Supporting older people’s transport and mobility needs to promote healthy ageing

Unprecedented population ageing and rapid urbanisation combine to pose a unique challenge for policymakers– the challenge of ensuring that the greater numbers of older people are not left behind as cities dramatically evolve. As the ability of older people to move about the city and access activities in society are essential to their well-being, there is a large and untapped scope for contributions from the population health sciences to address this challenge. To date, the limited consideration of health and healthy ageing in transport policy has contributed to the high and unsustainable car dependence in Western Europe, North America, and Australia, and the resultant lack of non-driving transport options for older people. This scenario constrains older people’s mobility and well-being, as older people have diverse mobility needs and expectations which can only be met through a range of transportation options. This thesis aims to develop a coherent approach to support older people’s mobility through non-driving transport options by examining population needs and barriers and contextual influences and interventions. To address this aim, four empirical studies were conducted, each responding to one of the four objectives that logically flow from the aim. Driven by a transdisciplinary approach, various methods were used, drawing on both primary and secondary data sources and qualitative and quantitative data types. The thesis identified the specific variables intrinsic to the population to be served that must be considered in efforts to support older people’s mobility, provided evidence of the multifactorial and interactive nature of the influences on older people’s mobility, and illustrated the need for interventions to be holistic and systemic. These four studies contribute guiding principles that constitute the approach that the thesis has set out to develop. As the evidence base from which these guiding principles are developed is grounded in the population health sciences and an appreciation for transport and mobility as a social determinant of health, this thesis has also built a case for a health promotion and, specifically, a healthy public policy approach to efforts to support older people’s mobility. Finally, the thesis has delineated the stakeholders and sectors that need to be in involved in a coherent approach to support older people’s mobility and articulated how they affect each other and why their joint and coordinated contributions are necessary

Protocol for studying cough frequency in people with pulmonary tuberculosis.

INTRODUCTION: Cough is a key symptom of tuberculosis (TB) as well as the main cause of transmission. However, a recent literature review found that cough frequency (number of coughs per hour) in patients with TB has only been studied once, in 1969. The main aim of this study is to describe cough frequency patterns before and after the start of TB treatment and to determine baseline factors that affect cough frequency in these patients. Secondarily, we will evaluate the correlation between cough frequency and TB microbiological resolution. METHODS: This study will select participants with culture confirmed TB from 2 tertiary hospitals in Lima, Peru. We estimated that a sample size of 107 patients was sufficient to detect clinically significant changes in cough frequency. Participants will initially be evaluated through questionnaires, radiology, microscopic observation drug susceptibility broth TB-culture, auramine smear microscopy and cough recordings. This cohort will be followed for the initial 60 days of anti-TB treatment, and throughout the study several microbiological samples as well as 24 h recordings will be collected. We will describe the variability of cough episodes and determine its association with baseline laboratory parameters of pulmonary TB. In addition, we will analyse the reduction of cough frequency in predicting TB cure, adjusted for potential confounders. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the ethics committees at each participating hospital in Lima, Peru, Asociación Benéfica PRISMA in Lima, Peru, the Universidad Peruana Cayetano Heredia in Lima, Peru and Johns Hopkins University in Baltimore, USA. We aim to publish and disseminate our findings in peer-reviewed journals. We also expect to create and maintain an online repository for TB cough sounds as well as the statistical analysis employed

A role for tumor necrosis factor-alpha in remodeling the splenic marginal zone during Leishmania donovani infection.

The development of secondary lymphoid organs is a highly regulated process, mediated by tumor necrosis factor (TNF) family cytokines. In contrast, the mechanisms controlling changes in lymphoid architecture that occur during infectious disease are poorly understood. Here we demonstrate that during infection with Leishmania donovani, the marginal zone of mice undergoes extensive remodeling, similar in extent to developmental abnormalities in mice lacking some TNF family cytokines. This process is selective, comprising a dramatic and rapid loss of marginal zone macrophages (MZMs). As a functional consequence, lymphocyte traffic into the white pulp is impaired during chronic leishmaniasis. Significantly, MZMs were preserved in L. donovani-infected B6.TNF-alpha(-/-) mice or mice that received anti-TNF-alpha antibodies, whereas studies in CD8(+) T-cell-deficient mice and in mice lacking functional CD95L, excluded a direct role for either cytotoxic T lymphocyte activity or CD95-mediated apoptosis in this process. Loss of MZMs was independent of parasite burden, yet could be partially prevented by chemotherapy, which in turn reduced endogenous TNF-alpha levels. This is the first report of an infectious agent causing selective and long-lasting changes to the marginal zone via TNF-alpha-mediated mechanisms, and illustrates that those cytokines involved in establishing lymphoid architecture during development, may also play a role in infection-induced lymphoid tissue remodeling

The Ankyrin Repeat Domain of the TRPA Protein Painless Is Important for Thermal Nociception but Not Mechanical Nociception

The Drosophila TRPA channel Painless is required for the function of polymodal nociceptors which detect noxious heat and noxious mechanical stimuli. These functions of Painless are reminiscent of mammalian TRPA channels that have also been implicated in thermal and mechanical nociception. A popular hypothesis to explain the mechanosensory functions of certain TRP channels proposes that a string of ankyrin repeats at the amino termini of these channels acts as an intracellular spring that senses force. Here, we describe the identification of two previously unknown Painless protein isoforms which have fewer ankyrin repeats than the canonical Painless protein. We show that one of these Painless isoforms, that essentially lacks ankyrin repeats, is sufficient to rescue mechanical nociception phenotypes of painless mutant animals but does not rescue thermal nociception phenotypes. In contrast, canonical Painless, which contains Ankyrin repeats, is sufficient to largely rescue thermal nociception but is not capable of rescuing mechanical nociception. Thus, we propose that in the case of Painless, ankryin repeats are important for thermal nociception but not for mechanical nociception

