Analysis of Cell Signaling Perturbations in Response to Chronic Localized Infections

The tissue-level response to pathogens involves an intricate series of signal transduction events, influenced by immune and healing mediators that alert the host to danger and eliminate the infection. Disruptions to normal signaling events can compromise the host’s ability to respond and lead to the development of chronic infections that cannot be resolved without clinical intervention. Prolonged inflammation due to chronic infection can damage tissues and compromise healing processes, thus, the interactions of immune and healing mediators in signaling cascades are intimately linked to tissue health outcomes. Studying signaling networks relevant to these responses provided a more thorough understanding of localized tissue health to identify the drivers of disruptions to signaling cascades, and this knowledge can lead to the development of improved diagnostic and therapeutic biomarkers to combat chronic infections. The work presented here focused on elucidating the relationships between immune and wound healing factors in an in vivo rodent model and a clinical cohort to understand the tissue-level responses to chronic inflammation and infection. Specifically, extracellular inflammatory immune responses (i.e., cytokines and chemokines) related to intracellular signaling (i.e., phosphorylation of proteins) were investigated to identify alterations in native responses compared to those provoked by chronic inflammation and infection. Reponses in native tissues were compared to tissues with inflammatory and infectious stimuli to test if levels of immune related cytokines were elevated in response to chronic joint infections. Wound healing phosphoproteins were also included to look for shifts in wound healing-related processes across groups. Traditional statistical approaches and network analysis were used to dissect these complex biological datasets and identified drivers of network disruptions in response to inflammation and infection. The spatial analysis suggested that changes in biological responses were related to proximity to inflammation and infection, and the degree of response differed across spatial gradients, which demonstrated the ability for these chronic insults to affect disparate tissues in a clinically-relevant manner. The objective of this research and future related research is to facilitate new clinical strategies to combat chronic infection, and monitoring alterations to cell signaling pathways in this work highlighted the value of using network analysis to approach biological interrogation of signal disruptions related to these insults

The effect of electrically induced strength training on triceps brachii strength

Twenty-seven apparently healthy females volunteered for the study to compare the effects of neuromuscular electrical stimulation (NMES) (N = 7), traditional isotonic weight training (N = 9) and NMES combined with isotonic weight training (N = 11) on triceps branchii strength. Strength was measured isotonically (1-RM) and isometrically (MVIC). The Weight and Weight/NMES groups performed 3 sets of 8 to 10 reps at 60% of 1-RM, 3 times per week. The NMES group received NMES 3 times per week. All groups were pre- and post-tested to determine 1-RM and Mvic Strength was also tested after four weeks, in order to ensure the Weight and NMES/Weight groups were training at a minimum of 60% of 1-RM. Two mixed factor design ANOVAs (Group {dollar}\times{dollar} Time {dollar}\times{dollar} Arm) found no significant difference between groups at pretest (.05). All three groups demonstrated significant increases in strength, both isometrically and isotonically. A statistical difference was not found between the three training methods and their effect on isotonic strength. However, the Weight and the NMES/Weight group demonstrated significantly greater gains in isotonic strength than the NMES group. The NMES/Weight group demonstrated the largest mean increase in strength, followed by the Weight group and the NMES group, respectively. The results indicated that groups NMES/Weight and Weight were equivalent. Therefore, the combination of NMES and isotonic weight training has no greater effect on strength than traditional isotonic training

Urban Land-based Healing: A Northern Intervention Strategy

Urban Indigenous populations face significant health and social disparities across Canada. With high rates of homelessness and substance abuse, there are often few options for urban Indigenous Peoples to access land-based healing programs despite the increasingly known and appreciated benefits. In May 2018, the first urban land-based healing camp opened in Yellowknife, Northwest Territories, Canada, one of the first to our knowledge in Canada or the United States. This camp may serve as a potential model for an Indigenous-led and Indigenous-based healing camp in an urban setting. We seek to present preliminary outcome data from the healing camp in a setting with a high-risk population struggling with substance use and homelessness. Reflections are presented for challenging logistical and methodological considerations for applications elsewhere. This northern based effort affords us ample opportunity for expanding the existing knowledge base for land-based healing applied to an urban Indigenous high-risk setting

Patronage Politics and Clientelism in Housing Welfare: The Case of Gawad Kalinga (GK) Villages in Parañaque City, The Philippines

Patronage politics has become a defining charac-teristic of the Philippine political landscape. Clientelism, a form of patronage, is often studied as disadvantageous in governance and democratic consolidation. While the patron-client framework remains the most influential among schools of thought that explain Philippine politics, transforma-tions in a clientelist exchange are evident given changes in political, cultural and economic settings. Using this frame of new clientelism, we look at and revisit the structure of patronage in the provision of housing welfare in the Philippines, focusing now on the roles of three important actors— the nongov-ernmental organization, the state through the local government and the recipients or beneficiaries— in an urban setting, thus deviating from the traditional conception of patronage and clientelist politics. This relationship of clientelist exchange is presented in our Accomplice-Principal-Accessory (APA) model ofclientelism, with the local government unit of Parañaque City as accomplice, the Gawad Kalinga (GK) as the principal agent, and the recipients or beneficiaries as accessories in the provision of hous-ing welfare

