TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

Significance Alzheimer’s disease (AD) is the most common cause of dementia and is a major public health problem for which there is currently no disease-modifying treatment. There is an urgent need for greater understanding of the molecular mechanisms underlying neurodegeneration in patients to create better therapeutic options. Recently, genetic studies uncovered novel AD risk variants in the microglial receptor, triggering receptor expressed on myeloid cells 2 (TREM2). Previous studies suggested that loss of TREM2 function worsens amyloid-β (Aβ) plaque-related toxicity. In contrast, we observe TREM2 deficiency mitigates neuroinflammation and protects against brain atrophy in the context of tau pathology. These findings indicate dual roles for TREM2 and microglia in the context of amyloid versus tau pathology, which are important to consider for potential treatments targeting TREM2.</jats:p

Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer.

BACKGROUND AND AIM: During prostate development, mesenchymal-epithelial interactions regulate organ growth and differentiation. In adult prostate, stromal-epithelial interactions are important for tissue homeostasis and also play a significant role in prostate cancer. In this study we have identified molecules that show a mesenchymal expression pattern in the developing prostate, and one of these showed reduced expression in prostate cancer stroma. METHODOLOGY AND PRINCIPAL FINDINGS: Five candidate molecules identified by transcript profiling of developmental prostate mesenchyme were selected using a wholemount in situ hybridisation screen and studied Decorin (Dcn), Semaphorin6D (Sema6D), SPARC/Osteonectin (SPARC), Sprouty1 (Spry-1) and Tsukushi (Tsku). Expression in rat tissues was evaluated using wholemount in situ hybridisation (postnatal day (P) 0.5) and immunohistochemistry (embryonic day (E) E17.5, E19.5; P0.5; P6; 28 & adult). Four candidates (Decorin, SPARC, Spry-1, Tsukushi) were immunolocalised in human foetal prostate (weeks 14, 16, 19) and expression of Decorin was evaluated on a human prostate cancer tissue microarray. In embryonic and perinatal rats Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi were expressed with varying distribution patterns throughout the mesenchyme at E17.5, E19.5, P0.5 and P6.5. In P28 and adult prostates there was either a decrease in the expression (Semaphorin6D) or a switch to epithelial expression of SPARC, and Spry-1, whereas Decorin and Tsukushi were specific to mesenchyme/stroma at all ages. Expression of Decorin, SPARC, Spry-1 and Tsukushi in human foetal prostates paralleled that in rat. Decorin showed mesenchymal and stromal-specific expression at all ages and was further examined in prostate cancer, where stromal expression was significantly reduced compared with non-malignant prostate. CONCLUSION AND SIGNIFICANCE: We describe the spatio-temporal expression of Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi in developing prostate and observed similar mesenchymal expression patterns in rat and human. Additionally, Decorin showed reduced expression in prostate cancer stroma compared to non-malignant prostate stroma

Stakeholder narratives on trypanosomiasis, their effect on policy and the scope for One Health

Background This paper explores the framings of trypanosomiasis, a widespread and potentially fatal zoonotic disease transmitted by tsetse flies (Glossina species) affecting both humans and livestock. This is a country case study focusing on the political economy of knowledge in Zambia. It is a pertinent time to examine this issue as human population growth and other factors have led to migration into tsetse-inhabited areas with little historical influence from livestock. Disease transmission in new human-wildlife interfaces such as these is a greater risk, and opinions on the best way to manage this are deeply divided. Methods A qualitative case study method was used to examine the narratives on trypanosomiasis in the Zambian policy context through a series of key informant interviews. Interviewees included key actors from international organisations, research organisations and local activists from a variety of perspectives acknowledging the need to explore the relationships between the human, animal and environmental sectors. Principal Findings Diverse framings are held by key actors looking from, variously, the perspectives of wildlife and environmental protection, agricultural development, poverty alleviation, and veterinary and public health. From these viewpoints, four narratives about trypanosomiasis policy were identified, focused around four different beliefs: that trypanosomiasis is protecting the environment, is causing poverty, is not a major problem, and finally, that it is a Zambian rather than international issue to contend with. Within these narratives there are also conflicting views on the best control methods to use and different reasoning behind the pathways of response. These are based on apparently incompatible priorities of people, land, animals, the economy and the environment. The extent to which a One Health approach has been embraced and the potential usefulness of this as a way of reconciling the aims of these framings and narratives is considered throughout the paper. Conclusions/Significance While there has historically been a lack of One Health working in this context, the complex, interacting factors that impact the disease show the need for cross-sector, interdisciplinary decision making to stop rival narratives leading to competing actions. Additional recommendations include implementing: surveillance to assess under-reporting of disease and consequential under-estimation of disease risk; evidence-based decision making; increased and structurally managed funding across countries; and focus on interactions between disease drivers, disease incidence at the community level, and poverty and equity impacts

Assessment of animal African trypanosomiasis (AAT) vulnerability in cattle-owning communities of sub-Saharan Africa