Resistance to HER2-targeted therapies in HER2-positive breast cancer

Breast cancer accounts for 522,000 deaths worldwide each year and is the most common cancer in women. It is classified according to the cell of origin and its expression of several receptors: oestrogen and progesterone receptors, and human epidermal growth factor receptor 2 (HER2). Historically, HER2-positive breast cancers had a worse survival prognosis than oestrogen or progesterone receptor-positive cancers, but the development of HER2-targeted therapies led to significant survival improvements. Despite this, patients often present with de novo resistance, or will develop acquired resistance to targeted therapies. Several resistance mechanisms have been identified but attempts to target them have failed. Thus, it is of paramount importance to identify the mechanisms used, to prevent development of resistance or resensitise tumours to HER2-targeted therapies. Objectives of this study were: to understand the link between epithelial to mesenchymal transition (EMT) and loss of HER2, seen in a model of acquired resistance to the HER2-targeted therapy, sapatinib, and to characterise and validate tumours from a sapatinib-treated spontaneous mouse model of HER2-positive breast cancer. The EMT-linked transcription factor ZEB1 was associated with acquired resistance to sapatinib in tumours that had undergone EMT and concurrently lost HER2. Generation of drug resistant cell lines failed to recapitulate the in vivo phenotype. Transient overexpression of ZEB1 in vitro did not induce clear EMT or loss of HER2, despite a trend towards lower HER2 expression. However, we found that treatment of cells with ERBB2 shRNA, the gene encoding HER2, increased levels of ZEB1 and enhanced migration, but did not induce overt EMT. This may be the result of differing PTEN status between in vivo and in vitro models. Treatment of a spontaneous mouse model of HER2-positive breast cancer with sapatinib revealed that progressing tumours had an increase in proteins associated with cellular iron homeostasis. Further investigation revealed increased heme oxygenase-1 (HO-1), iron exporter ferroportin and altered iron storage. To ascertain if modulation of dietary iron intake could affect the development of resistance to sapatinib, mice were given a control or iron-deficient diet and treated with vehicle or sapatinib. This showed that in sapatinib-treated mice fed an iron-deficient diet, HO-1 was not increased as in tumours from mice fed a iron-low control diet. We looked at the possibility of HER2-targeting therapies inducing ferroptosis, an iron-dependent form of cell death. Sapatinib-treated tumours from mice on a iron-low control diet had increased cyclooxygenase 2 (COX2), a marker of ferroptosis, which was not seen in sapatinib-treated tumours from mice on an iron-deficient diet. Additionally, in vitro drug treatments with HER2-targeting agents showed that SKBR3 cell death could be rescued by iron chelation. HO-1 overexpression in SKBR3 cells revealed increased autophagic flux and resistance to HER2-targeted therapies. Inhibition of autophagy reversed resistance, rendering them susceptible to sapatinib- and lapatinib-induced cell death. Further, increased autophagic flux was seen in all progressive tumours on sapatinib. The increased resistance to sapatinib in mice fed an iron-deficient diet was also associated with increased autophagic flux, although this was HO-1-independent. Taken together, the results presented here provide a novel mechanism of cell death induced by HER2-targeting agents in vitro and in vivo. We have shown that increased HO-1 and reducing dietary iron can affect the development of resistance to sapatinib, which is reliant on autophagy induction. Further, inhibiting autophagy can resensitise cells to sapatinib and lapatinib treatment

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Differences in Longer-Term Smoking Abstinence After Treatment by Specialist or Nonspecialist Advisors: Secondary Analysis of Data From a Relapse Prevention Trial.

INTRODUCTION: Smokers receiving support in specialist centers tend to have a higher short-term quit rate, compared with those receiving support in other settings from professionals for whom smoking cessation is only a part of their work. We investigated the difference in longer-term abstinence after short-term smoking cessation treatment from specialist and nonspecialist smoking cessation services. METHODS: We conducted a secondary analysis of data from a randomized controlled trial of self-help booklets for the prevention of smoking relapse. The trial included 1088 short-term quitters from specialist stop smoking clinics and 316 from nonspecialist cessation services (such as general practice, pharmacies, and health trainer services). The difference in prolonged smoking abstinence from months 4 to 12 between specialist and nonspecialist services was compared. Multivariable logistic regression analyses were conducted to investigate the association between continuous smoking abstinence and the type of smoking cessation services, adjusted for possible confounding factors (including demographic, socioeconomic, and smoking history variables). RESULTS: The proportion of continuous abstinence from 4 to 12 months was higher in short-term quitters from specialist services compared with those from nonspecialist services (39% vs. 32%; P = .023). After adjusting for a range of participant characteristics and smoking variables, the specialist service was significantly associated with a higher rate of longer-term smoking abstinence (odds ratio: 1.48, 95% CI = 1.09% to 2.00%; P = .011). CONCLUSIONS: People who receive support to stop smoking from a specialist appear to be at lower risk of relapse than those receiving support from a nonspecialist advisor

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally