Triarylphosphine-Coordinated Bipyridyl Ru(II) Complexes Induce Mitochondrial Dysfunction.

While cancer cells rely heavily upon glycolysis to meet their energetic needs, reducing the importance of mitochondrial oxidative respiration processes, more recent studies have shown that their mitochondria still play an active role in the bioenergetics of metastases. This feature, in combination with the regulatory role of mitochondria in cell death, has made this organelle an attractive anticancer target. Here, we report the synthesis and biological characterization of triarylphosphine-containing bipyridyl ruthenium (Ru(II)) compounds and found distinct differences as a function of the substituents on the bipyridine and phosphine ligands. 4,4'-Dimethylbipyridyl-substituted compound 3 exhibited especially high depolarizing capabilities, and this depolarization was selective for the mitochondrial membrane and occurred within minutes of treatment in cancer cells. The Ru(II) complex 3 exhibited an 8-fold increase in depolarized mitochondrial membranes, as determined by flow cytometry, which compares favorably to the 2-fold increase observed by carbonyl cyanide chlorophenylhydrazone (CCCP), a proton ionophore that shuttles protons across membranes, depositing them into the mitochondrial matrix. Fluorination of the triphenylphosphine ligand provided a scaffold that maintained potency against a range of cancer cells but avoided inducing toxicity in zebrafish embryos at higher concentrations, displaying the potential of these Ru(II) compounds for anticancer applications. This study provides essential information regarding the role of ancillary ligands for the anticancer activity of Ru(II) coordination compounds that induce mitochondrial dysfunction.

The relationship between wealth and loneliness among older people across Europe: Is social participation protective?

OBJECTIVE: 1. Examine the relationship between household wealth, social participation and loneliness among older people across Europe. 2. Investigate whether relationships vary by type of social participation (charity/volunteer work, sports/social clubs, educational/training course, and political/community organisations) and gender. 3. Examine whether social participation moderates the association between wealth and loneliness. METHODS: Data (N=29,795) were taken from the fifth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE), which was collected during 2013 from 14 European countries. Loneliness was measured using the short version of the Revised-University of California, Los Angeles (R-UCLA) Loneliness Scale. We used multilevel logistic models stratified by gender to examine the relationships between variables, with individuals nested within countries. RESULTS: The risk of loneliness was highest in the least wealthy groups and lowest in the wealthiest groups. Frequent social participation was associated with a lower risk of loneliness and moderated the association between household wealth and loneliness, particularly among men. Compared to the wealthiest men who often took part in formal social activities, the least wealthy men who did not participate had greater risk of loneliness (OR=1.91, 95% CI: 1.44 to 2.51). This increased risk was not observed among the least wealthy men who reported frequent participation in formal social activities (OR=1.12, 95% CI: 0.76 to 1.67). CONCLUSION: Participation in external social activities may help to reduce loneliness among older adults and potentially acts as a buffer against the adverse effects of socioeconomic disadvantage.

Are migration patterns and mortality related among European regions?

Geographical inequalities in mortality across Europe may be influenced by migration between regions. The relationship between age- and sex-standardised death rates, 2008-2010, and population change resulting from migration 2000-2010, was analysed in 250 'Nomenclature of Statistical Territorial Units' (NUTS) level 2 regions in 26 European countries. Across Europe death rates were significantly higher in regions experiencing population loss. This association continued after adjustment for 2005 household income among all regions and Western regions but not among Eastern areas. This analysis suggests migration could contribute to Europe's persistent inequalities in mortality, and highlights the problems of Eastern regions with the highest death rates, lowest incomes and declining populations.

Social protection spending and inequalities in depressive symptoms across Europe.

PURPOSE: Common mental disorders are an increasing global public health concern. The least advantaged in society experience a greater burden of mental illness, but inequalities in mental health vary by social, political, and economic contexts. This study investigates whether spending on different types of social protection alters the extent of social inequality in depressive symptoms. METHODS: Data were obtained from the 2006 and 2012 cross-sectional waves of the European Social Survey, which included 48,397 individuals from 18 European countries. Depressive symptoms were measured using the Centre for Epidemiologic Studies-Depression Scale (CES-D 8). Statistical interactions between country-level social protection spending and individuals' education level, employment and family status were explored using multilevel regression models. RESULTS: Higher spending on active labour market programmes was related to narrower inequality in depressive symptoms by education level. Compared to men with high education, the marginal effect of having low education was 1.67 (95 % CI, 1.46-1.87) among men in countries with lower spending and 0.85 (95 % CI, 0.66-1.03) in higher spending countries. Single parents exhibited fewer depressive symptoms, as spending on family policies increased. Little evidence was found for an overall association between spending on unemployment benefits and employment-related inequalities in depressive symptoms, but in 2012, unemployment spending appeared beneficial to mental health among the unemployed. CONCLUSIONS: Greater investment in social protection may act to reduce inequalities in depressive symptoms. Reductions in spending levels or increased conditionality may adversely affect the mental health of disadvantaged social groups.

