Access to a dementia-friendly garden on behavioural and psychological symptoms of dementia, falls and psychotropic medication use in residents of an aged care home in Melbourne, Australia.

OBJECTIVE: Residents of care homes need access to outdoors. This may improve behavioural and psychological symptoms of dementia (BPSD) and quality of life in residents living with dementia. Barriers including lack of accessibility and increased falls risk, which may be mitigated using dementia-friendly design. This prospective cohort study followed a group of residents in the first 6 months after the opening of a new dementia-friendly garden. METHOD: Nineteen residents participated. The Neuropsychiatric Inventory - Nursing Home Version (NPI-NH) and psychotropic medication use were collected at baseline, 3 and 6 months. The facility's falls rate during this time and feedback from staff and residents' next of kin were collected. RESULTS: Total NPI-NH scores decreased, though not significantly. Feedback was positive overall; the falls rate decreased. Usage of the garden was low. CONCLUSIONS: Despite its limitations, this pilot study adds to the literature about the importance of access to the outdoors for people who are experiencing BPSD. Staff remain concerned about falls risk despite the dementia-friendly design, and many residents do not access outdoors frequently. Further education may help to remove barriers to encouraging residents to access the outdoors.

Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-ß Activity.

Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-ß (TGF-ß) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-ß. In the current study, we examine the contribution of TGF-ß activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-ß expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFßRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-ß activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-ß.

Reliability and validity of the Edinburgh Postnatal Depression Scale (EPDS) for detecting perinatal common mental disorders (PCMDs) among women in low-and lower-middle-income countries: a systematic review.

BACKGROUND: The Edinburgh Postnatal Depression Scale (EPDS), originally developed in Britain, is one of the most widely used screening instruments for assessing symptoms of the Perinatal Common Mental Disorders (PCMDs) of depression and anxiety. However, its potential to detect PCMDs in culturally diverse low- and lower-middle income countries (LALMICs) is unclear. This systematic review aimed to appraise formally validated local language versions of the EPDS from these resource-constrained settings. METHODS: Following the PRISMA protocol, we searched MEDLINE-OVID, CINAHL-Plus and PUBMED to identify studies reporting translation, cultural adaptation and formal validation of the EPDS to detect PCMDs among women in LALMICs. The quality of the studies meeting inclusion criteria was assessed using standard criteria and a new process-based criteria; which was developed specifically for this study. RESULTS: We identified 1281 records among which 16 met inclusion criteria; three further papers were identified by hand-searching reference lists. The publications reported findings from 12 LALMICs in 14 native languages. Most of these local language versions of the EPDS (LLV-EPDS) had lower precision for identifying true cases of PCMDs among women in the general perinatal population compared to the original English version. Only one study met all criteria for culturally sensitive translation, the others had not established the comprehensibility of the local version amongst representative groups of women in pre-testing. Many studies tested the LLV-EPDS only amongst convenience samples recruited at single health facilities. Diagnostic interviews for confirmation of mental disorders could have been influenced by the mental health professionals' lack of blinding to the initial screening results. Additionally, even when diagnostic-interviews were carried out in the local language, questions might not have been understood as most studies followed standard diagnostic protocol which had not been culturally adapted. CONCLUSIONS: Most of the LLV-EPDS from non-English speaking low- and middle-income-countries did not meet all criteria for formal validation of a screening instrument. Psychometric properties of LLV-EPDS could be enhanced by adopting the new process-based criteria for translation, adaptation and validation.

The lung inflammation and skeletal muscle wasting induced by subchronic cigarette smoke exposure are not altered by a high-fat diet in mice.

Obesity and cigarette smoking independently constitute major preventable causes of morbidity and mortality and obesity is known to worsen lung inflammation in asthma. Paradoxically, higher body mass index (BMI) is associated with reduced mortality in smoking induced COPD whereas low BMI increases mortality risk. To date, no study has investigated the effect of a dietary-induced obesity and cigarette smoke exposure on the lung inflammation and loss of skeletal muscle mass in mice. Male BALB/c mice were exposed to 4 cigarettes/day, 6 days/week for 7 weeks, or sham handled. Mice consumed either standard laboratory chow (3.5 kcal/g, 12% fat) or a high fat diet (HFD, 4.3 kcal/g, 32% fat). Mice exposed to cigarette smoke for 7 weeks had significantly more inflammatory cells in the BALF (P<0.05) and the mRNA expression of pro-inflammatory cytokines and chemokines was significantly increased (P<0.05); HFD had no effect on these parameters. Sham- and smoke-exposed mice consuming the HFD were significantly heavier than chow fed animals (12 and 13%, respectively; P<0.05). Conversely, chow and HFD fed mice exposed to cigarette smoke weighed 16 and 15% less, respectively, compared to sham animals (P<0.05). The skeletal muscles (soleus, tibialis anterior and gastrocnemius) of cigarette smoke-exposed mice weighed significantly less than sham-exposed mice (P<0.05) and the HFD had no protective effect. For the first time we report that cigarette smoke exposure significantly decreased insulin-like growth factor-1 (IGF-1) mRNA expression in the gastrocnemius and tibialis anterior and IGF-1 protein in the gastrocnemius (P<0.05). We have also shown that cigarette smoke exposure reduced circulating IGF-1 levels. IL-6 mRNA expression was significantly elevated in all three skeletal muscles of chow fed smoke-exposed mice (P<0.05). In conclusion, these findings suggest that a down-regulation in local IGF-1 may be responsible for the loss of skeletal muscle mass following cigarette smoke exposure in mice.

Regenerating endometrium from stem/progenitor cells: is it abnormal in endometriosis, Asherman's syndrome and infertility?

PURPOSE OF REVIEW: Stem/progenitor cells are present in human and rodent endometrium and have a key role in endometrial regeneration in normal cycling and after parturition. We review emerging evidence of multiple types of endometrial stem/progenitor cells, and that abnormalities in their location and function may contribute to endometriosis. RECENT FINDINGS: Candidate human endometrial stem/progenitors have been identified as clonogenic, Side Population and possessing tissue reconstitution activity. Markers have been identified for human endometrial mesenchymal stem cells, showing their perivascular location in functionalis and basalis endometrium. Human embryonic stem cells can be induced to develop endometrial epithelium, recapitulating endometrial development. In rodent studies, endometrial stem/progenitor cells were identified as label-retaining cells and their role in endometrial repair and regeneration revealed, perhaps via mesenchymal to epithelial transition. Studies of Wnt signalling in the regulation of endometrial stem/progenitor cells may yield insights into their function in endometrial regeneration. Stem/progenitor cells can be isolated from endometrial biopsy or menstrual blood and may be used autologously to regenerate endometrium in Asherman's syndrome. SUMMARY: There is much to be learnt about endometrial stem/progenitor cell biology and their role in endometriosis. Endometrial stem/progenitor cells hold great promise for new treatments for infertility associated disorders, including thin dysfunctional endometrium and Asherman's syndrome.

Glutathione peroxidase-1 reduces influenza A virus-induced lung inflammation.

Oxidative stress caused by excessive reactive oxygen species production is implicated in influenza A virus-induced lung disease. Glutathione peroxidase (GPx)-1 is an antioxidant enzyme that may protect lungs from such damage. The objective of this study was to determine if GPx-1 protects the lung against influenza A virus-induced lung inflammation in vivo. Male wild-type (WT) or GPx-1(-/-) mice were inoculated with HKx31 (H3N2, 1 × 10(4) plaque-forming units), and bronchoalveolar lavage fluid (BALF)/lung compartments were analyzed on Days 3 and 7 after infection for inflammatory marker expression, histology, and viral titer. WT mice infected with HKx31 had significantly more BALF total cells, macrophages, neutrophils, and lymphocytes at Days 3 and 7 compared with naive WT animals (n = 5-8; P < 0.05). However, infected GPx-1(-/-) mice had significantly more BALF inflammation, which included more total cells, macrophages, and neutrophils, compared with WT mice, and this was abolished by treatment with the GPx mimetic ebselen. BALF inflammation persisted in GPx-1(-/-) mice on Day 10 after infection, and GPx-1(-/-) mice had significantly more influenza-specific CD8(+) T cells in spleen compared with WT mice (n = 3-4; P < 0.05). Infected GPx-1(-/-) mice had greater peribronchial and parenchymal inflammation than WT mice, and viral titer was significantly reduced in GPx-1(-/-) mice at Day 3 (n = 5; P < 0.05). Gene expression analysis revealed that infected GPx-1(-/-) mice had higher whole lung TNF-α, macrophage inflammatory protein (MIP)-1α, MIP-2, KC, and matrix metalloproteinase (MMP)-12 mRNA compared with infected WT mice. GPx-1(-/-) mice had more MIP-2 protein in BALF at Day 3 and more active MMP-9 protease in BALF at Days 3 and 7 than WT mice. These data indicate that GPx-1 reduces influenza A virus-induced lung inflammation.

