Behavioural and morphological evidence for the involvement of glial cell activation in delta opioid receptor function: implications for the development of opioid tolerance

Previous studies have demonstrated that prolonged morphine treatment in vivo induces the translocation of delta opioid receptors (δORs) from intracellular compartments to neuronal plasma membranes and this trafficking event is correlated with an increased functional competence of the receptor. The mechanism underlying this phenomenon is unknown; however chronic morphine treatment has been shown to involve the activation and hypertrophy of spinal glial cells. In the present study we have examined whether activated glia may be associated with the enhanced δOR-mediated antinociception observed following prolonged morphine treatment. Accordingly, animals were treated with morphine with or without concomitant administration of propentofylline, an inhibitor of glial activation that was previously shown to block the development of morphine antinociceptive tolerance. The morphine regimen previously demonstrated to initiate δOR trafficking induced the activation of both astrocytes and microglia in the dorsal spinal cord as indicated by a significant increase in cell volume and cell surface area. Consistent with previous data, morphine-treated rats displayed a significant augmentation in δOR-mediated antinociception. Concomitant spinal administration of propentofylline with morphine significantly attenuated the spinal immune response as well as the morphine-induced enhancement of δOR-mediated effects. These results complement previous reports that glial activation contributes to a state of opioid analgesic tolerance, and also suggest that neuro-glial communication is likely responsible in part for the altered functional competence in δOR-mediated effects following morphine treatment

Secular trends in pediatric antiretroviral treatment programs in rural and urban Zambia: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Since 2003 pediatric antiretroviral treatment (ART) programs have scaled-up in sub-Saharan Africa and should be evaluated to assess progress and identify areas for improvement. We evaluated secular trends in the characteristics and treatment outcomes of children in three pediatric ART clinics in urban and rural areas in Zambia.</p> <p>Methods</p> <p>Routinely collected data were analyzed from three ART programs in rural (Macha and Mukinge) and urban (Lusaka) Zambia between program implementation and July 2008. Data were obtained from electronic medical record systems and medical record abstraction, and were categorized by year of program implementation. Characteristics of all HIV-infected and exposed children enrolled in the programs and all children initiating treatment were compared by year of implementation.</p> <p>Results</p> <p>Age decreased and immunologic characteristics improved in all groups over time in both urban and rural clinics, with greater improvement observed in the rural clinics. Among children both eligible and ineligible for ART at clinic enrollment, the majority started treatment within a year. A high proportion of children, particularly those ineligible for ART at clinic enrollment, were lost to follow-up prior to initiating ART. Among children initiating ART, clinical and immunologic outcomes after six months of treatment improved in both urban and rural clinics. In the urban clinics, mortality after six months of treatment declined with program duration, and in the rural clinics, the proportion of children defaulting by six months increased with program duration.</p> <p>Conclusions</p> <p>Treatment programs are showing signs of progress in the care of HIV-infected children, particularly in the rural clinics where scale-up increased rapidly over the first three years of program implementation. However, continued efforts to optimize care are needed as many children continue to enroll in ART programs at a late stage of disease and thus are not receiving the full benefits of treatment.</p

cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.

Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites

Towards an ecology of participation: Process philosophy and co-creation of higher education curricula

This article brings together the authors' previous work on co-created curricula (Bovill et al., 2011; Bovill, 2013a; Bovill, 2014) and on partnership and ethics (Taylor and Robinson, 2014; Taylor, 2015), to develop the concept of co-created curricula as an ecology of participation. In doing so, it deploys Alfred North Whitehead’s process philosophy to formulate a new way of considering co-creation in the curriculum and co-creation of the curriculum in higher education. Two empirical examples are used to illuminate what such an approach offers. From this, we outline three dimensions of an ecology of participation: a process of becoming which recasts subjectivity; acting well in relation which enacts concern; and an orientation to harmony in which difference in equality is valued. The contribution of the article is twofold: first, the concept of an ecology of participation takes forward current thinking on higher education curricula and partnership ethics; second, its use of process philosophy provides a new lens to consider co-creation in the curriculum and co-creation of the curriculum

Linkage to HIV Care and Antiretroviral Therapy in Cape Town, South Africa

BACKGROUND: Antiretroviral therapy (ART) has been scaled-up rapidly in Africa. Programme reports typically focus on loss to follow-up and mortality among patients receiving ART. However, little is known about linkage and retention in care of individuals prior to starting ART. METHODOLOGY: Data on adult residents from a periurban community in Cape Town were collected at a primary care clinic and hospital. HIV testing registers, CD4 count results provided by the National Health Laboratory System and ART registers were linked. A random sample (n = 885) was drawn from adults testing HIV positive through antenatal care, sexual transmitted disease and voluntary testing and counseling services between January 2004 and March 2009. All adults (n = 103) testing HIV positive through TB services during the same time period were also included in the study. Linkage to HIV care was defined as attending for a CD4 count measurement within 6 months of HIV diagnosis. Linkage to ART care was defined as initiating ART within 6 months of HIV diagnosis in individuals with a CD4 count ≤200 cells/µl taken within 6 months of HIV diagnosis. FINDINGS: Only 62.6% of individuals attended for a CD4 count measurement within 6 months of testing HIV positive. Individuals testing through sexually transmitted infection services had the best (84.1%) and individuals testing on their own initiative (53.5%) the worst linkage to HIV care. One third of individuals with timely CD4 counts were eligible for ART and 66.7% of those were successfully linked to ART care. Linkage to ART care was highest among antenatal care clients. Among individuals not yet eligible for ART only 46.3% had a repeat CD4 count. Linkage to HIV care improved in patients tested in more recent calendar period. CONCLUSION: Linkage to HIV and ART care was low in this poor peri-urban community despite free services available within close proximity. More efforts are needed to link VCT scale-up to subsequent care

