Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens ...are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4(+) T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-alpha secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-alpha after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging.
1 Department of Cell Biology and 2 Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta
Submitted 2 May 2008
; accepted in final form 11 September 2008
The actin ...cytoskeleton regulates exocytosis in all secretory cells. In neutrophils, Rac2 GTPase has been shown to control primary (azurophilic) granule exocytosis. In this report, we propose that Rac2 is required for actin cytoskeletal remodeling to promote primary granule exocytosis. Treatment of neutrophils with low doses ( 10 µM) of the actin-depolymerizing drugs latrunculin B (Lat B) or cytochalasin B (CB) enhanced both formyl peptide receptor- and Ca 2+ ionophore-stimulated exocytosis. Higher concentrations of CB or Lat B, or stabilization of F-actin with jasplakinolide (JP), inhibited primary granule exocytosis measured as myeloperoxidase release but did not affect secondary granule exocytosis determined by lactoferrin release. These results suggest an obligatory role for F-actin disassembly before primary granule exocytosis. However, lysates from secretagogue-stimulated neutrophils showed enhanced actin polymerization activity in vitro. Microscopic analysis showed that resting neutrophils contain significant cortical F-actin, which was redistributed to sites of primary granule translocation when stimulated. Exocytosis and actin remodeling was highly polarized when cells were primed with CB; however, polarization was reduced by Lat B preincubation, and both polarization and exocytosis were blocked when F-actin was stabilized with JP. Treatment of cells with the small molecule Rac inhibitor NSC23766 also inhibited actin remodeling and primary granule exocytosis induced by Lat B/fMLF or CB/fMLF, but not by Ca 2+ ionophore. Therefore, we propose a role for F-actin depolymerization at the cell cortex coupled with Rac-dependent F-actin polymerization in the cell cytoplasm to promote primary granule exocytosis.
Rac guanosine triphosphatase; latrunculin; cytochalasin; jasplakinolide; NSC23766
Address for reprint requests and other correspondence: G. Eitzen, Dept. of Cell Biology, Univ. of Alberta, Edmonton, Alberta, Canada T6G 2H7 (e-mail: gary.eitzen{at}ualberta.ca )
Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell ...response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4(+)Foxp3(-) T cell populations, skin CD4(+)Foxp3(+) T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4(+) T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4(+) T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses.
The Spitzer Adaptation of the Red-sequence Cluster Survey (SpARCS) is a deep z'-band imaging survey covering the Spitzer Wide-Area Infrared Extragalactic Survey (SWIRE) Legacy fields designed to ...create the first large homogeneously selected sample of massive clusters at z > 1 using an infrared adaptation of the cluster red-sequence method. We present an overview of the northern component of the survey which has been observed with Canada-France-Hawaii Telescope (CFHT)/MegaCam and covers 28.3 deg2. The southern component of the survey was observed with Cerro Tololo Inter-American Observatory (CTIO)/MOSAICII, covers 13.6 deg2, and is summarized in a companion paper by Wilson et al. We also present spectroscopic confirmation of two rich cluster candidates at z ~ 1.2. Based on Nod-and-Shuffle spectroscopy from GMOS-N on Gemini, there are 17 and 28 confirmed cluster members in SpARCS J163435+402151 and SpARCS J163852+403843 which have spectroscopic redshifts of 1.1798 and 1.1963, respectively. The clusters have velocity dispersions of 490 - 140 km s-1 and 650 - 160 km s-1, respectively, which imply masses (M 200) of (1.0 - 0.9) X 1014 M and (2.4 - 1.8) X 1014 M . Confirmation of these candidates as bonafide massive clusters demonstrates that two-filter imaging is an effective, yet observationally efficient, method for selecting clusters at z > 1.
Summary
Chapter 1: How Australia improved health equity through action on the social determinants of health
Do not think that the social determinants of health equity are old hat. In reality, ...Australia is very far away from addressing the societal level drivers of health inequity. There is little progressive policy that touches on the conditions of daily life that matter for health, and action to redress inequities in power, money and resources is almost non‐existent.