Glucocorticoid-resistant asthma and novel anti-inflammatory drugs.

Synthetic glucocorticoids are among the most commonly used prescription medicines. Nevertheless, their clinical efficacy is accompanied by dose- and indication-limiting acute and chronic adverse effects. Intrinsic or acquired resistance to glucocorticoid actions may also limit clinical efficacy. In chronic inflammatory conditions there has been a considerable focus on understanding mechanism(s) of resistance in cells with a primary immune and/or inflammatory function. However, it has become increasingly accepted that a substantial part of the efficacy of glucocorticoid treatments derives from actions on 'structural' cell types (smooth muscle, fibroblasts, epithelia). In this article we review the mechanism of action of glucocorticoids on structural cells and contrast knowledge of resistance mechanisms between structural and inflammatory cell types, using asthma as an exemplar chronic inflammatory condition associated with glucocorticoid resistance.

Sexual dimorphism in lung function responses to acute influenza A infection.

BACKGROUND: Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females. OBJECTIVES: To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza. METHODS: Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post-inoculation. RESULTS: Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness. CONCLUSIONS: We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation.

Oseltamivir treatment of mice before or after mild influenza infection reduced cellular and cytokine inflammation in the lung.

BACKGROUND: Lung inflammation is a critical determinant of influenza infection outcomes but is seldom evaluated in animal studies of oseltamivir (OS), which have focused on viral titre and survival. OBJECTIVES: To study the effects of pre- and post-infection dosing with OS on viral replication and inflammation in a mouse model of non-lethal influenza infection. METHODS: BALB/c mice were infected with a laboratory-adapted H3N1 strain of influenza. In pre-dosing studies, OS was gavaged twice daily (1 and 10 mg/kg/day) from 4 hours prior to infection and continuing for 5 days (d) post-infection (p.i). In the second post-infection dosing study, dosing at 10 mg/kg/day began at 24-48 hours p.i. Mice were dissected at d3, d5 and d7 p.i. (pre-dosing study) and d5 p.i. (post-dosing study). Lung viral titres were determined by plaque assay. Bronchoalveolar lavage fluid (BALF) was collected and used for the quantitation of inflammatory cells and mediators. RESULTS: Pre-infection dosing of OS reduced total cells, neutrophils and macrophages in BALF. With pre- or post-infection dosing, the pro-inflammatory mediators TNF-α, IL-1ß, IL-6 and granulocyte-macrophage colony-stimulating factor, the neutrophil chemokines keratinocyte-derived chemokine and MIP-1α and the macrophage chemokine MCP-1 were reduced in BALF. Pre-dosing with 1 mg/kg OS did not reduce viral titres, while 10 mg/kg slightly reduced viral titres at d3 and d5 p.i. CONCLUSIONS: Oseltamivir reduced the inflammatory response to influenza when given pre- or post-infection. This anti-inflammatory effect may contribute to the clinical benefit of OS.

Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice.

BACKGROUND: Cigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection. METHODS: BALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection. RESULTS: Inflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice. CONCLUSION: Smoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.

Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection.