Establishment of an ES Cell-Derived Murine Megakaryocytic Cell Line, MKD1, with Features of Primary Megakaryocyte Progenitors

Because of the scarcity of megakaryocytes in hematopoietic tissues, studying megakaryopoiesis heavily relies on the availability of appropriate cellular models. Here, we report the establishment of a new mouse embryonic stem (ES) cell-derived megakaryocytic cell line, MKD1. The cells are factor-dependent, their cell surface immunophenotype and gene expression profile closely resemble that of primary megakaryocyte progenitors (MkPs) and they further differentiate along the megakaryocyte lineage upon valproic acid treatment. At a functional level, we show that ablation of SCL expression, a transcription factor critical for MkP maturation, leads to gene expression alterations similar to that observed in primary, Scl-excised MkPs. Moreover, the cell line is amenable to biochemical and transcriptional analyses, as we report for GpVI, a direct target of SCL. Thus, the MKD1 cell line offers a pertinent experimental model to study the cellular and molecular mechanisms underlying MkP biology and more broadly megakaryopoiesis

Improving the development, monitoring and reporting of stroke rehabilitation research: consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable (SRRR)

Recent reviews have demonstrated that the quality of stroke rehabilitation research has continued to improve over the last four decades but despite this progress there are still many barriers in moving the field forward. Rigorous development, monitoring and complete reporting of interventions in stroke trials are essential in providing rehabilitation evidence that is robust, meaningful and implementable. An international partnership of stroke rehabilitation experts committed to develop consensus-based core recommendations with a remit of addressing the issues identified as limiting stroke rehabilitation research in the areas of developing, monitoring and reporting stroke rehabilitation interventions. Work exploring each of the three areas took place via multiple teleconferences and a two-day meeting in Philadelphia in May 2016. A total of 15 recommendations were made. To validate the need for the recommendations the group reviewed all stroke rehabilitation trials published in 2015 (n=182 papers). Our review highlighted that the majority of publications did not clearly describe how interventions were developed or monitored during the trial. In particular, under-reporting of the theoretical rationale for the intervention and the components of the intervention calls into question many interventions that have been evaluated for efficacy. More trials were found to have addressed the reporting of interventions recommendations than those related to development or monitoring. Nonetheless the majority of reporting recommendations were still not adequately described. To progress the field of stroke rehabilitation research and to ensure stroke patients receive optimal evidence based clinical care we urge the research community to endorse and adopt our recommendations

Dichotomous factor analysis of symptoms reported by UK and US veterans of the 1991 Gulf War

BACKGROUND: Factor analysis is one of the most used statistical techniques to analyze the inter-relationships among symptoms reported by Gulf War veterans. The objective of this study was to apply factor analyses to binary symptom data from the UK study of Gulf War illness and the US Air Force study of Gulf War veterans, and to compare the symptom domains derived from the distinct samples. METHODS: UK veterans of the 1991 Gulf War (n = 3,454), individuals deployed to Bosnia on U.N. peacekeeping operations (n = 1,979) and Gulf War-era servicemen (n = 2,577) who were not deployed to the Gulf were surveyed in 1997–1998, and US 1991 Gulf War veterans from four Air Force units (n = 1,163) were surveyed in 1995 to collect health characteristics including symptoms. Each sample was randomly split in half for exploratory and confirmatory dichotomous factor analyses with promax oblique rotation. RESULTS: Four correlated factors were identified in each of the samples. Three factors (Respiratory, Mood-Cognition, Peripheral Nervous) overlapped considerably across the UK cohorts. The Gastrointestinal/Urogenital factor in the UK Gulf cohort was noticeably different from the Gastrointestinal factor identified from the Bosnia and Era cohorts. Symptoms from Gulf War UK and U.S cohorts yielded similar Gastrointestinal, Respiratory and Mood-Cognition factors, despite differences in symptom inventories between the two surveys. A Musculoskeletal factor was only elicited from the US Gulf sample. CONCLUSION: Findings of this report are consistent with those from other factor analysis studies that identified similar symptom dimensions between Gulf and non-Gulf War veterans, except that the Gastrointestinal factor in Gulf veterans included other symptom types. Correlations among factors raise the question as to whether there is a general illness, even if not unique to Gulf veterans, representing the common pathway underlying the identified factors. Hierarchical factor analysis models may be useful to address this issue

Conversion of t11t13 CLA into c9t11 CLA in Caco-2 Cells and Inhibition by Sterculic Oil

Background : Conjugated linoleic acids (CLA), and principally c9t11 CLA, are suspected to have numerous preventive properties regarding non-infectious pathologies such as inflammatory diseases, atherosclerosis and several types of cancer. C9t11 CLA is produced in the rumen during biohydrogenation of linoleic acid, but can also be synthesized in mammalian tissues from trans-vaccenic acid (C18:1 t11) through the action of delta-9 desaturase (D9D). For several years, it is also known that c9t11 CLA can be synthesized from conjugated linolenic acids (CLnA), i.e. c9t11c13 CLnA and c9t11t13 CLnA. This study aimed at investigating to which extent and by which route c9t11 CLA can be produced from another isomer of CLA, the t11t13 CLA that is structurally very similar to c9t11t13 CLnA, in Caco-2 cells