Synthesis and photobiological evaluation of Ru(II) complexes with expanded chelate polypyridyl ligands.

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH2, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions.

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin.

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,2':6',2''-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(ii)-based monofunctional agents. Notably, the extension of the terpyridine at the 4' position with an aromatic ring resulted in a molecule that was cytotoxic in several cancer cell lines with sub-micromolar IC50 values, induced ribosome biogenesis stress, and exhibited minimal zebrafish embryo toxicity. This study demonstrates the successful design of a Ru(ii) agent that mimics many of the biological effects and phenotypes seen with phenanthriplatin, despite numerous differences in both the ligands and metal center structure.

Biofilm accumulation on additive manufactured Ti-6Al-4V alloy surfaces.

PURPOSE: This study investigated whether additive manufactured (AM) surfaces inhibit accumulation of bacterial biofilm on the surfaces of Ti-6Al-4V alloy dental implants. Bacterial biofilms are thought to cause peri-implant disease, which develops in mucosa surrounding titanium (Ti) and Ti alloy dental implants and can lead to bone loss and implant failure. METHODS: Accumulation of a Streptococcus mutans (ATCC 25175) biofilm on Ti-6Al-4V alloy was compared in relation to fabrication method, ie, AM using electron beam melting (EBM) or laser beam melting (LBM). Conventional lost-wax casting was used as positive control, and Teflon was used as negative control. Biofilm accumulation on the alloys and negative control (each n = 10) was conducted at 37°C under anaerobic conditions. After 4 h, the number of metabolically active S. mutans bacteria adhering to the alloy was determined with a bioluminescence assay. RESULTS: The quantitative roughness values of the specimens, before exposure to bacteria, ranked EBM > LBM > cast > Teflon. CONCLUSION: The amount of biofilm accumulation on the investigated AM metals and cast metal controls did not significantly differ.

The essential work of fracture of thermoplastic orthodontic retainer materials.

OBJECTIVE: To investigate whether oral cleansing agents affect the essential work of fracture (EWF) and plastic work of fracture (PWF) for two types of orthodontic thermoplastic retainer materials. MATERIALS AND METHODS: Polyethylene-terephthalate-glycol (PETG; Tru-Tain Splint) and polypropylene/ethylene-propylene rubber (PP-EPR) blend (Essix-C+) sheets were compared. For each material, six sets of 25 sheets were thermoformed into double-edge-notched-tension specimens; subsets of five specimens were formed with internotch distances (L) equal to 6, 8, 10, 12, or 14 mm, respectively. Sets were stored (160 hours, 25 degrees C) in air (DRY), distilled water (DW), Original Listerine (LIS), mint Crest ProHealth (CPH), 3% hydrogen peroxide (HP), or Polident solution (POL). Specimens were fractured in tension at 2.54 mm/min. Areas under load-elongation curves were measured to determine total work of fracture (W(f)). Linear regressions (W(f) vs L [n = 25]) yielded intercepts (EWF) and slopes (PWF). Ninety-five percent confidence intervals were used to evaluate differences in EWF and PWF estimates. RESULTS: PP-EPR blends showed higher EWFs after storage in HP vs storage in DW. PP-EPR blend showed higher EWFs after storage in CPH vs PETG. After HP storage, PP-EPR exhibited lower PWFs than with any other storage conditions. PP-EPR exhibited higher PWFs than PETG after storage in DRY, DW, and LIS. CONCLUSIONS: Compared with DW, none of the cleansers decreased the energy to initiate fracture. With one exception, no cleanser decreased the energy to continue plastic fracture extension. In PP-EPR blend, increased resistance to fracture initiation was observed with CPH and HP, yet, surprisingly, HP decreased resistance to plastic fracture growth.

Evidence-based selection of environmental factors and datasets for measuring multiple environmental deprivation in epidemiological research.

This Environment and Human Health project aims to develop a health-based summary measure of multiple physical environmental deprivation for the UK, akin to the measures of multiple socioeconomic deprivation that are widely used in epidemiology. Here we describe the first stage of the project, in which we aimed to identify health-relevant dimensions of physical environmental deprivation and acquire suitable environmental datasets to represent population exposure to these dimensions at the small-area level. We present the results of this process: an evidence-based list of environmental dimensions with population health relevance for the UK, and the spatial datasets we obtained and processed to represent these dimensions. This stage laid the foundations for the rest of the project, which will be reported elsewhere.

Removal time of fiber posts versus titanium posts.

PURPOSE: To evaluate the time needed to remove a glass reinforced fiber post versus a titanium post. METHODS: 40 extracted anterior teeth were mounted in acrylic blocks then treated endodontically. They were randomly assigned to three groups. The teeth were sectioned horizontally, with the coronal portion removed. The fiber posts were cemented with resin cement and the titanium posts were cemented with glass ionomer or resin cement. The fiber posts were removed by coring them out internally. The titanium posts were removed by creating a trough around the post then vibrating with ultrasonic energy. The teeth were examined visually and radiographically to ensure complete removal of the post and cement. Removal time included the time to make radiographs necessary to ensure complete removal. RESULTS: Post-cement combination significantly affected the median rank of the removal time (Kruskal-Wallis test; H = 12.709; P = 0.002). The mean rank removal time of titanium posts cemented with resin cement were significantly higher than the mean rank of the other two post-cement combinations (Dunn's multiple comparison test; P < 0.05). There was no significant difference between the other two combinations.

Tobacco outlet density and tobacco knowledge, beliefs, purchasing behaviours and price among adolescents in Scotland.

Despite long-term falls in global adult smoking prevalence and over 50 years of tobacco control policies, adolescent smoking persists. Research suggests greater densities of tobacco retail outlets in residential neighbourhoods are associated with higher adolescent smoking rates. Policies to reduce retail outlets have therefore been identified by public health researchers as a potential 'new frontier' in tobacco control. Better understanding of the pathways linking density of tobacco retailers and smoking behaviour could support these policies. In this study we use path analysis to assess how outlet density in the home environment is related to adolescent tobacco knowledge, beliefs, retail purchases and price in Scotland. We assessed 22,049 13 and 15 year old respondents to the nationally representative cross-sectional 2010 Scottish School Adolescent Lifestyle and Substance Use Survey. Outlet density was based on Scottish Tobacco Retailers Register, 2012, data. A spatially-weighted Kernel Density Estimation measure of outlet density within 400 m of respondents' home postcode was grouped into tertiles. The analysis considered whether outlet density was associated with the number of cigarette brands adolescents could name, positive beliefs about smoking, whether smokers purchased cigarettes from shops themselves or through adult proxies and perceived cost of cigarettes. Models were stratified by adolescent smoking status. The path analyses indicated that outlet density was not associated with most outcomes, but small, significant direct effects on knowledge of cigarette brands among those who had never smoked were observed. With each increase in outlet density tertile the mean number of brands adolescents could name rose by 0.07 (mean = 1.60; SD = 1.18; range = 4). This suggests greater outlet densities may have affected adolescents' knowledge of cigarette brands but did not encourage positive attitudes to smoking, purchases from shops or lower cigarette prices. Exposure to tobacco outlets may influence adolescents' awareness of tobacco products, a potential pathway to smoking behaviour.

Green space and cognitive ageing: A retrospective life course analysis in the Lothian Birth Cohort 1936.

International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a "life-grid" questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups. Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics.

Posterior amalgam restorations--usage, regulation, and longevity.

The use of dental amalgam has declined, but in most of the world, amalgam is the most widely used and widely taught direct restorative material for load-bearing posterior restorations. There are few national regulations on the use of amalgam; however, there are several nations where few amalgam restorations are placed. Long-term studies have shown that under optimum conditions, posterior restorations of amalgam and resin composite last longer than reported previously and that amalgam restorations outlast composite restorations. In general practice settings, posterior amalgam and composite restorations both have lower longevities.

Non-carious cervical lesions imaged by focus variation microscopy.

OBJECTIVE: The aim of this study is to characterize the morphological and histological features of NCCLs in a group of extracted teeth using a focus variation optical microscopic technique that is capable of detecting minute variation in surface topography. METHODS: Twenty three extracted teeth containing NCCLs were collected. Histological features of the surface and longitudinal cross sections were examined using a focus variation microscope (FVM). RESULTS: The sample included 8 teeth with wedge-shaped lesions; the remaining 15 contained saucer-shaped lesions. Wedge-shaped lesions showed obliterated dentinal tubules, parallel furrows and micro-fractures in the surface; longitudinal cross sections revealed subsurface micro-fractures extending toward the pulp chamber. The surfaces of typical saucer-shaped lesions were smooth and relatively featureless. CONCLUSIONS: FVM imaging shows microstructures that are consistent with simultaneous erosion and toothbrush abrasion. Saucer shaped lesions have a smooth featureless surface as well as craters and dimples that could be attributed to uneven acid attack. In wedge-shaped lesions, the presence of scratches and furrows could be attributed to mechanical forces such as tooth brush abrasion. The furrows and in-surface micro-factures of wedge shaped lesions suggest a possible role of tensile stresses but require further investigation. CLINICAL SIGNIFICANCE: NCCLs present in two morphologies, either saucer-shaped or wedge-shaped. Erosion and toothbrush abrasion are important in both types of lesions. Tensile stresses due to occlusal loading may be important in some wedge-shaped lesions. Knowing the etiology of cervical lesions is the key for their prevention.

Dental amalgam restorations: daily mercury dose and biocompatibility.

Over the past 150 years, silver-tin-copper amalgam has been the most frequently used dental restorative material. Amalgam may be the single most frequently used implant material. In the early 1980s, researchers discovered that amalgam restorations release mercury vapor during chewing. This review describes the research that has led to an estimate of the daily dose of mercury that will be absorbed by a subject with a large number of amalgam restorations. Along the way, the history and chemistry of dental amalgam are outlined. The routes of absorption of liquid mercury, ionic mercury, organic mercury, and mercury vapor are also briefly described. The daily dose is found to be 14% of the threshold above which observable adverse neurological symptoms are expected. The review concludes with a summary of the research on the adverse effects of dental amalgam. As expected from the low daily dose, few adverse neurological symptoms have been reported. There is also little evidence of an association of amalgam restorations with neurodegenerative diseases, altered renal function, adverse pregnancy outcomes, or autoimmune diseases. There is a lack of data on neurobiological and neurodevelopmental effects on children who may be exposed to mercury from maternal amalgam restorations during gestation. Additional data on the role of amalgam, if any, in Alzheimers disease and multiple sclerosis are needed.

Difficult Life Events, Selective Migration and Spatial Inequalities in Mental Health in the UK.

OBJECTIVE: Research has indicated that people moving towards neighbourhoods with disadvantaged socio-economic status have poor health, in particular mental health, but the reasons for this are unclear. This study aims to assess why people moving towards more socio-economically deprived areas have poor mental health. It focuses upon the role of difficult life events that may both trigger moves and damage mental health. This study investigates how mental health and socio-spatial patterns of mobility vary between people moving following difficult life events and for other reasons. METHODS: Longitudinal analysis of British Household Panel Survey data describing adults' moves between annual survey waves, pooled over ten years, 1996-2006 (N=122,892 observations). Respondents were defined as 'difficult life event movers' if they had experienced relationship breakdown, housing eviction/repossession, or job loss between waves. Respondents were categorised as moving to more or less deprived quintiles using their Census Area Statistic residential ward Carstairs score. Mental health was indicated by self-reported mental health problems. Binary logistic regression models of weighted data were adjusted for age, sex, education and social class. RESULTS: The migration rate over one year was 8.5%; 14.1% of movers had experienced a difficult life event during this time period. Adjusted regression model odds of mental health problems among difficult life event movers were 1.67 (95% CI 1.35-2.07) relative to other movers. Odds of difficult life events movers, compared to other movers, moving to a less deprived area, relative to an area with a similar level of deprivation, were 0.70 (95% CI 0.58-0.84). Odds of mental health problems among difficult life event movers relocating to more deprived areas were highly elevated at 2.40 (95% CI 1.63-3.53), relative to stayers. CONCLUSION: Difficult life events may influence health selective patterns of migration and socio-spatial trajectories, reducing moves to less deprived neighbourhoods among people with mental illness.

Neighborhood Environments and Socioeconomic Inequalities in Mental Well-Being.