Localized cytokine responses to total knee arthroplasty and total knee revision complications

Background The study of localized immune-related factors has proven beneficial for a variety of conditions, and one area of interest in the field of orthopaedics is the impact of implants and localized infections on immune response. Several cytokines have shown increased systemic concentrations (in serum/plasma) in response to implants and infection, but tissue-level cytokines have not been investigated as thoroughly. Methods This exploratory study investigated tissue-level cytokines in a cohort of patients (N = 17) in response to total knee arthroplasty and total knee revision to better understand the immune response to implants and localized infection (e.g., prosthetic joint infection). The overall goal of this study was to provide insight into the localized cytokine response of tissues and identify tissue-level markers specific to inflammation caused by implants vs. inflammation caused by infection. Tissues were collected across several anatomical locations and assayed with a panel of 20 human inflammatory cytokines to understand spatial differences in cytokine levels. Results In this study, six cytokines were elevated in implanted joints, as compared to native joints: IL-10, IL-12p70, IL-13, IL-17A, IL-4, and TNF-α (p \u3c 0.05). Seven cytokines showed infection-dependent increases in localized tissues: IL-1α, IL-1β, IL-6, IL-8, MCP-1, MIP-1α, and MIP-1β (p \u3c 0.05). Conclusions This study demonstrated that differences exist in tissue-level cytokines in response to presence of implant, and some cytokines were specifically elevated for infection; these responses may be informative of overall tissue health. These results highlight the utility of investigating localized cytokine concentrations to offer novel insights for total knee arthroplasty and total knee revision procedures, as well as their complications. Ultimately, this information could provide additional, quantitative measurements of tissue to aid clinical decision making and patient treatment options

Indigenous Natural or First Law in planetary health

Indigenous Peoples associate their own laws with the laws of the natural world, which are formally known as or translated as Natural or First Law. These laws come from the Creator and the Land through our ancestral stories and therefore, they are sacred. All aspects of life and existence depend on living and following these natural First Laws. Since colonization, Indigenous Peoples’ Natural Laws have been forcibly replaced by modern-day laws that do not take into account the sacred relationship between the Earth and all of her inhabitants. The force of societies who live outside of Natural Law has ensured the modern-day consequences of not living in balance with nature. Pandemics and global environmental change, including climate change, are all consequences of not following the Natural Laws that are encapsulated by the interconnected nature of the universe. Here we discuss Natural Law from an Indigenous paradigm and worldview which carries implications for planetary health and wider environmental movements around the globe

High prevalence of HIV-1 drug resistance among patients on first-line antiretroviral treatment in Lomé, Togo

<p>Abstract</p> <p>Background</p> <p>With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. Our objective is to evaluate the virological failure and genotypic drug-resistance mutations in patients receiving first-line highly active antiretroviral therapy (HAART) in routine clinics that use the World Health Organization public health approach to monitor antiretroviral treatment (ART) in Togo.</p> <p>Methods</p> <p>Patients on HAART for one year (10-14 months) were enrolled between April and October 2008 at three sites in Lomé, the capital city of Togo. Plasma viral load was measured with the NucliSENS EasyQ HIV-1 assay (Biomérieux, Lyon, France) and/or a Generic viral load assay (Biocentric, Bandol, France). Genotypic drug-resistance testing was performed with an inhouse assay on plasma samples from patients with viral loads of more than 1000 copies/ml. CD4 cell counts and demographic data were also obtained from medical records.</p> <p>Results</p> <p>A total of 188 patients receiving first-line antiretroviral treatment were enrolled, and 58 (30.8%) of them experienced virologic failure. Drug-resistance mutations were present in 46 patients, corresponding to 24.5% of all patients enrolled in the study. All 46 patients were resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTIs): of these, 12 were resistant only to NNRTIs, 25 to NNRTIs and lamivudine/emtricitabine, and eight to all three drugs of their ARV regimes. Importantly, eight patients were already predicted to be resistant to etravirine, the new NNRTI, and three patients harboured the K65R mutation, inducing major resistance to tenofovir.</p> <p>Conclusions</p> <p>In Togo, efforts to provide access to ARV therapy for infected persons have increased since 2003, and scaling up of ART started in 2007. The high number of resistant strains observed in Togo shows clearly that the emergence of HIV drug resistance is of increasing concern in countries where ART is now widely used, and can compromise the long-term success of first- and second-line ART.</p

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection

As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations

Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review

Diseases diagnosed in adulthood may have antecedents throughout (including prenatal) life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes. This systematic literature review explores MR methods used to perform lifecourse investigations and reviews previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted searches in PubMed, Embase, Medline and MedRXiv databases. Thirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures in the interpretation of "standard" MR techniques, five presented methods for repeat measures of the same exposure, and four described methodological approaches to handling multigenerational exposures. A further 127 studies presented the results of an applied research question. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. The remaining mostly estimated maternal effects. There is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The underlying assumptions require careful consideration and the interpretation of results rely on select conditions. Whilst we do not advocate for a particular strategy, we encourage practitioners to make informed decisions on how to approach a research question in this field with a solid understanding of the limitations present and how these may be affected by the research question, modelling approach, instrument selection, and data availability

Effect of HIV-infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract

This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP)