desmognathus ochrophaeus) are reported to defend cover objects, a form of territorial behaviour. We conducted an experiment to determine whether or not adult salamanders of this species exhibit prior residence effect during staged encounters involving size‐matched, same sex conspecifics (i.e. does familiarity with a territory predict successful defence?). We tested 154 adult salamanders (72 female, 82 male) in reciprocal trials in which each animal acted as a resident and as an intruder. We recorded multiple agonistic behaviours including: front‐trunk raised, all‐trunk raised, nudge, bite, bite‐and‐hold and jaw‐lock. We assigned these behaviours scaled point values and calculated an index of aggression for each animal as a resident and as an intruder. We found that in same sex trials, males were significantly more aggressive than females. Although D. ochrophaeus exhibited stereotypical, agonistic behaviours similar to those reported for Plethodon, unlike Plethodon the outcomes of symmetrical social encounters were not influenced by residential status. Prior residence is documented to be a major determinant of territorial disputes among diverse animal taxa, including salamanders. However, our research suggests that the phenomenon is not universal and may depend on qualities of the microhabitat in which a species has evolved.     

A decade of change in the saproxylic beetle fauna of eucalypt logs in the Warra long-term log-decay experiment,Tasmania. 2. Log-size effects,succession, and the functional significance of rare species

The first decade of sequential and cyclical sampling of the saproxylic beetles of twelve freshly felled Eucalyptus obliqua logs at Warra, Tasmania has allowed comparisons between larger-diameter mature and smaller-diameter regrowth log-classes and between successive sampling cycles and years; and consideration of the interplay between these two aspects. The two log-classes support different assemblages, with the mature log-class hosting consistently more species, more unique species, and proportionally more obligately saproxylic species. Assemblages change seasonally and year-to-year, demonstrating succession. While changes in the assemblages of mature and regrowth log-classes follow similar trajectories, they remain distinct at every point in time. These differences remain apparent when considering sub-sets of the assemblages based on the rarity of the species involved, their flightedness, saproxylicity and larval feeding guild. This study suggests a need to incorporate the conservation of coarse woody debris derived from mature trees into production forestry practices. There is a particular need to devise silvicultural and/or planning systems that cater for the retention and long-term recruitment of mature trees, since these are the only source of the larger-diameter logs that were identified in this study as having particular ecological value. Through continuing the Warra long-term log-decay experiment over the next century or more, a more complete picture of the saproxylic beetle fauna will progressively emerge, together with a better understanding of the management requirements of the fauna.     

Chemobrain Experienced by Breast Cancer Survivors: A Meta-Ethnography Study Investigating Research and Care Implications

BackgroundCognitive impairment, colloquially termed “chemobrain”, occurs in 10–40% of all cancer patients, and is an emerging target of cancer survivorship research.AimThis study reviews published qualitative studies to explore cognitive impairments or chemobrain among breast cancer survivors, with particular attention given to the impact on quality of life.MethodUsing keywords, we searched ten electronic databases (CINAHL, EMBASE, Proquest, OVID SP, MEDLINE, Oxford Journal, Science Direct, PubMED).FindingsOf 457 papers, seven relevant papers were included. Data was extracted and concepts were analysed using a meta ethnography approach. Four second order intepretations were identified, on the basis of which, four third order intrepretations were constructed. Linked together in a line of argument, was a consistent account on their struggles to self-manage the chemobrain impairments that impact their daily lives. Five concepts emerged from the analysis of the primary findings: i) real experiences of cognitive changes, ii) calls for help, iii) impact of cognitive impairments, iv) coping and v) survivorship and meaning. Further synthesis resulted in four new order intepretations: i) The chemobrain struggle, ii) The substantial impact of chemobrain on life domains, iii) The struggle to readjust and to self manage, and iv) ‘thankful yet fearful’ representation.DiscussionAwareness of cognitive changes were context-dependent on healthcare settings and cultural contexts as strong determinants. Subjects verified the existence of chemobrain but healthcare providers mis-recognised, under-recognised, and sometimes negated it perhaps due to its unknown aetiology. Asian breast cancer survivors appear less vocal than their western counterparts.ConclusionThe current literature on the lived experiences of how women experienced chemobrain provides a consistent report that chemobrain is real, persistent and with detrimental impacts on quality of life - manifested as a constant struggles. A greater awareness of the effects of chemobrain with improved functional assessment and interventions is warranted.     

Dynamic Imaging of Experimental Leishmania donovani-Induced Hepatic Granulomas Detects Kupffer Cell-Restricted Antigen Presentation to Antigen-Specific CD8+ T Cells

Kupffer cells (KCs) represent the major phagocytic population within the liver and provide an intracellular niche for the survival of a number of important human pathogens. Although KCs have been extensively studied in vitro, little is known of their in vivo response to infection and their capacity to directly interact with antigen-specific CD8⁺ T cells. Here, using a combination of approaches including whole mount and thin section confocal microscopy, adoptive cell transfer and intra-vital 2-photon microscopy, we demonstrate that KCs represent the only detectable population of mononuclear phagocytes within granulomas induced by Leishmania donovani infection that are capable of presenting parasite-derived peptide to effector CD8⁺ T cells. This restriction of antigen presentation to KCs within the Leishmania granuloma has important implications for the identification of new candidate vaccine antigens and for the design of novel immuno-therapeutic interventions.     