INTRODUCTION: It has been suggested that socioeconomic inequalities in health might be reduced among populations with good access to green space. However, the potential for other neighborhood characteristics to reduce socioeconomic health inequalities, or to confound the effects of green space, has not been well explored. Therefore, this study investigates which, if any, neighborhood characteristics are associated with narrower socioeconomic inequalities in mental well-being in a large, international sample of urban residents. METHODS: The 2012 European Quality of Life Survey provided data on 21,294 urban residents from 34 European nations. Associations between mental well-being (captured by the WHO-5 scale) and level of financial strain were assessed for interaction with five different neighborhood characteristics, including reported access to recreational/green areas, financial services, transport, and cultural facilities. Multilevel regression models allowed for clustering of individuals within region and country in this cross-sectional, observational study. Data were analyzed in 2014. RESULTS: Socioeconomic inequality in mental well-being was 40% (8.1 WHO-5 points) narrower among respondents reporting good access to green/recreational areas, compared with those with poorer access. None of the other neighborhood characteristics or services were associated with narrower inequality. CONCLUSIONS: If societies cannot, or will not, narrow socioeconomic inequality, research should explore the so-called equigenic environments-those that can disrupt the usual conversion of socioeconomic inequality to health inequality. This large, international, observational study suggests that access to recreational/green areas may offer such a disruption.

Surface coating and leakage of dentin-bonded resin composite restorations.

OBJECTIVES: To compare the marginal leakage of dentin-bonded resin composite restorations in tooth sections coated with nail varnish and similarly restored sections coated with cyanoacrylate cement. METHODS: MO and DO cavities were prepared with the gingival floor below the CEJ in 11 non-carious extracted human molars. Each cavity was restored with a dentin adhesive and resin composite. Sectioning yielded four specimens per tooth (N=44). One specimen from each restoration was coated with varnish. The other specimen was coated with cyanoacrylate cement. The coatings were applied to all surfaces except that a 1mm window on either side of the interproximal gingival margin was left uncoated. Specimens were thermocycled and stained with silver nitrate. Silver penetration into the gingival margin of each section was measured with a measuring microscope. The predominant leakage path for each coating type was determined by scanning electron microscopy. RESULTS: There was no significant difference between the leakage of the varnish-coated and cyanoacrylate-coated specimens. No marginal gaps were observed either by optical or by electron microscopy. However, the both optical and electron microscopy revealed leakage in nearly all specimens. This leakage was confined to either the dentin/hybrid layer interface or the adhesive resin/hybrid layer interface. CONCLUSIONS: The results suggest that these coating materials are not confounding factors in laboratory investigations of marginal leakage along dentin-bonded interfaces of resin composite restorations. Although marginal gaps were undetectable even at high magnification, leakage was observed along the gingival margin of almost all of these Class II resin composite restorations.

Mortality inequalities by environment type in New Zealand.

In previous work a multivariate measure of health-related physical environment - the Multiple Environmental Deprivation Classification (MEDClass) - was created to investigate relationships between exposure to differing types of physical environment and health for the UK. Associations between MEDClass and all cause mortality, mortality from certain specific causes, and self-reported morbidity, independent of the level of socio-economic deprivation, were found. In this short report we determine whether the MEDClass approach has potential for international replication and whether the relationships with health prevails. We use New Zealand as a case study. Six environmental clusters were identified and similar associations between environmental classification and health outcomes were observed. Whilst this report shows that the framework used to create MEDClass can be transferred to an international context, we are reminded of the need to engage locally with place based research upon which an evidence base of cumulative impacts of the environment can be built.

Environmental justice and health: a study of multiple environmental deprivation and geographical inequalities in health in New Zealand.

There is an increasing interest in the unequal socio-spatial distribution of environmental 'goods' and 'bads' and the associated implications for geographical inequalities in health. Until recently, research in this area has focused on solitary environmental characteristics and has been hindered by the absence of geographically-specific measures that recognise the multifactorial nature of the physical environment. However, recent work in the United Kingdom has developed an area-level multivariate index of health-related physical environmental deprivation that captures both pathogenic and salutogenic environmental characteristics. Applications of this index have demonstrated that, at the national level, multiple environmental deprivation increased as the degree of income deprivation rose. Further, after adjusting for key confounders, there was a significant association between multiple environmental deprivation and the health outcomes of local residents. In the current study we tested the methods developed in the UK to create the New Zealand Multiple Environmental Deprivation Index (NZ-MEDIx) for small areas across the country (n = 1860). We considered whether socially disadvantaged places in New Zealand had higher levels of multiple environmental deprivation, and if environmental disadvantage exerted an influence on health after adjustment for key confounders such as socioeconomic status. We found that although neighbourhoods with higher levels of multiple environmental deprivation tended to have greater social disadvantage, this association was not linear. Further, multiple environmental deprivation tended to exert a modest effect on health that was independent of the age, sex and socioeconomic structure of the population. These findings demonstrate that it is possible to develop an index of multiple environmental deprivation in an alternative national context which has utility in epidemiological investigations.