In this chapter we ask you to pause this reality and come on a fantastic journey where we envisage how COVID‐19 was a great disruptor and accelerator of positive progressive action. We offer glimmers of what life could be like if there was committed and real policy action on the social determinants of health equity. It is vital that the health sector assists in convening the multisectoral stakeholders necessary to turn this fantasy into reality.
Chapter 2: Aboriginal and Torres Strait Islander connection to culture: building stronger individual and collective wellbeing
Aboriginal and Torres Strait Islander peoples have long maintained that culture (ie, practising, maintaining and reclaiming it) is vital to good health and wellbeing. However, this knowledge and understanding has been dismissed or described as anecdotal or intangible by Western research methods and science. As a result, Aboriginal and Torres Strait Islander culture is a poorly acknowledged determinant of health and wellbeing, despite its significant role in shaping individuals, communities and societies.
By extension, the cultural determinants of health have been poorly defined until recently. However, an increasing amount of scientific evidence supports what Aboriginal and Torres Strait Islander people have always said — that strong culture plays a significant and positive role in improved health and wellbeing.
Owing to known gaps in knowledge, we aim to define the cultural determinants of health and describe their relationship with the social determinants of health, to provide a full understanding of Aboriginal and Torres Strait Islander wellbeing. We provide examples of evidence on cultural determinants of health and links to improved Aboriginal and Torres Strait Islander health and wellbeing.
We also discuss future research directions that will enable a deeper understanding of the cultural determinants of health for Aboriginal and Torres Strait Islander people.
Chapter 3: Physical determinants of health: healthy, liveable and sustainable communities
Good city planning is essential for protecting and improving human and planetary health. Until recently, however, collaboration between city planners and the public health sector has languished.
We review the evidence on the health benefits of good city planning and propose an agenda for public health advocacy relating to health-promoting city planning for all by 2030.
Over the next 10 years, there is an urgent need for public health leaders to collaborate with city planners — to advocate for evidence-informed policy, and to evaluate the health effects of city planning efforts. Importantly, we need integrated planning across and between all levels of government and sectors, to create healthy, liveable and sustainable cities for all.
Chapter 4: Health promotion in the Anthropocene: the ecological determinants of health
Human health is inextricably linked to the health of the natural environment. In this chapter, we focus on ecological determinants of health, including the urgent and critical threats to the natural environment, and opportunities for health promotion arising from the human health co-benefits of actions to protect the health of the planet.
We characterise ecological determinants in the Anthropocene and provide a sobering snapshot of planetary health science, particularly the momentous climate change health impacts in Australia. We highlight Australia’s position as a major fossil fuel producer and exporter, and a country lacking cohesive and timely emissions reduction policy.
We offer a roadmap for action, with four priority directions, and point to a scaffold of guiding approaches — planetary health, Indigenous people’s knowledge systems, ecological economics, health co-benefits and climate-resilient development. Our situation requires a paradigm shift, and this demands a recalibration of health promotion education, research and practice in Australia over the coming decade.
Chapter 5: Disrupting the commercial determinants of health
Our vision for 2030 is an Australian economy that promotes optimal human and planetary health for current and future generations. To achieve this, current patterns of corporate practice and consumption of harmful commodities and services need to change.
In this chapter, we suggest ways forward for Australia, focusing on pragmatic actions that can be taken now to redress the power imbalances between corporations and Australian governments and citizens.
We begin by exploring how the terms of health policy making must change to protect it from conflicted commercial interests. We also examine how marketing unhealthy products and services can be more effectively regulated, and how healthier business practices can be incentivised.
Finally, we make recommendations on how various public health stakeholders can hold corporations to account, to ensure that people come before profits in a healthy and prosperous future Australia.
Chapter 6: Digital determinants of health: the digital transformation
We live in an age of rapid and exponential technological change. Extraordinary digital advancements and the fusion of technologies, such as artificial intelligence, robotics, the Internet of Things and quantum computing constitute what is often referred to as the digital revolution or the Fourth Industrial Revolution (Industry 4.0).
Reflections on the future of public health and health promotion require thorough consideration of the role of digital technologies and the systems they influence. Just how the digital revolution will unfold is unknown, but it is clear that advancements and integrations of technologies will fundamentally influence our health and wellbeing in the future.
The public health response must be proactive, involving many stakeholders, and thoughtfully considered to ensure equitable and ethical applications and use.
Chapter 7: Governance for health and equity: a vision for our future
Coronavirus disease 2019 has caused many people and communities to take stock on Australia’s direction in relation to health, community, jobs, environmental sustainability, income and wealth.
A desire for change is in the air. This chapter imagines how changes in the way we govern our lives and what we value as a society could solve many of the issues Australia is facing — most pressingly, the climate crisis and growing economic and health inequities.
We present an imagined future for 2030 where governance structures are designed to ensure transparent and fair behaviour from those in power and to increase the involvement of citizens in these decisions, including a constitutional voice for Indigenous peoples.
We imagine that these changes were made by measuring social progress in new ways, ensuring taxation for public good, enshrining human rights (including to health) in legislation, and protecting and encouraging an independent media. Measures to overcome the climate crisis were adopted and democratic processes introduced in the provision of housing, education and community development.
1. Population viability analysis (PVA) is widely used to assess the extinction risk of threatened species and to evaluate different management strategies. However, conventional PVA neglects important ...biotic interactions and therefore can fail to identify important threatening processes. 2. We designed a new PVA approach that includes species interactions explicitly by networking species models within a single 'metamodel'. We demonstrate the utility of PVA metamodels by employing them to reinterpret the extinction of the carnivorous, marsupial thylacine Thylacinus cynocephalus in Tasmania. In particular, we test the claim that well-documented impacts of European settlement cannot account for this extinction and that an unknown disease must have been an additional and necessary cause. 3. We first constructed a classical, single-species PVA model for thylacines, which was then extended by incorporation within a dynamic predator—herbivore—vegetation metamodel that accounted for the influence of Europeans on the thylacine's prey base. Given obvious parameter uncertainties, we explored both modelling approaches with rigorous sensitivity analyses. 4. Single-species PVA models were unable to recreate the thylacine's extinction unless a high human harvest, small starting population size or low maximum population growth rate was assumed, even if disease effects were included from 1906 to 1909. In contrast, we readily recreated the thylacine's demise using disease-free multi-species metamodels that simulated declines in native prey populations (particularly due to competition with introduced sheep). 5. Dynamic, multi-species metamodels provide a simple, flexible framework for studying current species declines and historical extinctions caused by complex, interacting factors.
Two major genetic categories of multiple myeloma (MM) exist. Hyperdiploid MM (48 to 74 chromosomes, median 53 chromosomes) is associated with trisomies especially of chromosomes 3, 7, 9, 11, 15, and ...19, whereas the nonhyperdiploid (< 48 chromosomes or more than 74 chromosomes) MM is associated with primary translocations such as t(11;14), t(4;14), and t(14;16). Whether this dichotomy exists in monoclonal gammopathy of undetermined significance (MGUS) is uncertain due to limitations of current methods in the study of ploidy. This is especially true in MGUS where the number of clonal plasma cells is small. In this study, we derived a fluorescent in situ hybridization (FISH)-based trisomy index from pooled cytogenetic data (karyotype analysis) from 2 large cohorts of patients with MM with abnormal karyotype, and then validated it in 2 independent cohorts of patients who had known ploidy status either by karyotyping or DNA content measurement using flow cytometry. Using the criteria of 2 or more trisomies from a 3-chromosome combination, hyperdiploid myeloma can be detected with high specificity. Applying this index on 28 patients with smoldering multiple myeloma (SMM) or MGUS (11 SMM, 17 MGUS) who had normal karyotype, 11 cases of hyperdiploid SMM/MGUS were detected. This percentage (40%) is remarkably similar to the percentage of hyperdiploid MM reported in the literature, suggesting that hyperdiploid MM may originate early during disease evolution. (Blood. 2005;106: 2156-2161)
Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due ...to the lack of high-quality evidence.
An individual level, stepped-wedge randomised trial has been designed to allow observer-blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) pre-operative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates.
An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks).
ISRCTN registry, ISRCTN11747152 . Registered on 30 September 2015. The trial was prospectively registered (first patient enrolled on 21 March 2016).
PDF