In vivo analysis of serotonin clearance in rat hippocampus reveals that repeated administration of p-methoxyamphetamine (PMA), but not 3,4-methylenedioxymethamphetamine (MDMA), leads to long-lasting deficits in serotonin transporter function

p-Methoxyamphetamine (PMA) has been implicated in fatalities as a result of 'ecstasy' (MDMA) overdose worldwide. Like MDMA, acute effects are associated with marked changes in serotonergic neurotransmission, but the long-term effects of PMA are poorly understood. The aim of this study was to determine the effect of repeated PMA administration on in vitro measures of neurodegeneration: serotonin (5-HT) uptake, 5-HT transporter (SERT) density and 5-HT content in the hippocampus, and compare with effects on in vivo 5-HT clearance. Male rats received PMA, MDMA (4 or 15 mg/kg s.c., twice daily) or vehicle for 4 days and 2 weeks later indices of SERT function were measured. [(3)H]5-HT uptake into synaptosomes and [(3)H]cyanoimipramine binding to the SERT were significantly reduced by both PMA and MDMA treatments. 5-HT content was reduced in MDMA-, but not PMA-treatment. In contrast, clearance of locally applied 5-HT measured in vivo by chronoamperometry was only reduced in rats treated with 15 mg/kg PMA. The finding that 5-HT clearance in vivo was unaltered by MDMA treatment suggests that in vitro measures of 5-HT axonal degeneration do not necessarily predict potential compensatory mechanisms that maintain SERT function under basal conditions.     

Impact of the economic recession on companion animal relinquishment, adoption, and euthanasia: a Chicago animal shelter's experience

This study investigated how the current economic recession (since December 2007) has affected dog and cat relinquishment, adoption, and euthanasia at the Anti-Cruelty Society animal shelter in Chicago, Illinois. The study compared temporal patterns of the investigated statistics before (2000-2007) the start of the current recession with the patterns after the start of the recession (2008-2010). The results showed that once the guardianship (ownership) of a nonhuman animal had been established, the recession did not greatly affect the owner's decision on relinquishment-except for the relinquishment of senior dogs, which may be associated with increased costs of care. However, an unfavorable economic environment may have reduced adoption of animals. The consequences of a decline in adoptions might be reflected in an increase in the proportion or number of sheltered animals euthanized. This study demonstrated how monitoring changes in temporal patterns in these shelter statistics can help guide animal shelters to better prepare for the current recession.     

Physical Activity and Welfare of Guide Dogs and Walking Activity of Their Partners

ABSTRACT

Appropriate physical activity is beneficial for physical and psychosocial wellbeing, and it is recommended for people to have 30 minutes of activity on most days of the week, to yield 150 minutes per week. Getting sufficient physical activity particularly challenges people with visual disabilities, and few health-promotion interventions have focused on adults with this disability. Recently, dog walking has been promoted in communities as a way to increase people's physical activity. We surveyed guide-dog partners to assess whether their guide dogs facilitated walking. We also assessed the welfare of these dogs, including their physical activity and social interactions with other dogs and people, especially as there is some concern that these dogs have too little freedom. For comparison, we assessed large and small companion dogs and their handlers, as well. A web-based survey was conducted among people living with guide dogs or companion (pet) dogs: large companion dogs (51 lb or more) and small companion dogs (50 lb or less). Guide-dog partners walked significantly more than handlers of either small or large companion dogs (Guide-dog partners met the healthy standard of 150 min per week of walking, at a level 10 times more than owners of large companion dogs). Guide dogs walked with their partners more frequently and for longer durations per day than owners of companion dogs. Guide dogs with their handlers met more people outside of their homes than did owners of companion dogs, but the groups did not differ in the number of dogs they greeted outside of the house. The frequencies of going to off-leash areas did not differ among the three groups. The findings indicate that having a dog as a guide can lead to a higher amount of walking among guide-dog partners, and that guide dogs have a higher quality of life, in terms of quantity of physical activity and social interactions, compared with large or small companion dogs.     

Meeting Report: Metagenomics, Metadata and MetaAnalysis (M3) at ISMB 2010

This report summarizes the proceedings of the first day of the Metagenomics, Metadata and MetaAnalysis (M3) workshop held at the Intelligent Systems for Molecular Biology 2010 conference. The second day, which was dedicated to the inaugural meeting of the BioSharing initiative is presented in a separate report. The Genomic Standards Consortium (GSC) hosted the first day of this Special Interest Group (SIG) at ISMB to continue exploring the bottlenecks and emerging solutions for obtaining biological insights through large-scale comparative analysis of metagenomic datasets. The M3 SIG included invited and selected talks and a panel discussion at the end of the day involving the plenary speakers. Further information about the GSC and its range of activities can be found at http://gensc.org. Information about the newly established BioSharing effort can be found at http://biosharing.org/.     

Gene technologies in Pinus radiata and Picea abies: tools for conifer biotechnology in the 21st century

Conifer biotechnology is reviewed, covering transformation, molecular analysis of transgenic material, functional analysis of genes and promoters in conifers and model systems, and the development of early screening technologies for new introduced traits. Technologies and concepts that promise to be of significant advantage to conifer biotechnology in the new century are discussed.