Background: Animal African trypanosomiasis (AAT) is one of the biggest constraints to livestock production and a threat to food security in sub-Saharan Africa. In order to optimise the allocation of resources for AAT control, decision makers need to target geographic areas where control programmes are most likely to be successful and sustainable and select control methods that will maximise the benefits obtained from resources invested. Methods: The overall approach to classifying cattle-owning communities in terms of AAT vulnerability was based on the selection of key variables collected through field surveys in five sub-Saharan Africa countries followed by a formal Multiple Correspondence Analysis (MCA) to identify factors explaining the variations between areas. To categorise the communities in terms of AAT vulnerability profiles, Hierarchical Cluster Analysis (HCA) was performed. Results: Three clusters of community vulnerability profiles were identified based on farmers’ beliefs with respect to trypanosomiasis control within the five countries studied. Cluster 1 communities, mainly identified in Cameroon, reported constant AAT burden, had large trypanosensitive (average herd size = 57) communal grazing cattle herds. Livestock (cattle and small ruminants) were reportedly the primary source of income in the majority of these cattle-owning households (87.0 %). Cluster 2 communities identified mainly in Burkina Faso and Zambia, with some Ethiopian communities had moderate herd sizes (average = 16) and some trypanotolerant breeds (31.7 %) practicing communal grazing. In these communities there were some concerns regarding the development of trypanocide resistance. Crops were the primary income source while communities in this cluster incurred some financial losses due to diminished draft power. The third cluster contained mainly Ugandan and Ethiopian communities which were mixed farmers with smaller herd sizes (average = 8). The costs spent diagnosing and treating AAT were moderate here. Conclusions: Understanding how cattle-owners are affected by AAT and their efforts to manage the disease is critical to the design of suitable locally-adapted control programmes. It is expected that the results could inform priority setting and the development of tailored recommendations for AAT control strategies

A Geographically-Restricted but Prevalent Mycobacterium tuberculosis Strain Identified in the West Midlands Region of the UK between 1995 and 2008

Background: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Methodology/Principal Findings: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95% CI = 4.56-17.87, p 65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95% CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.Conclusions/Significance: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain

Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Quantitative and systematic review of the literature on the consequences of chronic maternal opioid use during pregnancy on neurobehavioral function of children was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched Cinahl, EMBASE, PsychINFO and MEDLINE between the periods of January 1995 to January 2012.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; There were only 5 studies out of the 200 identified that quantitatively reported on neurobehavioral function of children after maternal opioid use during pregnancy. All 5 were case control studies with the number of exposed subjects within the studies ranging from 33–143 and 45–85 for the controls. This meta-analysis showed no significant impairments, at a non-conservative significance level of p &#60; 0.05, for cognitive, psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children. However, all domains suggested a trend to poor outcomes in infants/children of opioid using mothers. The magnitude of all possible effects was small according to Cohen’s benchmark criteria.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers, although in all domains there was a trend to poorer outcomes. The findings of this review are limited by the small number of studies analysed, the heterogenous populations and small numbers within the individual studies. Longitudinal studies are needed to determine if any neuropsychological impairments appear after the age of 5 years and to help investigate further the role of environmental risk factors on the effect of ‘core’ phenotypes

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation

Pain after disease/damage of the nervous system is predominantly treated with opioids, but without exploration of the long-term consequences. We demonstrate that a short course of morphine after nerve injury doubles the duration of neuropathic pain. Using genetic and pharmacological interventions, and innovative Designer Receptor Exclusively Activated by Designer Drugs disruption of microglia reactivity, we demonstrate that opioid-prolonged neuropathic pain arises from spinal microglia and NOD-like receptor protein 3 inflammasome formation/activation. Inhibiting these processes permanently resets amplified pain to basal levels, an effect not previously reported. These data support the “two-hit hypothesis” of amplification of microglial activation—nerve injury being the first “hit,” morphine the second. The implications of such potent microglial “priming” has fundamental clinical implications for pain and may extend to many chronic neurological disorders

The Vehicle, Fall 1985

Vol. 27, No. 1 Table of Contents Satchel AssMichael D. Smithpage 3 PhotoDoug Andersonpage 7 CounselingChristy Dunphypage 8 Grave SiteJay D. Fiskpage 8 Sight-Seeing Outside PhoenixBob Zordanipage 9 PerformanceDan Von Holtenpage 10 NightmareKandy Bellpage 10 Photo (The Loft)Lawrence McGownpage 11 LaboringJanet Gracepage 12 Blood DonorDan Von Holtenpage 13 Photo (Pier)Lawrence McGownpage 14 ExamplesChristopher Albinpage 14 Three PoemsPatrick Peterspage 15 Sometimes I Dream in Cotton CandyKathy Graypage 16 One Day While BoatingF. Link Rapierpage 17 DepartureBob Zordanipage 17 140 Print That\u27s Life Peter Dowlingpage 18 Photo (Around the Bend)Mike Freckerpage 20 Light ConversationDan Hintzpage 22 She Waits For the WorldJim Harrispage 22 HoneyKathy Graypage 23 Photo AlbumPatrick Peterspage 24 Photo (Stairs)Lawrence McGownpage 25 Fallen From Grace to SaturdayF. Link Rapierpage 26 Post MortemF. Link Rapierpage 27 ConfessionJohn Kayserpage 27 Child\u27s PlayChristopher Albinpage 27 Seeking A Friend\u27s Advice on DietingKathy Graypage 28 PhotoDoug Andersonpage 28 She Came Back to MeJim Harrispage 29 Farm BoyDiana Winsonpage 30 DilemmaJanet Wilhelmpage 31 In a Rock or StoneRichard Donnellypage 32 In November He Came To MeJean Kover Chandlerpage 33 EndingChristy Dunphypage 34 The Honor GradEddie Simpsonpage 35 Photo (Thirst)Mike Freckerpage 40https://thekeep.eiu.edu/vehicle/1046/thumbnail.jp