Rhinovirus infection is the most common cause of acute exacerbations of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease, where it provokes steroid refractory and abnormally intense neutrophilic inflammation that can be life threatening. Epidermal growth factor receptor (EGFR) expression correlates with disease severity and neutrophil infiltration in these conditions. However, the role of EGFR signaling in rhinovirus infection is unknown. We measured the key determinants of neutrophilic inflammation interleukin (IL)-8 and ICAM-1 in rhinovirus (RV16 serotype)-infected bronchial epithelial cells, BEAS-2B. RV16 infection stimulated IL-8 and ICAM-1 expression, which was further elevated (2-fold) by transient up-regulation of EGFR levels. Detection of viral RNA by quantitative real time PCR confirmed that enhanced expression was not associated with increased viral replication. EGFR ligands (epiregulin, amphiregulin, and heparin-binding epidermal growth factor) were induced by RV16 infection, and inhibition of metalloproteases responsible for ligand shedding partially suppressed this response. The EGFR inhibitor AG1478, completely blocked IL-8 and ICAM-1 expression to basal levels, as did the specific Erk1/2 inhibitor U0126. The p38 mitogen-activated protein kinase inhibitor SB203580 blocked IL-8 secretion but not ICAM-1 expression, whereas the PI3K inhibitor wortmannin was ineffective in both responses. Kinase inactive K721R EGFR, which is selectively deficient in STAT signaling, reversed RV16 responses associated with EGFR overexpression. In conclusion, RV16 infection rapidly promotes induction of EGFR ligands and utilizes EGFR signaling to increase IL-8 and ICAM-1 levels. These results suggest that targeting EGFR may provide a selective therapy that dampens neutrophil-driven inflammation without compromising essential antiviral pathways mediated by pathogen recognition receptors such as TLR3.

Lack of long-term effects of respiratory syncytial virus infection on airway function in mice.

Epidemiological data suggests lower respiratory infections (LRI) with respiratory syncytial virus (RSV) are capable of causing long-term abnormalities in airway function. To directly test the effects of RSV LRI, we infected adult and weanling BALB/c mice with RSV (A2) or vehicle. Respiratory system impedance was used to assess baseline airway function and responses to iv methacholine (MCh) at 4, 8, 24 and 34 weeks post infection. In vitro airway responses were measured 24 weeks post infection using electrical field stimulation and MCh. Mice infected as adults showed no alterations in airway function. Mice infected as weanlings had increased MCh responses 24 weeks post infection. However, the increased response was not present 34 weeks post infection nor accompanied by alterations in in vitro responses or airway morphometry. This study did not detect long-lasting changes in airway function following RSV infection in mice. These data do not provide support for alterations in airway structure or function being responsible for the observed relationship between RSV infection in infants and asthma in later life.

Therapeutic prospects to treat skeletal muscle wasting in COPD (chronic obstructive lung disease).

Chronic obstructive pulmonary disease (COPD) is an incurable group of lung diseases characterised by progressive airflow limitation and loss of lung function, which lead to profound disability. It is mostly caused by cigarette smoke. Although COPD is one of the most prevalent diseases worldwide and its incidence is increasing, current therapies do little to improve the condition. Much current research focuses on strategies to halt the accelerated rate of decline in lung function that occurs in the disease. However, as most symptoms occur when the lungs are already extensively and irreversibly damaged, it is uncertain whether an agent able to slow or halt decline in lung function would actually provide relief to COPD patients. As lung function worsens, systemic comorbidities contribute markedly to disability. Loss of lean body mass (skeletal muscle) has recently been identified as a major determinant of disability in COPD and an independent predictor of mortality. In contrast to lung structure damage, skeletal muscle retains regenerative capacity in COPD. In this review, we discuss mechanisms of wasting in COPD, focusing on therapeutic strategies that might improve the health and productive life expectancy of COPD patients by improving skeletal muscle mass and function. Single or combination approaches exploiting the suppression of procatabolic inflammatory mediators, inhibition of ubiquitin ligases, repletion of anabolic hormones and growth factors, inhibition of myoblast apoptosis, remediation of systemic oxidative stress and promotion of repair, and regeneration via stimulation of satellite cell differentiation hold considerable therapeutic promise.

What is the contribution of respiratory viruses and lung proteases to airway remodelling in asthma and chronic obstructive pulmonary disease?

It is well known that the lungs of asthmatics show airway wall remodelling and that asthma exacerbations are linked to respiratory infections. There is some evidence that respiratory infections in early childhood may increase the risk of developing asthma later in life. Chronic obstructive pulmonary disease (COPD), by definition, involves structural changes to the airways. However, very little is known about what role virus infections play in the development of this remodelling. This review considers the role of matrix metalloproteases and neutrophil elastase in remodelling, and whether the induction of proteases and other mediators during respiratory virus infections may contribute to the development of airway remodelling.

Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice.

BACKGROUND: To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice. METHODS: BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 x 10(5) pfu of RSV A2 or vehicle (intranasal, 30 microl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001-30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6-96 microg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5-20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data. RESULTS: Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) x 10(4) cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC200 Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC200 Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE2 at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d. CONCLUSION: Infection with 1 x 10(5) pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice.