Serum Amyloid A induces toll-like receptor 2-dependent inflammatory cytokine expression and atrophy in C2C12 skeletal muscle myotubes

Background Skeletal muscle wasting is an important comorbidity of Chronic Obstructive Pulmonary Disease (COPD) and is strongly correlated with morbidity and mortality. Patients who experience frequent acute exacerbations of COPD (AECOPD) have more severe muscle wasting and reduced recovery of muscle mass and function after each exacerbation. Serum levels of the pro-inflammatory acute phase protein Serum Amyloid A (SAA) can rise more than 1000-fold in AECOPD and are predictively correlated with exacerbation severity. The direct effects of SAA on skeletal muscle are poorly understood. Here we have examined SAA effects on pro-inflammatory cachectic cytokine expression (IL-6 and TNFα) and atrophy in C2C12 myotubes. Results SAA increased IL-6 (31-fold) and TNFα (6.5-fold) mRNA levels compared to control untreated cells after 3h of SAA treatment, and increased secreted IL-6 protein at 24h. OxPAPC, a dual TLR2 and TLR4 inhibitor, reduced the response to SAA by approximately 84% compared to SAA alone, and the TLR2 neutralising antibody T2.5 abolished SAA-induced expression of IL-6, indicating that SAA signalling in C2C12 myotubes is primarily via TLR2. SAA also reduced myotube width by 10-13% and induced a 2.5-fold increase in the expression of the muscle atrophy gene Atrogin-1, suggesting direct effects of SAA on muscle wasting. Blocking of TLR2 inhibited the SAA-induced decrease in myotube width and Atrogin-1 gene expression, indicating that SAA induces atrophy through TLR2. Conclusions These data demonstrate that SAA stimulates a robust pro-inflammatory response in skeletal muscle myotubes via the TLR2-dependent release of IL-6 and TNFα. Furthermore, the observed atrophy effects indicate that SAA could also be directly contributing to the wasting and poor recovery of muscle mass. Therapeutic strategies targeting this SAA-TLR2 axis may therefore ameliorate muscle wasting in AECOPD and a range of other inflammatory conditions associated with loss of m

Preparation and some reactions of ω-chloro derivatives from aleuritic acid and related compounds

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Community based service providers' perspectives on frequent and/or avoidable admission of older people with chronic disease in rural NSW: a qualitative study

Background: Frequent and potentially avoidable hospital admission amongst older patients with ambulatory care sensitive (ACS) chronic conditions is a major topic for research internationally, driven by the imperative to understand and therefore reduce hospital admissions. Research to date has mostly focused on analysis of routine data using ACS as a proxy for 'potentially avoidable'. There has been less research on the antecedents of frequent and/or avoidable admission from the perspectives of patients or those offering community based care and support for these patients. This study aimed to explore community based service providers' perspectives on the factors contributing to admission among older patients with chronic disease and a history of frequent and potentially avoidable admission. Methods. 15 semi-structured interviews with community based providers of health care and other services, and an emergency department physician were conducted. Summary documents were produced and thematic analysis undertaken. Results: A range of complex barriers which limit or inhibit access to services were reported. We classified these as external and internal barriers. Important external barriers included: complexity of provision of services, patients' limited awareness of different services and their inexperience in accessing services, patients needing a higher level or longer length of service than they currently have access to, or an actual lack of available services, patient poverty, rurality, and transport. Important internal barriers included: fear (of change for example), a 'stoic' attitude to life, and for some, the difficulty of accepting their changed health status. Conclusions: The factors underlying frequent and/or potentially avoidable admission are numerous and complex. Identifying strategies to improve services or interventions for this group requires understanding patient, carer and service providers' perspectives. Improving accessibility of services is also complex, and includes consideration of patients' social, emotional and psychological ability and willingness to use services as well as those services being available and easily accessed

Volume, scope, and consideration of ethical issues in Indigenous cognitive impairment and dementia research: A systematic scoping review of studies published between 2000-2021

Introduction High quality research involving Indigenous people with cognitive impairment and dementia is critical for informing evidence-based policy and practice. We examined the volume, scope and ethical considerations of research related to dementia with Indigenous populations globally from January 2000–December 2021. Methods Studies were included if they were published in English from 2000 to 2021 and provided original data that focused on cognitive impairment or dementia in any Indigenous population. Results The search yielded 13,009 papers of which, 76 met inclusion criteria. The overall number of papers increased over time. Studies were mostly conducted in Australia with Aboriginal and Torres Strait Islander people (n = 30; 39%). Twenty-six papers directly involved Indigenous participants with cognitive impairment or dementia. Of these studies, ethics approval was commonly required from two or more committees (n = 23, 88.5%). Ethical and legal governance frameworks were rarely discussed. Discussion There is a clear need for further robust studies examining cognitive impairment and dementia with Indigenous populations. Future research should consider the ethical aspects of involving Indigenous participants with cognitive impairment in research. </jats:sec

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

The Prevalence of Sexually Transmitted Infections in Papua New Guinea: A Systematic Review and Meta-Analysis

Patellofemoral osteoarthritis (PF OA) is more prevalent than previously thought and contributes to patient's suffering from knee OA. Synthesis of prevalence data can provide estimates of the burden of PF OA

Effects of Global Warming on Ancient Mammalian Communities and Their Environments

Current global warming affects the composition and dynamics of mammalian communities and can increase extinction risk; however, long-term effects of warming on mammals are less understood. Dietary reconstructions inferred from stable isotopes of fossil herbivorous mammalian tooth enamel document environmental and climatic changes in ancient ecosystems, including C(3)/C(4) transitions and relative seasonality.Here, we use stable carbon and oxygen isotopes preserved in fossil teeth to document the magnitude of mammalian dietary shifts and ancient floral change during geologically documented glacial and interglacial periods during the Pliocene (approximately 1.9 million years ago) and Pleistocene (approximately 1.3 million years ago) in Florida. Stable isotope data demonstrate increased aridity, increased C(4) grass consumption, inter-faunal dietary partitioning, increased isotopic niche breadth of mixed feeders, niche partitioning of phylogenetically similar taxa, and differences in relative seasonality with warming.Our data show that global warming resulted in dramatic vegetation and dietary changes even at lower latitudes (approximately 28 degrees N). Our results also question the use of models that predict the long term decline and extinction of species based on the assumption that niches are conserved over time. These findings have immediate relevance to clarifying possible biotic responses to current global warming in modern ecosystems

Winking at Facebook: capturing digitally-mediated classroom learning

In this article I present an innovative combination of methods, used in a study of the use of Facebook as an educational resource by five dyslexic students at a Sixth Form College in north-west England. Through a project in which teacher-researcher and student-participants co-constructed a Facebook group page about the students’ scaffolded research into dyslexia, the study examined the educational affordances of a digitally-mediated social network. Combining multiple data-collection methods including participant-observation, semi-structured interviews, video recordings, dynamic screen capture (Cox, 2007), protocol analysis (Ericsson & Simon, 1993) helped to capture in detail multiple perspectives on the learning that happened in the classroom over the five weeks of the research project's lifetime. Aggregating the resulting data in turn enabled meticulous, comprehensive analysis and rigorous theorising. The article presents and analyses excerpts from the data which help to illustrate the insights gained into one participant's learning trajectory. I argue that the combination of methods employed could be used with any range of research participants in other studies exploring learning through Facebook and other Web 2.0 spaces. The article concludes by suggesting further refinements to the methods used

Paradoxes in carcinogenesis: New opportunities for research directions

<p>Abstract</p> <p>Background</p> <p>The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored.</p> <p>Discussion</p> <p>Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1) the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2) the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3) spontaneous regression, (4) higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5) lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6) cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7) the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8) the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena.</p> <p>Summary</p> <p>The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril.</p